Continuous subcutaneous administration of mesna to prevent ifosfamide-induced hemorrhagic cystitis.

Hemorrhagic cystitis is a major potential toxicity of ifosfamide that can be prevented by administering mesna along with the cytotoxic agent. Mesna is generally administered by the intravenous route, although experience with oral delivery of the drug has increased. The continuous subcutaneous administration of mesna has the advantage of not requiring intravenous access. In addition, subcutaneous delivery of the neutralizing agent will not be associated with the risk of inadequate urinary mesna concentrations, such as in a patient taking oral mesna who experiences severe ifosfamide-induced emesis and is unable to absorb the drug. Limited clinical experience with continuous subcutaneous mesna administration suggests it is a safe, practical, and economic method of drug delivery that permits ifosfamide to be administered successfully in the outpatient setting.

mesna

ifosfamide

hemorrhagic cystitis

hemorrhagic

cystitis

Hemorrhagic cystitis

Hemorrhagic

cystitis

toxicity

ifosfamide

mesna

Mesna

mesna

mesna

mesna

ifosfamide

emesis

mesna

ifosfamide


Modification of drug action by hyperammonemia.

Pretreatment with ammonium acetate (NH4Ac) (6 mmol/kg s.c.) approximately doubled the time morphine-treated mice remained on a hot surface and similarly increased muscular incoordination by diazepam, but NH4Ac treatment alone had no effect. Thus, hyperammonemia is capable of altering drug action and must be considered along with impaired drug metabolism in enhanced drug responses associated with liver disease. Experiments in vitro showed that acetylcholine-induced catecholamine release from bovine adrenal medulla is depressed as much as 50% by 0.3 mM NH4Ac and KCl-induced contractions of guinea-pig ileum were inhibited 20% by 5 mM NH4Ac. Addition of excess calcium reversed the depression in both tissues, but calcium-independent catecholamine release by acetaldehyde was not blocked by NH4Ac. These results suggested that ammonia blocks calcium channels. Parallels in the actions of NH4Ac and the calcium channel blocker verapamil support this concept. Both verapamil (10 mg/kg i.p.) and NH4Ac pretreatment enhanced morphine analgesia- and diazepam-induced muscular incoordination and antagonized amphetamine-induced motor activity, and neither verapamil nor NH4Ac affected the convulsant action of metrazol. The data suggest that hyperammonemia exerts a calcium channel blocking action which enhances the effects of central nervous system depressants and certain opioid analgesics.

hyperammonemia

ammonium acetate

morphine

incoordination

diazepam

hyperammonemia

liver disease

acetylcholine

catecholamine

KCl

calcium

depression

calcium

catecholamine

acetaldehyde

ammonia

calcium

calcium

verapamil

verapamil

morphine

analgesia

diazepam

incoordination

amphetamine

verapamil

metrazol

hyperammonemia

calcium


Risk of nephropathy after consumption of nonionic contrast media by children undergoing cardiac angiography: a prospective study.

Despite increasing reports on nonionic contrast media-induced nephropathy (CIN) in hospitalized adult patients during cardiac procedures, the studies in pediatrics are limited, with even less focus on possible predisposing factors and preventive measures for patients undergoing cardiac angiography. This prospective study determined the incidence of CIN for two nonionic contrast media (CM), iopromide and iohexol, among 80 patients younger than 18 years and compared the rates for this complication in relation to the type and dosage of CM and the presence of cyanosis. The 80 patients in the study consecutively received either iopromide (group A, n = 40) or iohexol (group B, n = 40). Serum sodium (Na), potassium (K), and creatinine (Cr) were measured 24 h before angiography as baseline values, then measured again at 12-, 24-, and 48-h intervals after CM use. Urine samples for Na and Cr also were checked at the same intervals. Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal damage (RIFLE criteria) were used to define CIN and its incidence in the study population. Accordingly, among the 15 CIN patients (18.75%), 7.5% of the patients in group A had increased risk and 3.75% had renal injury, whereas 5% of group B had increased risk and 2.5% had renal injury. Whereas 33.3% of the patients with CIN were among those who received the proper dosage of CM, the percentage increased to 66.6% among those who received larger doses, with a significant difference in the incidence of CIN related to the different dosages of CM (p = 0.014). Among the 15 patients with CIN, 6 had cyanotic congenital heart diseases, but the incidence did not differ significantly from that for the noncyanotic patients (p = 0.243). Although clinically silent, CIN is not rare in pediatrics. The incidence depends on dosage but not on the type of consumed nonionic CM, nor on the presence of cyanosis, and although CIN usually is reversible, more concern is needed for the prevention of such a complication in children.

nephropathy

contrast media

contrast media

nephropathy

CIN

CIN

contrast media

CM

iopromide

iohexol

CM

cyanosis

iopromide

iohexol

sodium

potassium

K

creatinine

Cr

CM

Cr

renal failure

Injury to the kidney

Failure of kidney function

Loss of kidney function

renal damage

CIN

CIN

renal injury

renal injury

CIN

CM

CIN

CM

CIN

congenital heart diseases

CIN

CM

cyanosis

CIN


A case of ventricular tachycardia related to caffeine pretreatment.

Suboptimal seizure duration is commonly encountered in electroconvulsive therapy practice, especially in older patients with higher seizure thresholds. Intravenous caffeine is commonly used to improve seizure duration and quality in such patients and is generally well tolerated aside from occasional reports of relatively benign ventricular ectopy. We describe a patient with no previous history of cardiac disease or arrhythmia who developed sustained bigeminy and 2 brief runs of ventricular tachycardia after caffeine administration. Although intravenous caffeine is generally well tolerated, the clinician should be aware of the potential for unpredictable and serious ventricular arrhythmias.

ventricular tachycardia

caffeine

seizure

seizure

caffeine

seizure

ventricular ectopy

cardiac disease

arrhythmia

ventricular tachycardia

caffeine

caffeine

ventricular arrhythmias


Optical coherence tomography can measure axonal loss in patients with ethambutol-induced optic neuropathy.

PURPOSE: To map and identify the pattern, in vivo, of axonal degeneration in ethambutol-induced optic neuropathy using optical coherence tomography (OCT). Ethambutol is an antimycobacterial agent often used to treat tuberculosis. A serious complication of ethambutol is an optic neuropathy that impairs visual acuity, contrast sensitivity, and color vision. However, early on, when the toxic optic neuropathy is mild and partly reversible, the funduscopic findings are often subtle and easy to miss. METHODS: Three subjects with a history of ethambutol (EMB)-induced optic neuropathy of short-, intermediate-, and long-term visual deficits were administered a full neuro-ophthalmologic examination including visual acuity, color vision, contrast sensitivity, and fundus examination. In addition, OCT (OCT 3000, Humphrey-Zeiss, Dublin, CA) was performed on both eyes of each subject using the retinal nerve fiber layer (RNFL) analysis protocol. OCT interpolates data from 100 points around the optic nerve to effectively map out the RNFL. RESULTS: The results were compared to the calculated average RNFL of normal eyes accumulated from four prior studies using OCT, n=661. In all subjects with history of EMB-induced optic neuropathy, there was a mean loss of 72% nerve fiber layer thickness in the temporal quadrant (patient A, with eventual recovery of visual acuity and fields, 58% loss; patient B, with intermediate visual deficits, 68% loss; patient C, with chronic visual deficits, 90% loss), with an average mean optic nerve thickness of 26+/-16 microm. There was a combined mean loss of 46% of fibers from the superior, inferior, and nasal quadrants in the (six) eyes of all three subjects (mean average thickness of 55+/-29 microm). In both sets (four) of eyes of the subjects with persistent visual deficits (patients B and C), there was an average loss of 79% of nerve fiber thickness in the temporal quadrant. CONCLUSIONS: The OCT results in these patients with EMB-induced optic neuropathy show considerable loss especially of the temporal fibers. This is consistent with prior histopathological studies that show predominant loss of parvo-cellular axons (or small-caliber axons) within the papillo-macular bundle in toxic or hereditary optic neuropathies. OCT can be a valuable tool in the quantitative analysis of optic neuropathies. Additionally, in terms of management of EMB-induced optic neuropathy, it is important to properly manage ethambutol dosing in patients with renal impairment and to achieve proper transition to a maintenance dose once an appropriate loading dose has been reached.

ethambutol

optic neuropathy

axonal degeneration

ethambutol

optic neuropathy

Ethambutol

tuberculosis

ethambutol

optic neuropathy

optic neuropathy

ethambutol

EMB

optic neuropathy

visual deficits

EMB

optic neuropathy

visual deficits

visual deficits

visual deficits

EMB

optic neuropathy

optic neuropathies

optic neuropathies

EMB

optic neuropathy

ethambutol

renal impairment


Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis.

There have been concerns that the risk of cardiovascular thrombotic events may be higher with cyclooxygenase (COX)-2-specific inhibitors than nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We evaluated cardiovascular event data for valdecoxib, a new COX-2-specific inhibitor in approximately 8000 patients with osteoarthritis and rheumatoid arthritis treated with this agent in randomized clinical trials. The incidence of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic) was determined by analyzing pooled valdecoxib (10-80 mg daily), nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg tid, or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis and rheumatoid arthritis trials that were 6-52 weeks in duration. The incidence rates of events were determined in all patients (n = 7934) and in users of low-dose (< or =325 mg daily) aspirin (n = 1051) and nonusers of aspirin (n = 6883). Crude and exposure-adjusted incidences of thrombotic events were similar for valdecoxib, NSAIDs, and placebo. The risk of serious thrombotic events was also similar for each valdecoxib dose. Thrombotic risk was consistently higher for users of aspirin users than nonusers of aspirin (placebo, 1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9% vs. 0.5%). The rates of events in users of aspirin were similar for all 3 treatment groups and across valdecoxib doses. Short- and intermediate-term treatment with therapeutic (10 or 20 mg daily) and supratherapeutic (40 or 80 mg daily) valdecoxib doses was not associated with an increased incidence of thrombotic events relative to nonselective NSAIDs or placebo in osteoarthritis and rheumatoid arthritis patients in controlled clinical trials.

valdecoxib

thrombotic

arthritis

thrombotic

valdecoxib

osteoarthritis

rheumatoid arthritis

thrombotic

thrombotic

valdecoxib

diclofenac

ibuprofen

naproxen

osteoarthritis

rheumatoid arthritis

aspirin

aspirin

thrombotic

valdecoxib

thrombotic

valdecoxib

Thrombotic

aspirin

aspirin

valdecoxib

aspirin

valdecoxib

valdecoxib

thrombotic

osteoarthritis

rheumatoid arthritis


A randomized, placebo-controlled, crossover study of ephedrine for SSRI-induced female sexual dysfunction.

The objective of this study was to determine whether ephedrine, an alpha- and beta-adrenergic agonist previously shown to enhance genital blood flow in women, has beneficial effects in reversing antidepressant-induced sexual dysfunction. Nineteen sexually dysfunctional women receiving either fluoxetine, sertraline, or paroxetine participated in an eight-week, double-blind, placebo-controlled, cross-over study of the effects of ephedrine (50 mg) on self-report measures of sexual desire, arousal, orgasm, and sexual satisfaction. Although there were significant improvements relative to baseline in sexual desire and orgasm intensity/pleasure on 50 mg ephedrine 1-hr prior to sexual activity, significant improvements in these measures, as well as in sexual arousal and orgasmic ability also were noted with placebo. These findings highlight the importance of conducting placebo-controlled trials for this condition.

ephedrine

sexual dysfunction

ephedrine

sexual dysfunction

sexually dysfunctional

fluoxetine

sertraline

paroxetine

ephedrine

ephedrine


Erectile dysfunction occurs following substantia nigra lesions in the rat.

Erectile function was assessed 6 weeks following uni- and bilateral injections of 6-hydroxydopamine in the substantia nigra nucleus of the brain. Behavioral apomorphine-induced penile erections were reduced (5/8) and increased (3/8) in uni- and bilateral lesioned animals. Intracavernous pressures, following electrical stimulation of the cavernous nerve, decreased in lesioned animals. Lesions of the substantia nigra were confirmed by histology. Concentration of dopamine and its metabolites were decreased in the striatum of substantia nigra lesioned rats. Lesions of the substantia nigra are therefore associated with erectile dysfunction in rats and may serve as a model to study erectile dysfunction in Parkinson's disease.

Erectile dysfunction

apomorphine

dopamine

erectile dysfunction

erectile dysfunction

Parkinson's disease


Potential therapeutic use of the selective dopamine D1 receptor agonist, A-86929: an acute study in parkinsonian levodopa-primed monkeys.

The clinical utility of dopamine (DA) D1 receptor agonists in the treatment of Parkinson's disease (PD) is still unclear. The therapeutic use of selective DA D1 receptor agonists such as SKF-82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine hydrobromide) and A-77636 ([1R, 3S] 3-[1'-admantyl]-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzo pyran hydrochloride) seems limited because of their duration of action, which is too short for SKF-82958 (< 1 hr) and too long for A-77636 (> 20 hr, leading to behavioral tolerance). We therefore conducted the present acute dose-response study in four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed cynomolgus monkeys primed to exhibit levodopa-induced dyskinesias to evaluate the locomotor and dyskinetic effects on challenge with four doses (from 0.03 to 1.0 mg/kg) of A-86929 ([-]-[5aR,11bS]-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-+ ++azacyclopent-1- ena[c]phenathrene-9-10-diol), a selective and full DA D1-like receptor agonist with an intermediate duration of action. Levodopa and the DA D2-like receptor agonist, LY-171555 ([4aR-trans]-4,4a,5,6,7,8,8a,9-o-dihydro-5n-propyl-2H-pyrazo lo-3-4-quinoline hydrochloride) were also used for comparison. Acute administration of A-86929 was as efficacious in alleviating MPTP-induced parkinsonism as levodopa and LY-171555, but was less likely to reproduce the levodopa-induced dyskinesias in these animals than with either LY-171555 or subsequent challenge of levodopa. Selective stimulation of the DA D1 receptor may provide better integration of neural inputs transmitted to the internal segment of the globus pallidus (referred to as the basal ganglia output) compared with levodopa and selective DA D2 receptor agonist. Potent DA D1 receptor agents with an intermediate duration of efficacy such as A-86929 (approximately 4 hr at higher doses tested) are potential therapeutic tools in PD and merit further attention.

dopamine

parkinsonian

levodopa

dopamine

DA

Parkinson's disease

PD

DA

MPTP

levodopa

dyskinesias

dyskinetic

DA

Levodopa

DA

MPTP

parkinsonism

levodopa

levodopa

dyskinesias

levodopa

DA

levodopa

DA

DA

PD


Deaths from local anesthetic-induced convulsions in mice.

Median convulsant (CD50) and median lethal (LD50) doses of three representative local anesthetics were determined in adult mice to evaluate the threat to life of local anesthetic-induced convulsions. The CD50 and LD50, respectively, were 57.7 and 58.7 mg/kg for bupivacaine, 111.0 and 133.1 mg/kg for lidocaine, and 243.4 and 266.5 mg/kg for chloroprocaine. When given intraperitoneally, bupivacaine thus was only about twice as toxic as lidocaine and four times as toxic as chloroprocaine. Convulsions always preceded death, except after precipitous cardiopulmonary arrest from extreme doses. A CD50 dose of local anesthetic (causing convulsions in 50% of mice) was fatal in 90% of bupivacaine-induced seizures, in 57% of the chloroprocaine group, and in 6% of the lidocaine group. The narrow gap between convulsant and lethal doses of local anesthetics indicates that untreated convulsions present much more of a threat to life than heretofore appreciated.

convulsions

convulsions

bupivacaine

lidocaine

chloroprocaine

bupivacaine

lidocaine

chloroprocaine

Convulsions

cardiopulmonary arrest

convulsions

bupivacaine

seizures

chloroprocaine

lidocaine

convulsions


Myoclonic, atonic, and absence seizures following institution of carbamazepine therapy in children.

Five children, aged 3 to 11 years, treated with carbamazepine for epilepsy, had an acute aberrant reaction characterized by the onset of myoclonic, atypical absence and/or atonic (minor motor) seizures within a few days. When the carbamazepine was discontinued, two of the children returned to their former state very quickly, two had the minor motor seizures resolve in 3 and 6 months, and one had the seizures persist. The child in whom the seizures persisted was later found to have ceroid lipofuscinosis. The other children are doing well on other anticonvulsants.

Myoclonic, atonic, and absence seizures

Myoclonic seizures

absence seizures

carbamazepine

carbamazepine

epilepsy

myoclonic seizures

atypical absence
seizures

carbamazepine

seizures

seizures

seizures

ceroid lipofuscinosis


Naloxone reversal of hypotension due to captopril overdose.

The hemodynamic effects of captopril and other angiotensin-converting enzyme inhibitors may be mediated by the endogenous opioid system. The opioid antagonist naloxone has been shown to block or reverse the hypotensive actions of captopril. We report a case of an intentional captopril overdose, manifested by marked hypotension, that resolved promptly with the administration of naloxone. To our knowledge, this is the first reported case of captopril-induced hypotension treated with naloxone. Our experience demonstrates a possible role of naloxone in the reversal of hypotension resulting from captopril.

Naloxone

hypotension

captopril

overdose

captopril

naloxone

hypotensive

captopril

captopril

overdose

hypotension

naloxone

captopril

hypotension

naloxone

naloxone

hypotension

captopril


Carbamazepine-induced cardiac dysfunction. Characterization of two distinct clinical syndromes.

A patient with sinus bradycardia and atrioventricular block, induced by carbamazepine, prompted an extensive literature review of all previously reported cases. From the analysis of these cases, two distinct forms of carbamazepine-associated cardiac dysfunction emerged. One patient group developed sinus tachycardias in the setting of a massive carbamazepine overdose. The second group consisted almost exclusively of elderly women who developed potentially life-threatening bradyarrhythmias or atrioventricular conduction delay, associated with either therapeutic or modestly elevated carbamazepine serum levels. Because carbamazepine is widely used in the treatment of many neurologic and psychiatric conditions, the recognition of the latter syndrome has important implications for the use of this drug in elderly patients.

Carbamazepine

cardiac dysfunction

bradycardia

atrioventricular block

carbamazepine

carbamazepine

cardiac dysfunction

sinus tachycardias

carbamazepine

overdose

bradyarrhythmias

atrioventricular conduction delay

carbamazepine

carbamazepine

psychiatric


Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy.

The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 microl) and AP7 (10 or 20 nmol/0.5 microl), or of the NMDA receptor agonist N-methyl-d-aspartate (NMDA, 20 or 30 nmol/0.5 microl). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity.

NMDA

haloperidol

catalepsy

amino acid

amino acid

catalepsy

dopamine

haloperidol

Haloperidol

catalepsy

glutamate

NMDA

NMDA

N-methyl-d-aspartate

NMDA

haloperidol

catalepsy

NMDA

glutamate

haloperidol

catalepsy


Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease.

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinson's disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.

glutamate

Parkinson's disease

glutamate

Parkinson's disease

PD

PD

PD

haloperidol

catalepsy

apomorphine

akinetic

PD

haloperidol

catalepsy

PD

dopamine


Nimodipine prevents memory impairment caused by nitroglycerin-induced hypotension in adult mice.

BACKGROUND: Hypotension and a resultant decrease in cerebral blood flow have been implicated in the development of cognitive dysfunction. We tested the hypothesis that nimodipine (NIMO) administered at the onset of nitroglycerin (NTG)-induced hypotension would preserve long-term associative memory. METHODS: The passive avoidance (PA) paradigm was used to assess memory retention. For PA training, latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock was automatically delivered. Latencies were recorded 48 h later for a testing trial. Ninety-six Swiss-Webster mice (30-35 g, 6-8 wk), were randomized into 6 groups 1) saline (control), 2) NTG immediately after learning, 3) NTG 3 h after learning, 4) NTG and NIMO, 5) vehicle, and 6) NIMO alone. The extent of hypotension and changes in brain tissue oxygenation (PbtO(2)) and in cerebral blood flow were studied in a separate group of animals. RESULTS: All groups exhibited similar training latencies (17.0 +/- 4.6 s). Mice subjected to hypotensive episodes showed a significant decrease in latency time (178 +/- 156 s) compared with those injected with saline, NTG + NIMO, or delayed NTG (580 +/- 81 s, 557 +/- 67 s, and 493 +/- 146 s, respectively). A Kruskal-Wallis 1-way analysis of variance indicated a significant difference among the 4 treatment groups (H = 15.34; P < 0.001). In a separate group of mice not subjected to behavioral studies, the same dose of NTG (n = 3) and NTG + NIMO (n = 3) caused mean arterial blood pressure to decrease from 85.9 +/- 3.8 mm Hg sem to 31.6 +/- 0.8 mm Hg sem and from 86.2 +/- 3.7 mm Hg sem to 32.6 +/- 0.2 mm Hg sem, respectively. Mean arterial blood pressure in mice treated with NIMO alone decreased from 88.1 +/- 3.8 mm Hg to 80.0 +/- 2.9 mm Hg. The intergroup difference was statistically significant (P < 0.05). PbtO(2) decreased from 51.7 +/- 4.5 mm Hg sem to 33.8 +/- 5.2 mm Hg sem in the NTG group and from 38.6 +/- 6.1 mm Hg sem to 25.4 +/- 2.0 mm Hg sem in the NTG + NIMO groups, respectively. There were no significant differences among groups. CONCLUSION: In a PA retention paradigm, the injection of NTG immediately after learning produced a significant impairment of long-term associative memory in mice, whereas delayed induced hypotension had no effect. NIMO attenuated the disruption in consolidation of long-term memory caused by NTG but did not improve latency in the absence of hypotension. The observed effect of NIMO may have been attributable to the preservation of calcium homeostasis during hypotension, because there were no differences in the PbtO(2) indices among groups.

Nimodipine

memory impairment

nitroglycerin

hypotension

Hypotension

cognitive dysfunction

nimodipine

NIMO

nitroglycerin

NTG

hypotension

NTG

NTG

NTG

NIMO

NIMO

hypotension

hypotensive

NTG

NIMO

NTG

NTG

NTG

NIMO

NIMO

NTG

NTG

NIMO

NTG

hypotension

NIMO

NTG

hypotension

NIMO

calcium

hypotension


Fatal haemopericardium and gastrointestinal haemorrhage due to possible interaction of cranberry juice with warfarin.

We report a case of fatal internal haemorrhage in an elderly man who consumed only cranberry juice for two weeks while maintaining his usual dosage of warfarin. We propose that naturally occurring compounds such as flavonoids, which are present in fruit juices, may increase the potency of warfarin by competing for the enzymes that normally inactivate warfarin. While traditionally regarded as foodstuffs, consumption of fruit juices should be considered when patients develop adverse drug reactions.

haemopericardium

gastrointestinal haemorrhage

warfarin

haemorrhage

warfarin

flavonoids

warfarin

warfarin


Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury.

The mechanism of isoproterenol-induced myocardial damage is unknown, but a mismatch of oxygen supply vs. demand following coronary hypotension and myocardial hyperactivity is the best explanation for the complex morphological alterations observed. Severe alterations in the structural integrity of the sarcolemma of cardiomyocytes have been demonstrated to be caused by isoproterenol. Taking into account that the sarcolemmal integrity is stabilized by the dystrophin-glycoprotein complex (DGC) that connects actin and laminin in contractile machinery and extracellular matrix and by integrins, this study tests the hypothesis that isoproterenol affects sarcolemmal stability through changes in the DGC and integrins. We found different sensitivity of the DGC and integrin to isoproterenol subcutaneous administration. Immunofluorescent staining revealed that dystrophin is the most sensitive among the structures connecting the actin in the cardiomyocyte cytoskeleton and the extracellular matrix. The sarcomeric actin dissolution occurred after the reduction or loss of dystrophin. Subsequently, after lysis of myofilaments, gamma-sarcoglycan, beta-dystroglycan, beta1-integrin, and laminin alpha-2 expressions were reduced followed by their breakdown, as epiphenomena of the myocytolytic process. In conclusion, administration of isoproterenol to rats results in primary loss of dystrophin, the most sensitive among the structural proteins that form the DGC that connects the extracellular matrix and the cytoskeleton in cardiomyocyte. These changes, related to ischaemic injury, explain the severe alterations in the structural integrity of the sarcolemma of cardiomyocytes and hence severe and irreversible injury induced by isoproterenol.

Isoproterenol

myocardial injury

isoproterenol

myocardial damage

oxygen

hypotension

myocardial hyperactivity

isoproterenol

isoproterenol

isoproterenol

isoproterenol

ischaemic injury

isoproterenol


High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity.

Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD(10) dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-alpha, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9+/-14.0 nmol/min/g heart in ND versus 400.2+/-11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-alpha2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating the JAK/STAT3 pathway.

fat

obese

doxorubicin

cardiotoxicity

doxorubicin

Adriamycin

cardiotoxicity

doxorubicin

cardiotoxicity

triglycerides

ATP

fat

obesity

doxorubicin

cardiotoxicity

doxorubicin

cardiotoxicity

cardiac dysfunction

obese

OB

renal or hepatic toxicity

renal toxicity

hepatic toxicity

Doxorubicin

doxorubicin

doxorubicinol

OB

OB

OB

AMP

ATP

ATP

ADP

doxorubicin

obese

doxorubicin

cardiotoxicity

ATP


Complete atrioventricular block secondary to lithium therapy.

Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction.

atrioventricular block

lithium

Sinus node dysfunction

lithium

atrioventricular (AV) block

syncopal attacks

lithium

lithium

syncopal attacks

Lithium


Neuroleptic malignant syndrome induced by ziprasidone on the second day of treatment.

Neuroleptic malignant syndrome (NMS) is the rarest and most serious of the neuroleptic-induced movement disorders. We describe a case of neuroleptic malignant syndrome (NMS) associated with the use of ziprasidone. Although conventional neuroleptics are more frequently associated with NMS, atypical antipsychotic drugs like ziprasidone may also be a cause. The patient is a 24-year-old male with a history of schizophrenia who developed signs and symptoms of NMS after 2 days of treatment with an 80-mg/day dose of orally administrated ziprasidone. This case is the earliest (second day of treatment) NMS due to ziprasidone reported in the literature.

Neuroleptic malignant syndrome

ziprasidone

Neuroleptic malignant syndrome

NMS

movement disorders

neuroleptic malignant syndrome

NMS

ziprasidone

NMS

ziprasidone

schizophrenia

NMS

ziprasidone

NMS

ziprasidone


Role of mangiferin on biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats.

The current study dealt with the protective role of mangiferin, a polyphenol from Mangifera indica Linn. (Anacardiaceae), on isoproterenol (ISPH)-induced myocardial infarction (MI) in rats through its antioxidative mechanism. Subcutaneous injection of ISPH (200 mg/kg body weight in 1 ml saline) to rats for 2 consecutive days caused myocardial damage in rat heart, which was determined by the increased activity of serum lactate dehydrogenase (LDH) and creatine phosphokinase isoenzymes (CK-MB), increased uric acid level and reduced plasma iron binding capacity. The protective role of mangiferin was analyzed by triphenyl tetrazolium chloride (TTC) test used for macroscopic enzyme mapping assay of the ischemic myocardium. The heart tissue antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase activities, non-enzymic antioxidants such as cerruloplasmin, Vitamin C, Vitamin E and glutathione levels were altered in MI rats. Upon pretreatment with mangiferin (100 mg/kg body weight suspended in 2 ml of dimethyl sulphoxide) given intraperitoneally for 28 days to MI rats protected the above-mentioned parameters to fall from the normal levels. Activities of heart tissue enzymic antioxidants and serum non-enzymic antioxidants levels rose significantly upon mangiferin administration as compared to ISPH-induced MI rats. From the present study it is concluded that mangiferin exerts a beneficial effect against ISPH-induced MI due to its antioxidant potential, which regulated the tissues defense system against cardiac damage.

mangiferin

isoproterenol

myocardial infarction

mangiferin

polyphenol

isoproterenol

ISPH

myocardial infarction

MI

ISPH

myocardial damage

lactate

creatine

uric acid

iron

mangiferin

triphenyl tetrazolium chloride

TTC

ischemic myocardium

superoxide

glutathione

glutathione

glutathione

Vitamin C

Vitamin E

glutathione

MI

mangiferin

dimethyl sulphoxide

MI

mangiferin

ISPH

MI

mangiferin

ISPH

MI

cardiac damage


Remifentanil pretreatment reduces myoclonus after etomidate.

STUDY OBJECTIVE: The aim of the study was to compare the effect of pretreatment with remifentanil 1 microg/kg and the effect of gender on the incidence of myoclonus after anesthesia induction with etomidate. DESIGN: This was a randomized, double-blind study. SETTING: The study was conducted at a university hospital. PATIENTS: Sixty patients were pretreated in a randomized double-blinded fashion with remifentanil 1 microg/kg or placebo. Two minutes after remifentanil or placebo injection, etomidate 0.3 mg/kg was given. MEASUREMENTS: Myoclonus was recorded with a scale of 0 to 3. The grade of sedation (none, mild, moderate, severe), nausea, pruritus, and apnea were recorded after injection of both drugs. MAIN RESULTS: The incidence of myoclonus was significantly lower in the remifentanil group (6.7%) than in the placebo group (70%) (P < 0.001). None of the patients experienced sedation, apnea, nausea, or pruritus after injection of both drugs. In the placebo group, male patients were associated with significantly increased incidence of myoclonus after etomidate administration. CONCLUSION: Pretreatment with remifentanil 1 microg/kg reduced myoclonus after etomidate induction without side effects such as sedation, apnea, nausea, or pruritus. Men experience increased incidence of myoclonus than women after etomidate administration.

Remifentanil

myoclonus

etomidate

remifentanil

myoclonus

etomidate

remifentanil

remifentanil

etomidate

Myoclonus

nausea

pruritus

apnea

myoclonus

remifentanil

apnea

nausea

pruritus

myoclonus

etomidate

remifentanil

myoclonus

etomidate

apnea

nausea

pruritus

myoclonus

etomidate


Daidzein activates choline acetyltransferase from MC-IXC cells and improves drug-induced amnesia.

The choline acetyltransferase (ChAT) activator, which enhances cholinergic transmission via an augmentation of the enzymatic production of acetylcholine (ACh), is an important factor in the treatment of Alzheimer's disease (AD). Methanolic extracts from Pueraria thunbergiana exhibited an activation effect (46%) on ChAT in vitro. Via the sequential isolation of Pueraria thunbergiana, the active component was ultimately identified as daidzein (4',7-dihydroxy-isoflavone). In order to investigate the effects of daidzein from Pueraria thunbergiana on scopolamine-induced impairments of learning and memory, we conducted a series of in vivo tests. Administration of daidzein (4.5 mg/kg body weight) to mice was shown significantly to reverse scopolamine-induced amnesia, according to the results of a Y-maze test. Injections of scopolamine into mice resulted in impaired performance on Y-maze tests (a 37% decreases in alternation behavior). By way of contrast, mice treated with daidzein prior to the scopolamine injections were noticeably protected from this performance impairment (an approximately 12%-21% decrease in alternation behavior). These results indicate that daidzein might play a role in acetylcholine biosynthesis as a ChAT activator, and that it also ameliorates scopolamine-induced amnesia.

Daidzein

choline

amnesia

choline

acetylcholine

ACh

Alzheimer's disease

AD

daidzein

daidzein

scopolamine

impairments of learning and memory

impairments of learning

impairments of
memory

daidzein

scopolamine

amnesia

scopolamine

daidzein

scopolamine

daidzein

acetylcholine

scopolamine

amnesia


Possible azithromycin-associated hiccups.

OBJECTIVE: To report a case of persistent hiccups associated by azithromycin therapy. CASE SUMMARY: A 76-year-old man presented with persistent hiccups after beginning azithromycin for the treatment of pharyngitis. Hiccups were persistent and exhausting. Discontinuation of azithromycin and therapy with baclofen finally resolved hiccups. No organic cause of hiccups was identified despite extensive investigation. DISCUSSION: Pharmacotherapeutic agents have been uncommonly associated with hiccups. Corticosteroids (dexamethasone and methylprednisolone), benzodiazepines (midazolam) and general anaesthesia have been the specific agents mentioned most frequently in the literature as being associated with the development of hiccups. Few cases of drug-induced hiccups have been reported related to macrolide antimicrobials. Using the Naranjo adverse effect reaction probability scale this event could be classified as possible (score 5 points), mostly because of the close temporal sequence, previous reports on this reaction with other macrolides and the absence of any alternative explanation for hiccups. Our hypothesis is that a vagal mechanism mediated by azithromycin could be the pathogenesis of hiccups in our patient. CONCLUSIONS: Diagnosis of drug-induced hiccups is difficult and often achieved only by a process of elimination. However, macrolide antimicrobials have been reported to be associated with hiccups and vagal mechanism could explain the development of this side-effect.

azithromycin

hiccups

hiccups

azithromycin

hiccups

azithromycin

pharyngitis

Hiccups

azithromycin

baclofen

hiccups

hiccups

hiccups

dexamethasone

methylprednisolone

benzodiazepines

midazolam

hiccups

hiccups

macrolide

macrolides

hiccups

azithromycin

hiccups

hiccups

macrolide

hiccups


Time trends in warfarin-associated hemorrhage.

The annual incidence of warfarin-related bleeding at Brigham and Women's Hospital increased from 0.97/1,000 patient admissions in the first time period (January 1995 to October 1998) to 1.19/1,000 patient admissions in the second time period (November 1998 to August 2002) of this study. The proportion of patients with major and intracranial bleeding increased from 20.2% and 1.9%, respectively, in the first time period, to 33.3% and 7.8%, respectively, in the second.

warfarin

hemorrhage

warfarin

bleeding

intracranial bleeding


Fatal haemorrhagic myocarditis secondary to cyclophosphamide therapy.

Haemorrhagic myocarditis is a rare but important complication of cyclophosphamide therapy. Echocardiographic identification of the disorder can be made. We believe that the ultrasound features of this disorder have not been previously reported.

haemorrhagic myocarditis

haemorrhagic

myocarditis

cyclophosphamide

Haemorrhagic myocarditis

Haemorrhagic

myocarditis

cyclophosphamide


Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura.

Migraine with aura and migraine without aura have the same pain phase, thus indicating that migraine with aura and migraine without aura share a common pathway of nociception. In recent years, increasing evidence has suggested that the messenger molecule nitric oxide (NO) is involved in pain mechanisms of migraine without aura. In order to clarify whether the same is true for migraine with aura, in the present study we examined the headache response to intravenous infusion of glyceryl trinitrate (GTN) (0.5 microg/kg/min for 20 min) in 12 sufferers of migraine with aura. The specific aim was to elucidate whether an aura and/or an attack of migraine without aura could be induced. Fourteen healthy subjects served as controls. Aura symptoms were not elicited in any subject. Headache was more severe in migraineurs than in the controls during and immediately after GTN infusion (p=0.037) as well as during the following 11 h (p = 0.008). In the controls, the GTN-induced headache gradually disappeared, whereas in migraineurs peak headache intensity occurred at a mean time of 240 min post-infusion. At this time the induced headache in 6 of 12 migraineurs fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. The results therefore suggest that NO is involved in the pain mechanisms of migraine with aura. Since cortical spreading depression has been shown to liberate NO in animals, this finding may help our understanding of the coupling between cortical spreading depression and headache in migraine with aura.

Glyceryl trinitrate

migraine without aura

migraine with aura

Migraine with aura

migraine without aura

pain

migraine with aura

migraine without aura

nitric oxide

NO

pain

migraine without aura

migraine with aura

headache

glyceryl trinitrate

GTN

migraine with aura

migraine without aura

Headache

migraineurs

GTN

GTN

headache

migraineurs

headache

headache

migraineurs

migraine without aura

Headache

NO

pain

migraine with aura

depression

NO

depression

headache

migraine with aura


Stroke and cocaine or amphetamine use.

The association of cocaine and amphetamine use with hemorrhagic and ischemic stroke is based almost solely on data from case series. The limited number of epidemiologic studies of stroke and use of cocaine and/or amphetamine have been done in settings that serve mostly the poor and/or minorities. This case-control study was conducted in the defined population comprising members of Kaiser Permanente of Northern and Southern California. We attempted to identify all incident strokes in women ages 15-44 years during a 3-year period using hospital admission and discharge records, emergency department logs, and payment requests for out-of-plan hospitalizations. We selected controls, matched on age and facility of usual care, at random from healthy members of the health plan. We obtained information in face-to-face interviews. There were 347 confirmed stroke cases and 1,021 controls. The univariate matched odds ratio for stroke in women who admitted to using cocaine and/or amphetamine was 8.5 (95% confidence interval = 3.6-20.0). After further adjustment for potential confounders, the odds ratio in women who reported using cocaine and/or amphetamine was 7.0 (95% confidence interval = 2.8-17.9). The use of cocaine and/or amphetamine is a strong risk factor for stroke in this socioeconomically heterogeneous, insured urban population.

Stroke

cocaine

amphetamine

cocaine

amphetamine

ischemic

stroke

stroke

cocaine

amphetamine

strokes

stroke

stroke

cocaine

amphetamine

cocaine

amphetamine

cocaine

amphetamine

stroke


Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study.

BACKGROUND: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive. METHODS: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat. FINDINGS: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen. INTERPRETATION: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

breast cancer

tamoxifen

Tamoxifen

Tamoxifen

breast cancer

endometrial cancer

tamoxifen

tamoxifen

breast cancer

tamoxifen

breast cancer

breast cancer

breast cancer

breast-cancer

tamoxifen

breast cancer

tamoxifen

breast cancer

tamoxifen

vascular events

hypertriglyceridaemia

tamoxifen

breast cancer

tamoxifen

tamoxifen

breast cancer

tamoxifen


A measure of pupillary oscillation as a marker of cocaine-induced paranoia.

Cocaine-induced paranoia (CIP) remains an important drug-induced model of idiopathic paranoia for which no psychophysiologic marker has yet emerged. Measures of pupillary oscillation were able to significantly distinguish a group of abstinent crack cocaine abusers endorsing past CIP (n = 32) from another group of crack addicts who denied past CIP (n = 29).

pupillary oscillation

cocaine

paranoia

Cocaine

paranoia

CIP

paranoia

pupillary oscillation

crack cocaine

CIP

crack

CIP


Seizures induced by combined levomepromazine-fluvoxamine treatment.

We report a case of combined levomepromazine-fluvoxamine treatment-induced seizures. It seems that combined treatment of fluvoxamine with phenothiazines may possess proconvulsive activity.

Seizures

levomepromazine

fluvoxamine

levomepromazine

fluvoxamine

seizures

fluvoxamine

phenothiazines


Why may epsilon-aminocaproic acid (EACA) induce myopathy in man? Report of a case and literature review.

A case of necrotizing myopathy due to a short epsilon-aminocaproic acid (EACA) treatment in a 72 year-old patient with subarachnoid haemorrhage (SAH) is described. Pathogenetic hypotheses are discussed.

epsilon-aminocaproic acid

EACA

myopathy

necrotizing myopathy

necrotizing

myopathy

epsilon-aminocaproic acid

EACA

subarachnoid haemorrhage

SAH


Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states.

The H2-histamine receptor antagonists ranitidine and cimetidine were compared for their abilities to control gastric acid hypersecretion on a short- and long-term basis in 22 patients with gastric acid hypersecretory states. Nineteen patients had Zollinger-Ellison syndrome, one patient had systemic mastocytosis, and two patients had idiopathic hypersecretion. The rates of onset of the action of cimetidine and ranitidine were the same. The actions of both drugs were increased by anticholinergic agents, and there was a close correlation between the daily maintenance dose of each drug needed to control acid secretion. However, ranitidine was threefold more potent than cimetidine both in acute inhibition studies and in the median maintenance dose needed (1.2 g per day for ranitidine and 3.6 g per day for cimetidine). Sixty percent of the males developed breast changes or impotence while taking cimetidine and in all cases these changes disappeared when cimetidine was replaced by ranitidine. Treatment with high doses of cimetidine (one to 60 months; median, 11 months) or ranitidine (two to 31 months; median, 14 months) was not associated with hepatic or hematologic toxicity or alterations of serum gastrin concentrations, but ranitidine therapy was associated with a significantly lower serum creatinine level than seen with cimetidine therapy. The results show that both drugs can adequately inhibit acid secretion in patients with gastric hypersecretory states. Both are safe at high doses, but ranitidine is threefold more potent and does not cause the antiandrogen side effects frequently seen with high doses of cimetidine.

ranitidine

cimetidine

histamine

ranitidine

cimetidine

Zollinger-Ellison syndrome

systemic mastocytosis

cimetidine

ranitidine

ranitidine

cimetidine

ranitidine

cimetidine

impotence

cimetidine

cimetidine

ranitidine

cimetidine

ranitidine

hepatic or hematologic toxicity

hepatic toxicity

hematologic toxicity

ranitidine

creatinine

cimetidine

ranitidine

cimetidine


A catch in the Reye.

Twenty-six cases of Reye syndrome from The Children's Hospital, Camperdown, Australia, occurring between 1973 and 1982 were reviewed. Of these, 20 cases met the US Public Health Service Centers for Disease Control criteria for the diagnosis of Reye syndrome. Aspirin or salicylate ingestion had occurred in only one of the 20 cases (5%), and paracetamol (acetaminophen) had been administered in only six of the cases (30%). Pathologic confirmation of the diagnosis of Reye syndrome was accomplished in 90% of the cases. The incidence of Reye syndrome in New South Wales, Australia, is estimated from this study to be approximately nine cases per 1 million children compared with recent US data of ten to 20 cases per 1 million children and three to seven cases per 1 million children in Great Britain. The mortality for these Reye syndrome cases in Australia was 45% as compared with a 32% case-fatality rate in the United States. In Australia, the pediatric usage of aspirin has been extremely low for the past 25 years (less than 1% of total dosage units sold), with paracetamol (acetaminophen) dominating the pediatric analgesic and antipyretic market. Reye syndrome may be disappearing from Australia despite a total lack of association with salicylates or aspirin ingestion, since there were no cases found at The Children's Hospital in 1983, 1984, or 1985.

Reye

Reye syndrome

Reye syndrome

Aspirin

salicylate

paracetamol

acetaminophen

Reye syndrome

Reye syndrome

Reye syndrome

aspirin

paracetamol

acetaminophen

Reye syndrome

salicylates

aspirin


St. Anthony's fire, then and now: a case report and historical review.

A rare case of morbid vasospasm, together with striking angiographic findings, is described secondary to the ingestion of methysergide by a 48-year-old woman. A brief review of the literature on similar cases is presented. A discussion of the history of ergot includes its original discovery, the epidemics of gangrene that it has caused through the ages and its past and present role in the management of migraine headache. Despite the advent of calcium channel blockers and beta-adrenergic antagonists, ergot preparations continue to play a major role in migraine therapy, so that the danger of St. Anthony's fire persists.

St. Anthony's fire

vasospasm

methysergide

ergot

gangrene

migraine headache

calcium

ergot

migraine

St. Anthony's fire


Beta-2-adrenoceptor-mediated hypokalemia and its abolishment by oxprenolol.

The time course and concentration-effect relationship of terbutaline-induced hypokalemia was studied, using computer-aided pharmacokinetic-dynamic modeling. Subsequently we investigated the efficacy of oxprenolol in antagonizing such hypokalemia, together with the pharmacokinetic interaction between both drugs. Six healthy subjects were given a 0.5 mg subcutaneous dose of terbutaline on two occasions: 1 hour after oral administration of a placebo and 1 hour after 80 mg oxprenolol orally. In the 7-hour period after terbutaline administration, plasma samples were taken for determination of plasma potassium levels and drug concentrations. The sigmoid Emax model offered a good description of the relation between terbutaline concentrations and potassium effects. Oxprenolol caused decreases of 65% and 56% of terbutaline volume of distribution and clearance, respectively, and an increase of 130% of its AUC. In spite of higher terbutaline concentrations after oxprenolol pretreatment, the hypokalemia was almost completely antagonized by the beta 2-blocking action.

hypokalemia

oxprenolol

terbutaline

hypokalemia

oxprenolol

hypokalemia

terbutaline

oxprenolol

terbutaline

potassium

terbutaline

potassium

Oxprenolol

terbutaline

terbutaline

oxprenolol

hypokalemia


Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa.

Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.

serotonin

hypotensive

methyldopa

methyldopa

serotonin

hypotensive

serotonin

hypertensive

stroke

methyldopa

serotonin

hypotension

serotonin

serotonin

hypotension

serotonin

serotonin

serotonin

methyldopa

methyldopa

hypotension

serotonin

hypotensive

methyldopa


Yohimbine treatment of sexual side effects induced by serotonin reuptake blockers.

BACKGROUND: Preclinical and clinical studies suggest that yohimbine facilitates sexual behavior and may be helpful in the treatment of male impotence. A single case report suggests that yohimbine may be used to treat the sexual side effects of clomipramine. This study evaluated yohimbine as a treatment for the sexual side effects caused by serotonin reuptake blockers. METHOD: Six patients with either obsessive compulsive disorder, trichotillomania, anxiety, or affective disorders who suffered sexual side effects after treatment with serotonin reuptake blockers were given yohimbine on a p.r.n. basis in an open clinical trial. Various doses of yohimbine were used to determine the ideal dose for each patient. RESULTS: Five of the six patients experienced improved sexual functioning after taking yohimbine. One patient who failed to comply with yohimbine treatment had no therapeutic effects. Side effects of yohimbine included excessive sweating, increased anxiety, and a wound-up feeling in some patients. CONCLUSION: The results of this study indicate that yohimbine may be an effective treatment for the sexual side effects caused by serotonin reuptake blockers. Future controlled studies are needed to further investigate the effectiveness and safety of yohimbine for this indication.

Yohimbine

sexual side effects

serotonin

yohimbine

male impotence

yohimbine

sexual side effects

clomipramine

yohimbine

sexual side effects

serotonin

obsessive compulsive disorder

trichotillomania

anxiety

affective disorders

sexual side effects

serotonin

yohimbine

yohimbine

yohimbine

yohimbine

yohimbine

anxiety

yohimbine

sexual side effects

serotonin

yohimbine


Hypersensitivity immune reaction as a mechanism for dilevalol-associated hepatitis.

OBJECTIVE: To assess lymphocyte reactivity to dilevalol and to serum containing putative ex vivo dilevalol antigens or metabolites in a case of dilevalol-induced liver injury. PATIENT: A 58-year-old woman with a clinical diagnosis of dilevalol-induced liver injury. METHODS: Peripheral blood mononuclear cells collected from the patient were cultured in the presence of a solution of dilevalol and also with sera collected from a volunteer before and after dilevalol intake. A similar protocol was performed with lymphocytes from a healthy subject. RESULTS: No lymphocyte proliferation was observed either in the patient or in the healthy volunteer in the presence of dilevalol solutions. A significant proliferative response to serum collected after dilevalol intake was observed in the case of the patient compared with the proliferative response to the serum collected before the drug intake. No reactivity was found when lymphocytes from the healthy subject were tested under similar conditions. CONCLUSIONS: The methodology used allowed the detection of lymphocyte sensitization to sera containing ex vivo-prepared dilevalol antigens, suggesting the involvement of an immunologic mechanism in dilevalol-induced liver injury.

Hypersensitivity

dilevalol

hepatitis

dilevalol

dilevalol

dilevalol

liver injury

dilevalol

liver injury

dilevalol

dilevalol

dilevalol

dilevalol

dilevalol

dilevalol

liver injury


Reversible myocardial hypertrophy induced by tacrolimus in a pediatric heart transplant recipient: case report.

Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement.

myocardial hypertrophy

tacrolimus

Tacrolimus

cardiac toxicity

myocardial hypertrophy

tacrolimus

hypertrophy

edema

myocardial hypertrophy

tacrolimus

tacrolimus

Myocardial hypertrophy

tacrolimus

tacrolimus

myocardial hypertrophy

tacrolimus


Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease.

A prospective, randomized, double-blind pilot study to compare the results of stereotactic unilateral pallidotomy and subthalamotomy in advanced idiopathic Parkinson's disease (PD) refractory to medical treatment was designed. Ten consecutive patients (mean age, 58.4 +/- 6.8 years; 7 men, 3 women) with similar characteristics at the duration of disease (mean disease time, 8.4 +/- 3.5 years), disabling motor fluctuations (Hoehn _ Yahr stage 3-5 in off-drug phases) and levodopa-induced dyskinesias were selected. All patients had bilateral symptoms and their levodopa equivalent dosing were analysed. Six patients were operated on in the globus pallidus interna (GPi) and four in the subthalamic nucleus (STN). Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn_Yahr score and Schwab England activities of daily living (ADL) score in 'on'- and 'off'-drug conditions before surgery and 6 months after surgery. There was statistically significant improvement in all contralateral major parkinsonian motor signs in all patients followed for 6 months. Levodopa equivalent daily intake was significantly reduced in the STN group. Changes in UPDRS, Hoehn _ Yahr and Schwab England ADL scores were similar in both groups. Cognitive functions were unchanged in both groups. Complications were observed in two patients: one had a left homonymous hemianopsia after pallidotomy and another one developed left hemiballistic movements 3 days after subthalamotomy which partly improved within 1 month with Valproate 1000 mg/day. The findings of this study suggest that lesions of the unilateral STN and GPi are equally effective treatment for patients with advanced PD refractory to medical treatment.

idiopathic Parkinson's disease

idiopathic Parkinson's disease

PD

levodopa

dyskinesias

levodopa

Parkinson's Disease

parkinsonian

Levodopa

homonymous hemianopsia

Valproate

PD


Protective effects of antithrombin on puromycin aminonucleoside nephrosis in rats.

We investigated the effects of antithrombin, a plasma inhibitor of coagulation factors, in rats with puromycin aminonucleoside-induced nephrosis, which is an experimental model of human nephrotic syndrome. Antithrombin (50 or 500 IU/kg/i.v.) was administered to rats once a day for 10 days immediately after the injection of puromycin aminonucleoside (50 mg/kg/i.v.). Treatment with antithrombin attenuated the puromycin aminonucleoside-induced hematological abnormalities. Puromycin aminonucleoside-induced renal dysfunction and hyperlipidemia were also suppressed. Histopathological examination revealed severe renal damage such as proteinaceous casts in tubuli and tubular expansion in the kidney of control rats, while an improvement of the damage was seen in antithrombin-treated rats. In addition, antithrombin treatment markedly suppressed puromycin aminonucleoside-induced apoptosis of renal tubular epithelial cells. Furthermore, puromycin aminonucleoside-induced increases in renal cytokine content were also decreased. These findings suggest that thrombin plays an important role in the pathogenesis of puromycin aminonucleoside-induced nephrotic syndrome. Treatment with antithrombin may be clinically effective in patients with nephrotic syndrome.

puromycin aminonucleoside

nephrosis

puromycin aminonucleoside

nephrosis

nephrotic syndrome

puromycin aminonucleoside

puromycin aminonucleoside

hematological abnormalities

Puromycin aminonucleoside

renal dysfunction

hyperlipidemia

renal damage

puromycin aminonucleoside

puromycin aminonucleoside

puromycin aminonucleoside

nephrotic syndrome

nephrotic syndrome


Reverse or inverted left ventricular apical ballooning syndrome (reverse Takotsubo cardiomyopathy) in a young woman in the setting of amphetamine use.

Transient left ventricular apical ballooning syndrome was first described in Japan as "Takotsubo cardiomyopathy." This syndrome has been identified in many other countries. Many variations of this syndrome have been recently described in the literature. One of the rarest is the reverse type of this syndrome, with hyperdynamic apex and complete akinesia of the base (as opposed to the classic apical ballooning). In this article, we report an interesting case of a young woman who presented with this rare type of reverse apical ballooning syndrome occurring after amphetamine use. This report is followed by review of the literature.

Takotsubo cardiomyopathy

amphetamine

Takotsubo cardiomyopathy

akinesia

apical ballooning

apical ballooning syndrome

amphetamine


Attenuated disruption of prepulse inhibition by dopaminergic stimulation after maternal deprivation and adolescent corticosterone treatment in rats.

The development of schizophrenia may include an early neurodevelopmental stress component which increases vulnerability to later stressful life events, in combination leading to overt disease. We investigated the effect of an early stress, in the form of maternal deprivation, combined with a later stress, simulated by chronic periadolescent corticosterone treatment, on behaviour in rats. Acute treatment with apomorphine caused disruption of prepulse inhibition (PPI) in controls and in rats that had undergone either maternal deprivation or corticosterone treatment, but was surprisingly absent in rats that had undergone the combined early and late stress. Amphetamine treatment significantly disrupted PPI in both non-deprived groups, but was absent in both maternally deprived groups. The serotonin-1A receptor agonist, 8-OH-DPAT, induced a significant disruption of PPI in all groups. Amphetamine-induced locomotor hyperactivity was similar in all groups. These results show an inhibitory interaction of early stress, caused by maternal deprivation, combined with 'adolescent' stress, simulated by corticosterone treatment, on dopaminergic regulation of PPI. The altered effects of apomorphine and amphetamine could indicate differential changes in dopamine receptor signalling leading to functional desensitisation, or altered modulation of sensory gating in the nucleus accumbens by limbic structures such as the hippocampus.

corticosterone

schizophrenia

corticosterone

apomorphine

corticosterone

Amphetamine

serotonin

Amphetamine

locomotor hyperactivity

corticosterone

apomorphine

amphetamine

dopamine


Peripheral iron dextran induced degeneration of dopaminergic neurons in rat substantia nigra.

Iron accumulation is considered to be involved in the pathogenesis of Parkinson's disease. To demonstrate the relationship between peripheral iron overload and dopaminergic neuron loss in rat substantia nigra (SN), in the present study we used fast cyclic voltammetry, tyrosine hydroxylase (TH) immunohistochemistry, Perls' iron staining, and high performance liquid chromatography-electrochemical detection to study the degeneration of dopaminergic neurons and increased iron content in the SN of iron dextran overloaded animals. The findings showed that peripheral iron dextran overload increased the iron staining positive cells and reduced the number of TH-immunoreactive neurons in the SN. As a result, dopamine release and content, as well as its metabolites contents were decreased in caudate putamen. Even more dramatic changes were found in chronic overload group. These results suggest that peripheral iron dextran can increase the iron level in the SN, where excessive iron causes the degeneration of dopaminergic neurons. The chronic iron overload may be more destructive to dopaminergic neurons than the acute iron overload.

iron dextran

degeneration of dopaminergic neurons

Iron

Parkinson's disease

iron

tyrosine

iron

degeneration of dopaminergic neurons

iron

iron dextran

iron dextran

iron

dopamine

iron dextran

iron

iron

degeneration of dopaminergic neurons

iron

iron


Warfarin-induced leukocytoclastic vasculitis.

Skin reactions associated with oral coumarin-derived anticoagulants are an uncommon occurrence. Leukocytoclastic vasculitis (LV) is primarily a cutaneous small vessel vasculitis, though systemic involvement may be encountered. We report 4 patients with late-onset LV probably due to warfarin. All 4 patients presented with skin eruptions that developed after receiving warfarin for several years. The results of skin lesion biopsies were available in 3 patients, confirming LV Cutaneous lesions resolved in all patients after warfarin was discontinued. In 2 of the 4 patients, rechallenge with warfarin led to recurrence of the lesions. LV may be a late-onset adverse reaction associated with warfarin therapy.

Warfarin

leukocytoclastic vasculitis

coumarin

Leukocytoclastic vasculitis

LV

cutaneous small vessel vasculitis

LV

warfarin

skin eruptions

warfarin

skin lesion

LV Cutaneous lesions

warfarin

warfarin

LV

warfarin


The activation of spinal N-methyl-D-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia.

We investigated the relationship between the degeneration of spinal motor neurons and activation of N-methyl-d-aspartate (NMDA) receptors after neuraxial morphine following a noninjurious interval of aortic occlusion in rats. Spinal cord ischemia was induced by aortic occlusion for 6 min with a balloon catheter. In a microdialysis study, 10 muL of saline (group C; n = 8) or 30 mug of morphine (group M; n = 8) was injected intrathecally (IT) 0.5 h after reflow, and 30 mug of morphine (group SM; n = 8) or 10 muL of saline (group SC; n = 8) was injected IT 0.5 h after sham operation. Microdialysis samples were collected preischemia, before IT injection, and at 2, 4, 8, 24, and 48 h of reperfusion (after IT injection). Second, we investigated the effect of IT MK-801 (30 mug) on the histopathologic changes in the spinal cord after morphine-induced spastic paraparesis. After IT morphine, the cerebrospinal fluid (CSF) glutamate concentration was increased in group M relative to both baseline and group C (P < 0.05). This increase persisted for 8 hrs. IT MK-801 significantly reduced the number of dark-stained alpha-motoneurons after morphine-induced spastic paraparesis compared with the saline group. These data indicate that IT morphine induces spastic paraparesis with a concomitant increase in CSF glutamate, which is involved in NMDA receptor activation. We suggest that opioids may be neurotoxic in the setting of spinal cord ischemia via NMDA receptor activation.

N-methyl-D-aspartate

morphine

spinal cord ischemia

N-methyl-d-aspartate

NMDA

morphine

aortic occlusion

Spinal cord ischemia

aortic occlusion

morphine

morphine

morphine

spastic paraparesis

morphine

glutamate

morphine

spastic paraparesis

morphine

spastic paraparesis

glutamate

NMDA

neurotoxic

spinal cord ischemia

NMDA


Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits.

Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that beta2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.

sodium

seizures

sodium

Sodium

sodium

saxitoxin

STX

sodium

sodium

sodium

seizures

pilocarpine

seizures

sodium


Screening for stimulant use in adult emergency department seizure patients.

OBJECTIVE: The objective of this study was to determine the prevalence of positive plasma drug screening for cocaine or amphetamine in adult emergency department seizure patients. METHODS: This prospective study evaluated consecutive eligible seizure patients who had a plasma sample collected as part of their clinical evaluation. Plasma was tested for amphetamine and the cocaine metabolite benzoylecgonine using enzyme-mediated immunoassay methodology. Plasma samples with benzoylecgonine greater than 150 ng/mL or an amphetamine greater than 500 ng/mL were defined as positive. Patient demographics, history of underlying drug or alcohol-related seizure disorder, estimated time from seizure to sample collection, history or suspicion of cocaine or amphetamine abuse, results of clinical urine testing for drugs of abuse, and assay results were recorded without patient identifiers. RESULTS: Fourteen of 248 (5.6%, 95% CI 2.7%-8.5%) plasma samples were positive by immunoassay testing for benzoylecgonine and no samples (0%, 95% CI 0-1.2%) were positive for amphetamine. Positive test results were more common in patient visits where there was a history or suspicion of cocaine or amphetamine abuse (p < 0.0005). CONCLUSIONS: During this study period, routine plasma screening for cocaine and amphetamines in adult seizure patients had a low yield. As a result, routine plasma screening would yield few cases of stimulant drug in which there was neither a history nor suspicion of drug abuse in this population.

seizure

cocaine

amphetamine

seizure

seizure

amphetamine

cocaine

benzoylecgonine

benzoylecgonine

amphetamine

alcohol

seizure

seizure

cocaine or amphetamine abuse

cocaine abuse

amphetamine abuse

benzoylecgonine

amphetamine

cocaine or amphetamine abuse

cocaine abuse

amphetamine abuse

cocaine

amphetamines

seizure

drug abuse


Evidence of functional somatotopy in GPi from results of pallidotomy.

The objective of this study was to explore the functional anatomy of the globus pallidus internus (GPi) by studying the effects of unilateral pallidotomy on parkinsonian 'off' signs and levodopa-induced dyskinesias (LID). We found significant positive correlations between the preoperative levodopa responsiveness of motor signs and the levodopa responsiveness of scores in timed tests (Core Assessment Program for Intracerebral Transplantations) in the contralateral limbs and the improvement in these scores after surgery, whereas there was no correlation with the improvement in LID. We also found a highly significant correlation (P: < 0.0001, r = 0.8) between the volume of the ventral lesion in the GPi and the improvement in LID in the contralateral limbs, whereas there was no correlation between the ventral volume and the improvement in parkinsonian 'off' signs. The volumes of the total lesion cylinder and the dorsal lesion did not correlate with the outcome of either dyskinesias or parkinsonian 'off' signs. The differential predictive value of levodopa responsiveness for the outcome of parkinsonian 'off' signs and LID and the different correlations of ventral lesion volume with dyskinesias and parkinsonian 'off' signs indicate that different anatomical or pathophysiological substrates may be responsible for the generation of parkinsonian 'off' signs and dyskinesias. Whereas cells in a wider area of the GPi may be implicated in parkinsonism, the ventral GPi seems to be crucial for the manifestation of LID. We suggest that our observations are additional proof of the functional somatotopy of the systems within the GPi that mediate parkinsonism and dyskinesias, especially along the dorsoventral trajectory used in pallidotomy. The outcome of pallidotomy in which the lesion involves the ventral and dorsal GPi could be the net effect of alteration in the activity of pathways which mediate different symptoms, and hence could be variable.

parkinsonian

levodopa

dyskinesias

LID

levodopa

levodopa

LID

LID

parkinsonian

dyskinesias

parkinsonian

levodopa

parkinsonian

LID

dyskinesias

parkinsonian

parkinsonian

dyskinesias

parkinsonism

LID

parkinsonism

dyskinesias


Pain responses in methadone-maintained opioid abusers.

Providing pain management for known opioid abusers is a challenging clinical task, in part because little is known about their pain experience and analgesic requirements. This study was designed to describe pain tolerance and analgesic response in a sample of opioid addicts stabilized in methadone-maintenance (MM) treatment (n = 60) in comparison to matched nondependent control subjects (n = 60). By using a placebo-controlled, two-way factorial design, tolerance to cold-pressor (CP) pain was examined, both before and after oral administration of therapeutic doses of common opioid (hydromorphone 2 mg) and nonsteroidal anti-inflammatory (ketorolac 10 mg) analgesic agents. Results showed that MM individuals were significantly less tolerant of CP pain than control subjects, replicating previous work. Analgesic effects were significant neither for medication nor group. These data indicate that MM opioid abusers represent a pain-intolerant subset of clinical patients. Their complaints of pain should be evaluated seriously and managed aggressively.

Pain

methadone

pain

pain

pain

opioid addicts

methadone

pain

hydromorphone

ketorolac

pain

pain-intolerant

pain


Urine N-acetyl-beta-D-glucosaminidase--a marker of tubular damage?

BACKGROUND: Although an indicator of renal tubular dysfunction, an increased urinary N-acetyl-beta-D-glucosaminidase (NAG) activity might reflect increased lysosomal activity in renal tubular cells. METHODS: Puromycin aminonucleoside (PAN) was administered to Sprague Dawley rats to induce proteinuria. Total protein, albumin, NAG activity and protein electrophoretic pattern were assessed in daily urine samples for 33 days. The morphological appearance of the kidneys was examined on days three, four, six, eight and thirty three and the NAG isoenzyme patterns on days zero, four, eight and thirty three. RESULTS: Following intravenous PAN urine volume and urine NAG activity increased significantly by day two, but returned to normal by day four. After day four all treated animals exhibited a marked rise in urine albumin, total protein excretion and NAG activity. Electrophoresis showed a generalised increase in middle and high molecular weight urine proteins from day four onwards. Protein droplets first appeared prominent in tubular cells on day four. Peak urine NAG activity and a change in NAG isoenzyme pattern coincided with both the peak proteinuria and the reduction in intracellular protein and NAG droplets (day six onwards). CONCLUSIONS: This animal model demonstrates that an increase in lysosomal turnover and hence urine NAG activity, occurs when increased protein is presented to the tubular cells. Urine NAG activity is thus a measure of altered function in the renal tubules and not simply an indicator of damage.

renal tubular dysfunction

Puromycin aminonucleoside

PAN

proteinuria

PAN

proteinuria


Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis.

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fischer 344 rats. The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the role of estrogen in the regulation of tumor angiogenesis in the pituitary of female rats, the density of blood vessels was analysed using factor VIII related antigen (FVIIIRAg) immunohistochemistry and the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analysis. The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined by immunohistochemistry. The results demonstrated that 17beta-estradiol (E2) induces neovascularization, as well as the growth and enlargement of blood vessels after 7 days of exposure. The high tumor angiogenic potential was associated with an elevated VEGF/VPF protein expression in the E2 exposed pituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAg immunohistochemistry and endothelial specific lectin (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelial cells. After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restricted to the blood vessels. The function of non-endothelial-derived VEGF is not clear. Furthermore, immunohistochemical studies demonstrated that VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure. These findings suggest that over expression of VEGF and its receptor (VEGFR-2) may play an important role in the initial step of the regulation of estrogen induced tumor angiogenesis in the rat pituitary.

estrogen

pituitary tumors

estrogen

tumor

Estrogens

cancers

tumor

tumor

estrogen

carcinogenesis

estrogen

tumor

tumor

estrogen

tumor


Pravastatin-associated myopathy. Report of a case.

A case of acute inflammatory myopathy associated with the use of pravastatin, a new hydrophilic 3-hydroxy-3 methylglutaril coenzyme A reductase inhibitor, is reported. The patient, a 69-year-old man was affected by non-insulin-dependent diabetes mellitus and hypertension. He assumed pravastatin (20 mg/day) because of hypercholesterolemia. He was admitted with acute myopathy of the lower limbs which resolved in a few days after pravastatin discontinuation. A previously unknown hypothyroidism, probably due to chronic autoimmune thyroiditis, was evidenced. Muscle biopsy (left gastrocnemius) revealed a perimysial and endomysial inflammatory infiltrate with a prevalence of CD4+ lymphocytes. While lovastatin and simvastatin have been associated with toxic myopathy, pravastatin-associated myopathy could represent a distinct, inflammatory entity.

Pravastatin

myopathy

inflammatory myopathy

pravastatin

non-insulin-dependent diabetes mellitus

hypertension

pravastatin

hypercholesterolemia

myopathy

pravastatin

hypothyroidism

autoimmune thyroiditis

lovastatin

simvastatin

myopathy

pravastatin

myopathy


Dose-effect and structure-function relationships in doxorubicin cardiomyopathy.

The cardiomyopathy (CM) produced by the anticancer drug doxorubicin (DXR) (Adriamycin) provides a unique opportunity to analyze dose-effect and structure-function relationships during development of myocardial disease. We measured the degree of morphologic damage by ultrastructural examination of endomyocardial biopsy and the degree of performance abnormally by right heart catheterization in patients receiving DXR. Morphologic damage was variable but was proportional to the total cumulative DXR dose between 100 and 600 mg/m2. Performance abnormalities correlated weakly with dose, exhibited a curvilinear relationship, and had a "threshold" for expression. Catheterization abnormalities correlated well with morphologic damage (r = 0.57 to 0.78) in a subgroup of patients in whom exercise hemodynamics were measured, and this relationship also exhibited a curvilinear, threshold configuration. In DXR-CM myocardial damage is proportional to the degree of cytotoxic insult (DXR dose) while myocardial function is preserved until a critical dose or degree of damage is reached, after which myocardial performance deteriorates rapidly.

doxorubicin

cardiomyopathy

cardiomyopathy

CM

doxorubicin

DXR

Adriamycin

myocardial disease

DXR

DXR

DXR

CM

myocardial damage

DXR


Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol.

A 73-year-old woman died of aplastic anemia less than two months after undergoing cataract extraction and beginning topical therapy with chloramphenicol. The first signs of pancytopenia began within one month of the surgery. The pattern of the aplastic anemia was associated with an idiosyncratic response to chloramphenicol. This was the second report of fatal aplastic anemia after topical treatment with chloramphenicol for ocular conditions, although two cases of reversible bone marrow hypoplasia have also been reported. Any other suspected cases of ocular toxicity associated with topically applied chloramphenicol should be reported to the National Registry of Drug-Induced Ocular Side Effects, Oregon Health Sciences University, Portland, OR 97201.

aplastic anemia

chloramphenicol

aplastic anemia

cataract

chloramphenicol

pancytopenia

aplastic anemia

chloramphenicol

aplastic anemia

chloramphenicol

bone marrow hypoplasia

ocular toxicity

chloramphenicol


Bradycardia due to trihexyphenidyl hydrochloride.

A chronic schizophrenic patient was treated with an anticholinergic drug, trihexyphenidyl hydrochloride. The patient developed, paradoxically, sinus bradycardia. The reaction was specific to trihexyphenidyl and not to other anticholinergic drugs. This antidyskinetic drug is widely used in clinical psychiatric practice and physicians should be aware of this side effect.

Bradycardia

trihexyphenidyl hydrochloride

schizophrenic

trihexyphenidyl hydrochloride

bradycardia

trihexyphenidyl

psychiatric


Experimental cyclosporine nephrotoxicity: risk of concomitant chemotherapy.

The role of cyclosporine (CSA) alone or in combination with various chemotherapeutics in the development of renal toxicity was evaluated in rats. Administration of 20 mg/kg/day CSA for 4 weeks caused renal functional and structural changes similar to those reported in man. The combined administration of CSA and various chemotherapeutic drugs with a nephrotoxic potential, such as gentamicin (at therapeutic doses), amphothericin B and ketoconazole, which are frequently used in immunosuppressed patients, did not aggravate the CSA induced toxicity in the rat model. Gentamicin at toxic doses, however, increased CSA nephrotoxicity. Thus, the nephrotoxicity induced by CSA has a different pathogenetic mechanism.

cyclosporine

nephrotoxicity

cyclosporine

CSA

renal toxicity

CSA

CSA

nephrotoxic

gentamicin

amphothericin B

ketoconazole

CSA

toxicity

Gentamicin

CSA

nephrotoxicity

nephrotoxicity

CSA


Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats.

Rats were pretreated with saline or nicotine (1.5 mg/kg per day) by subcutaneously implanting each animal with an Alzet osmotic mini-pump which continuously released saline or nicotine for 1, 5 and 14 days. At the end of each pretreatment period, animals were used for (i) determining their locomotor response to acutely injected nicotine (0.2 mg/kg, s.c.) and (ii) measuring the density of L-[3H]nicotine and [3H]spiperone binding sites in the striatum. We observed no changes in nicotine-induced locomotor response, striatal L-[3H]nicotine and [3H]spiperone binding in the animals pretreated with nicotine for 1 day. In rats which were pretreated with nicotine for 5 days, there was a significant increase in the nicotine-stimulated locomotor response which was associated with an increase in the number of L-[3H]nicotine binding sites and also with an elevated dopamine (DA) level in the striatum. The number of striatal [3H]spiperone binding sites was not affected. In animals pretreated with nicotine for 14 days, the nicotine-induced locomotor response remained to be potentiated. However, this response was correlated with an elevated number of striatal [3H]spiperone binding sites, whereas the number of striatal L-[3H]nicotine binding sites and the striatal DA level were normal. These results suggest that chronic nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of nicotinic receptors and DA concentration, followed by inducing DA receptor supersensitivity in the striatum.

nicotine

locomotor hyperactivity

nicotine

nicotine

nicotine

nicotine

nicotine

spiperone

nicotine

nicotine

spiperone

nicotine

nicotine

nicotine

nicotine

dopamine

DA

spiperone

nicotine

nicotine

spiperone

nicotine

DA

nicotine

locomotor hyperactivity

nicotine

DA

DA


Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)

Hydrocortisone

hypertension

hydrocortisone

hydrocortisone

norepinephrine

increased cardiac output

norepinephrine

hydrocortisone

hydrocortisone

norepinephrine

norepinephrine

norepinephrine

rise in resting blood pressure

hydrocortisone

increased cardiac output


Effects of suprofen on the isolated perfused rat kidney.

Although suprofen has been associated with the development of acute renal failure in greater than 100 subjects, the mechanism of damage remains unclear. The direct nephrotoxic effects of a single dose of 15 mg of suprofen were compared in the recirculating isolated rat kidney perfused with cell-free buffer with or without the addition of 5 mg/dL of uric acid. There were no significant differences in renal sodium excretion, oxygen consumption, or urinary flow rates in kidneys perfused with suprofen compared with the drug-free control groups. In contrast, a significant decline in glomerular filtration rate was found after the introduction of suprofen to the kidney perfused with uric acid; no changes were found with suprofen in the absence of uric acid. A significant decrease in the baseline excretion rate of uric acid was found in rats given suprofen, compared with drug-free controls. However, the fractional excretion of uric acid was unchanged between the groups over the experimental period. In summary, suprofen causes acute declines in renal function, most likely by directly altering the intrarenal distribution of uric acid.

suprofen

suprofen

acute renal failure

nephrotoxic

suprofen

uric acid

sodium

oxygen

suprofen

suprofen

uric acid

suprofen

uric acid

uric acid

suprofen

uric acid

suprofen

acute declines in renal function

uric acid


Cocaine-induced brainstem seizures and behavior.

A variety of abnormal sensory/motor behaviors associated with electrical discharges recorded from the bilateral brainstem were induced in adult WKY rats by mechanical (electrode implants) and DC electrical current stimulations and by acute and chronic administration of cocaine. The electrode implant implicated one side or the other of the reticular system of the brainstem but subjects were not incapacitated by the stimulations. Cocaine (40 mg/kg) was injected subcutaneously for an acute experiment and subsequent 20 mg/kg doses twice daily for 3 days in a chronic study. Cocaine generated more abnormal behaviors in the brainstem perturbation group, especially the electrically perturbated subjects. The abnormal behaviors were yawning, retrocollis, hyperactivity, hypersensitivity, "beating drum" behavior, squealing, head bobbing, circling, sniffing, abnormal posturing, and facial twitching. Shifts in the power frequency spectra of the discharge patterns were noted between quiet and pacing behavioral states. Hypersensitivity to various auditory, tactile, and visual stimulation was present and shifts in the brainstem ambient power spectral frequency occurred in response to tactile stimulation. These findings suggest that the brainstem generates and propagates pathological discharges that can be elicited by mechanical and DC electrical perturbation. Cocaine was found to activate the discharge system and thus induce abnormal behaviors that are generated at the discharge site and at distant sites to which the discharge propagates. Cognitive functions may also be involved since dopaminergic and serotonergic cellular elements at the brainstem level are also implicated.

Cocaine

seizures

cocaine

Cocaine

Cocaine

hyperactivity

hypersensitivity

Hypersensitivity

Cocaine


Increased sulfation and decreased 7alpha-hydroxylation of deoxycholic acid in ethinyl estradiol-induced cholestasis in rats.

Deoxycholic acid conjugation, transport capacity, and metabolism were compared in control and ethinyl estradiol-treated rats. Control rats were found to have a lower capacity to transport deoxycholic acid than taurodeoxycholic acid, and both were decreased by ethinyl estradiol treatment. During [24-14C]sodium deoxycholate infusion, [14C]biliary bile acid secretion increased, but bile flow did not change significantly in either control or ethinyl estradiol-treated rats. Ethinyl estradiol-treated animals excreted significantly less 14C as taurocholic acid than did control animals, consistent with an impairment of 7alpha-hydroxylation of taurodeoxycholic acid. Ethinyl estradiol treatment did not impair conjugation of deoxycholic acid, but did result in an increase in sulfation of taurodeoxycholic acid from 1.5% in controls to nearly 4.0% (P less than 0.01). These results are consistent with the hypothesis that the rat has a poorer tolerance for deoxycholic acid than do certain other species. Furthermore, the rat converts deoxycholic acid, a poor choleretic, to taurocholic acid, a good choleretic. When this conversion is impaired with ethinyl estradiol treatment, sulfation may be an important alternate pathway for excretion of this potentially harmful bile acid.

deoxycholic acid

ethinyl estradiol

cholestasis

Deoxycholic acid

ethinyl estradiol

deoxycholic acid

taurodeoxycholic acid

ethinyl estradiol

sodium deoxycholate

bile acid

ethinyl estradiol

Ethinyl estradiol

taurocholic acid

taurodeoxycholic acid

Ethinyl estradiol

deoxycholic acid

taurodeoxycholic acid

deoxycholic acid

deoxycholic acid

taurocholic acid

ethinyl estradiol

bile acid