Anti-carcinogenic action of phenobarbital given simultaneously with diethylnitrosamine in the rat.

The present work has been planned in order to elucidate the effect of phenobarbital (PB: 15 mg per rat of ingested dose) on carcinogenesis when it is administered simultaneously with diethylnitrosamine (DEN: 10 mg/kg/day). Wistar rats (180 g) were treated by DEN alone or by DEN + PB during 2, 4 and 6 weeks according to our schedule for hepatocarcinogenesis. After the end of the treatment, the number and the size of induced PAS positive preneoplastic foci was significantly reduced when PB was given simultaneously with DEN for 4 and 6 weeks. The mitotic inhibition and the production of micronuclei normally observed after partial hepatectomy in DEN treated rats were also significantly decreased in DEN + PB treated rats. When the treatment last only 2 weeks, the presence of PB did not change significantly the last parameters. In DEN + PB treated rats, the survival was prolonged and the tumor incidence decreased as compared with the results obtained by DEN alone. It is concluded that PB, which promotes carcinogenesis when administered after the DEN treatment, reduces the carcinogen effect when given simultaneously with DEN. This 'anti-carcinogen' effect acts on the initiation as well as on the promotion of the precancerous lesions. Biochemical investigations are in progress to obtain more information about this 'paradoxical' PB effect.

carcinogenic

phenobarbital

diethylnitrosamine

phenobarbital

PB

carcinogenesis

diethylnitrosamine

DEN

DEN

DEN

PB

hepatocarcinogenesis

preneoplastic foci

PB

DEN

DEN

DEN

PB

PB

DEN

PB

tumor

DEN

PB

carcinogenesis

DEN

DEN

precancerous lesions

PB


Post-operative rigidity after fentanyl administration.

A case of thoraco-abdominal rigidity leading to respiratory failure is described in the post-operative period in an elderly patient who received a moderate dose of fentanyl. This was successfully reversed by naloxone. The mechanisms possibly implicated in this accident are discussed.

rigidity

fentanyl

rigidity

respiratory failure

fentanyl

naloxone


Postpartum psychosis induced by bromocriptine.

Two multigravida patients with no prior psychiatric history were seen with postpartum psychosis, having received bromocriptine for inhibition of lactation. Bromocriptine given in high doses has been associated with psychosis in patients receiving the drug for Parkinson's disease. These cases demonstrate that bromocriptine may cause psychosis even when given in low doses.

psychosis

bromocriptine

psychiatric

psychosis

bromocriptine

inhibition of lactation

Bromocriptine

psychosis

Parkinson's disease

bromocriptine

psychosis


A prospective study on the dose dependency of cardiotoxicity induced by mitomycin C.

Since 1975 mitomycin C (MMC) has been suggested to be cardiotoxic, especially when combined with or given following doxorubicin. Data on dose dependency or incidence concerning this side effect were not known. We have initiated a prospective study to obtain some more data on these subjects. Forty-four MMC-treated patients were studied, 37 of them could be evaluated. All patients were studied by repeated physical examinations, chest X-rays, electro- and echocardiography and radionuclide left ventricular ejection fraction (EF) determinations. The results were evaluated per cumulative dose level. One of the patients developed cardiac failure after 30 mg m-2 MMC and only 150 mg m-2 doxorubicin. The cardiac failure was predicted by a drop in EF determined during a cold pressor test. None of the other patients developed clinical cardiotoxicity, nor did the studied parameters change. The literature on this subject was also reviewed. Based on the combined data from the present study and the literature, we suggest that MMC-related cardiotoxicity is dose dependent, occurring at cumulative dose levels of 30 mg m-2 or more, mainly in patients also (previously or simultaneously) treated with doxorubicin. The incidence is likely to be less than 10% even for this risk group.

cardiotoxicity

mitomycin C

mitomycin C

MMC

cardiotoxic

doxorubicin

MMC

cardiac failure

MMC

doxorubicin

cardiac failure

cardiotoxicity

MMC

cardiotoxicity

doxorubicin


Phlorizin-induced glycosuria does not prevent gentamicin nephrotoxicity in rats.

Because rats with streptozotocin-induced diabetes mellitus (DM) have a high solute diuresis (glycosuria of 10 to 12 g/day), we have suggested that this may in part be responsible for their resistance to gentamicin-induced acute renal failure (ARF). The protection from gentamicin nephrotoxicity was studied in non-diabetic rats with chronic solute diuresis induced by blockage of tubular glucose reabsorption with phlorizin (P). DM rats with mild glycosuria (similar in degree to that of the P treated animals) were also studied. Unanesthetized adult female, Sprague-Dawley rats were divided in four groups and studied for 15 days. Group 1 (P alone) received P, 360 mg/day, for 15 days; Group II (P + gentamicin); Group III (gentamicin alone) and Group IV (mild DM + gentamicin). Nephrotoxic doses (40 mg/kg body wt/day) of gentamicin were injected during the last nine days of study to the animals of groups II to IV. In Group I, P induced a moderate and stable glycosuria (3.9 +/- 0.1 g/day, SE), and no functional or morphologic evidence of renal dysfunction (baseline CCr 2.1 +/- 0.1 ml/min, undetectable lysozymuria) or damage (tubular necrosis score [maximum 4], zero). In Group II, P did not prevent gentamicin-ARF (maximal decrease in CCr at day 9.89%, P less than 0.001; peak lysozymuria, 1863 +/- 321 micrograms/day; and tubular necrosis score, 3.9 +/- 0.1). These values were not different from those of Group III: maximal decrease in CCr 73% (P less than 0.001); lysozymuria, 2147 +/- 701 micrograms/day; tubular necrosis score, 3.8 +/- 0.1.(ABSTRACT TRUNCATED AT 250 WORDS)

Phlorizin

glycosuria

gentamicin

nephrotoxicity

streptozotocin

diabetes mellitus

DM

glycosuria

gentamicin

acute renal failure

ARF

gentamicin

nephrotoxicity

diabetic

glucose

phlorizin

P

DM

glycosuria

P

P

P

P

gentamicin

gentamicin

DM

gentamicin

Nephrotoxic

gentamicin

P

glycosuria

renal dysfunction

tubular necrosis

P

gentamicin

ARF

P

tubular necrosis

P

tubular necrosis


Tiapride in levodopa-induced involuntary movements.

Tiapride, a substituted benzamide derivative closely related to metoclopramide, reduced levodopa-induced peak dose involuntary movements in 16 patients with idiopathic Parkinson's disease. However, an unacceptable increase in disability from Parkinsonism with aggravation of end-of-dose akinesia led to its cessation in 14 patients. Tiapride had no effect on levodopa-induced early morning of "off-period" segmental dystonia. These results fail to support the notion that levodopa-induced dyskinesias are caused by overstimulation of a separate group of dopamine receptors.

Tiapride

levodopa

involuntary movements

Tiapride

benzamide

metoclopramide

levodopa

involuntary movements

idiopathic Parkinson's disease

Parkinsonism

akinesia

Tiapride

levodopa

dystonia

levodopa

dyskinesias

dopamine


Effects of the hippocampal deep brain stimulation on cortical epileptic discharges in penicillin - induced epilepsy model in rats.

AIM: Experimental and clinical studies have revealed that hippocampal DBS can control epileptic activity, but the mechanism of action is obscure and optimal stimulation parameters are not clearly defined. The aim was to evaluate the effects of high frequency hippocampal stimulation on cortical epileptic activity in penicillin-induced epilepsy model. MATERIAL AND METHODS: Twenty-five Sprague-Dawley rats were implanted DBS electrodes. In group-1 (n=10) hippocampal DBS was off and in the group-2 (n=10) hippocampal DBS was on (185 Hz, 0.5V, 1V, 2V, and 5V for 60 sec) following penicillin G injection intracortically. In the control group hippocampal DBS was on following 8  l saline injection intracortically. EEG recordings were obtained before and 15 minutes following penicillin-G injection, and at 10th minutes following each stimulus for analysis in terms of frequency, amplitude, and power spectrum. RESULTS: High frequency hippocampal DBS suppressed the acute penicillin-induced cortical epileptic activity independent from stimulus intensity. In the control group, hippocampal stimulation alone lead only to diffuse slowing of cerebral bioelectrical activity at 5V stimulation. CONCLUSION: Our results revealed that continuous high frequency stimulation of the hippocampus suppressed acute cortical epileptic activity effectively without causing secondary epileptic discharges. These results are important in terms of defining the optimal parameters of hippocampal DBS in patients with epilepsy.

epileptic

penicillin

epilepsy

epileptic

epileptic

penicillin

epilepsy

penicillin G

penicillin-G

penicillin

epileptic

epileptic

epileptic

epilepsy


Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency.

The glutamatergic N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction. In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency. Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia.

S-ketamine

psychosis

N-methyl-D-aspartate

NMDA

schizophrenia

NMDA

ketamine

schizophrenia

schizophrenia

ketamine

glutamatergic dysfunction

S-ketamine

Ketamine

Ketamine

psychosis

ketamine

Ketamine

Ketamine

schizophrenia

NMDA

schizophrenia


Dopamine is not essential for the development of methamphetamine-induced neurotoxicity.

It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of L-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature. Further, we show that mice genetically engineered to be deficient in brain DA develop METH neurotoxicity, as long as the thermic effects of METH are preserved. In addition, we demonstrate that mice genetically engineered to have unilateral brain DA deficits develop METH-induced dopaminergic deficits that are of comparable magnitude on both sides of the brain. Taken together, these findings demonstrate that DA is not essential for the development of METH-induced dopaminergic neurotoxicity and suggest that mechanisms independent of DA warrant more intense investigation.

Dopamine

methamphetamine

neurotoxicity

dopamine

DA

methamphetamine

METH

toxicity

DA

toxicity

DA

toxicity

DA

L-dihydroxyphenylalanine

alpha-methyl-para-tyrosine

METH

DA

neurotoxicity

DA

METH

neurotoxicity

METH

DA

METH

dopaminergic deficits

DA

METH

neurotoxicity

DA


Brainstem dysgenesis in an infant prenatally exposed to cocaine.

Many authors described the effects on the fetus of maternal cocaine abuse during pregnancy. Vasoconstriction appears to be the common mechanism of action leading to a wide range of fetal anomalies. We report on an infant with multiple cranial-nerve involvement attributable to brainstem dysgenesis, born to a cocaine-addicted mother.

Brainstem dysgenesis

cocaine

cocaine abuse

fetal anomalies

multiple cranial-nerve involvement

brainstem dysgenesis

cocaine-addicted


The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy is one of the major causes of renal failure, which is accompanied by the production of reactive oxygen species (ROS). Nrf2 is the primary transcription factor that controls the antioxidant response essential for maintaining cellular redox homeostasis. Here, we report our findings demonstrating a protective role of Nrf2 against diabetic nephropathy. RESEARCH DESIGN AND METHODS: We explore the protective role of Nrf2 against diabetic nephropathy using human kidney biopsy tissues from diabetic nephropathy patients, a streptozotocin-induced diabetic nephropathy model in Nrf2(-/-) mice, and cultured human mesangial cells. RESULTS: The glomeruli of human diabetic nephropathy patients were under oxidative stress and had elevated Nrf2 levels. In the animal study, Nrf2 was demonstrated to be crucial in ameliorating streptozotocin-induced renal damage. This is evident by Nrf2(-/-) mice having higher ROS production and suffering from greater oxidative DNA damage and renal injury compared with Nrf2(+/+) mice. Mechanistic studies in both in vivo and in vitro systems showed that the Nrf2-mediated protection against diabetic nephropathy is, at least, partially through inhibition of transforming growth factor-beta1 (TGF-beta1) and reduction of extracellular matrix production. In human renal mesangial cells, high glucose induced ROS production and activated expression of Nrf2 and its downstream genes. Furthermore, activation or overexpression of Nrf2 inhibited the promoter activity of TGF-beta1 in a dose-dependent manner, whereas knockdown of Nrf2 by siRNA enhanced TGF-beta1 transcription and fibronectin production. CONCLUSIONS: This work clearly indicates a protective role of Nrf2 in diabetic nephropathy, suggesting that dietary or therapeutic activation of Nrf2 could be used as a strategy to prevent or slow down the progression of diabetic nephropathy.

streptozotocin

diabetic nephropathy

Diabetic nephropathy

renal failure

oxygen

diabetic nephropathy

diabetic nephropathy

diabetic nephropathy

streptozotocin

diabetic nephropathy

diabetic nephropathy

streptozotocin

renal damage

renal injury

diabetic nephropathy

glucose

diabetic nephropathy

diabetic nephropathy


High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients.

BACKGROUND: In 2 separate centers, we observed a notable increase in the incidence of postoperative convulsive seizures from 1.3% to 3.8% in patients having undergone major cardiac surgical procedures. These events were temporally coincident with the initial use of high-dose tranexamic acid (TXA) therapy after withdrawal of aprotinin from general clinical usage. The purpose of this review was to perform a retrospective analysis to examine whether there was a relation between TXA usage and seizures after cardiac surgery. METHODS: An in-depth chart review was undertaken in all 24 patients who developed perioperative seizures. Electroencephalographic activity was recorded in 11 of these patients, and all patients had a formal neurological evaluation and brain imaging studies. RESULTS: Twenty-one of the 24 patients did not have evidence of new cerebral ischemic injury, but seizures were likely due to ischemic brain injury in 3 patients. All patients with seizures did not have permanent neurological abnormalities. All 24 patients with seizures received high doses of TXA intraoperatively ranging from 61 to 259 mg/kg, had a mean age of 69.9 years, and 21 of 24 had undergone open chamber rather than coronary bypass procedures. All but one patient were managed using cardiopulmonary bypass. No evidence of brain ischemic, metabolic, or hyperthermia-induced causes for their seizures was apparent. CONCLUSION: Our results suggest that use of high-dose TXA in older patients in conjunction with cardiopulmonary bypass and open-chamber cardiac surgery is associated with clinical seizures in susceptible patients.

tranexamic Acid

seizures

convulsive

seizures

tranexamic acid

TXA

TXA

seizures

seizures

cerebral ischemic injury

seizures

ischemic brain injury

seizures

neurological abnormalities

seizures

TXA

brain ischemic

hyperthermia

seizures

TXA

seizures


Recurrent dysosmia induced by pyrazinamide.

Pyrazinamide can have adverse effects such as hepatic toxicity, hyperuricemia or digestive disorders. In rare cases, alterations in taste and smell function have been reported for pyrazinamide when combined with other drugs. We report a case of reversible olfactory disorder related to pyrazinamide in a woman, with a positive rechallenge. The patient presented every day a sensation of smelling something burning 15 min after drug intake. Dysosmia disappeared completely after pyrazinamide withdrawal and recurred after its rechallenge. The case was reported to the Tunisian Centre of Pharmacovigilance.

dysosmia

pyrazinamide

Pyrazinamide

hepatic toxicity

hyperuricemia

pyrazinamide

olfactory disorder

pyrazinamide

Dysosmia

pyrazinamide


Longitudinal assessment of air conduction audiograms in a phase III clinical trial of difluoromethylornithine and sulindac for prevention of sporadic colorectal adenomas.

A phase III clinical trial assessed the recurrence of adenomatous polyps after treatment for 36 months with difluoromethylornithine (DFMO) plus sulindac or matched placebos. Temporary hearing loss is a known toxicity of treatment with DFMO, thus a comprehensive approach was developed to analyze serial air conduction audiograms. The generalized estimating equation method estimated the mean difference between treatment arms with regard to change in air conduction pure tone thresholds while accounting for within-subject correlation due to repeated measurements at frequencies. Based on 290 subjects, there was an average difference of 0.50 dB between subjects treated with DFMO plus sulindac compared with those treated with placebo (95% confidence interval, -0.64 to 1.63 dB; P = 0.39), adjusted for baseline values, age, and frequencies. In the normal speech range of 500 to 3,000 Hz, an estimated difference of 0.99 dB (-0.17 to 2.14 dB; P = 0.09) was detected. Dose intensity did not add information to models. There were 14 of 151 (9.3%) in the DFMO plus sulindac group and 4 of 139 (2.9%) in the placebo group who experienced at least 15 dB hearing reduction from baseline in 2 or more consecutive frequencies across the entire range tested (P = 0.02). Follow-up air conduction done at least 6 months after end of treatment showed an adjusted mean difference in hearing thresholds of 1.08 dB (-0.81 to 2.96 dB; P = 0.26) between treatment arms. There was no significant difference in the proportion of subjects in the DFMO plus sulindac group who experienced clinically significant hearing loss compared with the placebo group. The estimated attributable risk of ototoxicity from exposure to the drug is 8.4% (95% confidence interval, -2.0% to 18.8%; P = 0.12). There is a <2 dB difference in mean threshold for patients treated with DFMO plus sulindac compared with those treated with placebo.

difluoromethylornithine

sulindac

colorectal adenomas

adenomatous polyps

difluoromethylornithine

DFMO

sulindac

hearing loss

toxicity

DFMO

DFMO

sulindac

DFMO

sulindac

DFMO

sulindac

hearing loss

ototoxicity

DFMO

sulindac


Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly.

OBJECTIVES: The objectives of this study were to examine the relationship between APOE epsilon4 and subjective effects of trihexyphenidyl on measures reflecting sedation and confusion and to investigate the relationship between trihexyphenidyl-induced subjective effects and objective memory performance. METHODS: This study comprised 24 cognitively intact, health elderly adults (12 APOE epsilon4 carriers) at an outpatient geriatric psychiatry research clinic. This was a randomized, double blind, placebo-controlled, three-way, crossover experimental design. All participants received 1.0 mg or 2.0 mg trihexyphenidyl or placebo administered in counterbalanced sequences over a period of three consecutive weeks. Bond and Lader's visual analog scales and alternate versions of the Buschke Selective Reminding Test were administered in a repeated measures design at baseline, 1, 2.5, and 5 hours postdrug administration. RESULTS: A 2.0-mg oral dose of trihexyphenidyl resulted in increased subjective ratings of mental slowness in carriers of the APOE epsilon4 allele only. Drug effects as determined by difference scores between 2.0 mg trihexyphenidyl and placebo on ratings of mental slowness significantly correlated with total and delayed recall on the Buschke Selective Reminding Test in carriers of the APOE epsilon4 allele only. However, no significant effects were found with other visual analog scales reflecting subjective sedation and clear-headedness. CONCLUSION: The epsilon4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge.

mental slowing

trihexyphenidyl

trihexyphenidyl

confusion

trihexyphenidyl

trihexyphenidyl

trihexyphenidyl

mental slowness

trihexyphenidyl

mental slowness

mental slowing

trihexyphenidyl


Behavioral effects of pubertal anabolic androgenic steroid exposure in male rats with low serotonin.

The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.

steroid

serotonin

steroid

serotonin

Serotonin

parachlorophenylalanine

PCPA

PCPA

testosterone

T

irritability

aggression

aggression

5-hydroxyindoleacetic acid

PCPA

T

PCPA

PCPA

irritability

aggression

T

irritability

aggression

T

PCPA

aggressive behavior


Intracavitary chemotherapy (paclitaxel/carboplatin liquid crystalline cubic phases) for recurrent glioblastoma -- clinical observations.

Human malignant brain tumors have a poor prognosis in spite of surgery and radiation therapy. Cubic phases consist of curved biocontinuous lipid bilayers, separating two congruent networks of water channels. Used as a host for cytotoxic drugs, the gel-like matrix can easily be applied to the walls of a surgical resection cavity. For human glioblastoma recurrences, the feasibility, safety, and short-term effects of a surgical intracavitary application of paclitaxel and carboplatin encapsulated by liquid crystalline cubic phases are examined in a pilot study. A total of 12 patients with a recurrence of a glioblastoma multiforme underwent re-resection and received an intracavitary application of paclitaxel and carboplatin cubic phases in different dosages. Six of the patients received more than 15 mg paclitaxel and suffered from moderate to severe brain edema, while the remaining patients received only a total of 15 mg paclitaxel. In the latter group, brain edema was markedly reduced and dealt medically. Intracavitary chemotherapy in recurrent glioblastoma using cubic phases is feasible and safe, yet the clinical benefit remains to be examined in a clinical phase II study.

paclitaxel

carboplatin

glioblastoma

brain tumors

glioblastoma

paclitaxel

carboplatin

glioblastoma

paclitaxel

carboplatin

paclitaxel

brain edema

paclitaxel

brain edema

glioblastoma


Methylphenidate-induced obsessive-compulsive symptoms in an elderly man.

An 82-year-old man with treatment-resistant depression and early Alzheimer's disease was started on methylphenidate. Significant obsessive-compulsive behavior ensued but diminished over several weeks when methylphenidate was replaced by fluvoxamine. The patient had no prior psychiatric history, but he had a sister with obsessive-compulsive disorder. It appears that methylphenidate precipitated the patient's pathological behavior.

Methylphenidate

obsessive-compulsive symptoms

treatment-resistant depression

Alzheimer's disease

methylphenidate

obsessive-compulsive behavior

methylphenidate

fluvoxamine

psychiatric

obsessive-compulsive disorder

methylphenidate


Cardiac arrest after intravenous metoclopramide - a case of five repeated injections of metoclopramide causing five episodes of cardiac arrest.

We describe a patient where intravenous injection of metoclopramide was immediately followed by asystole repeatedly. The patient received metoclopramide 10 mg i.v. five times during 48 h. After interviewing the attending nurses and reviewing the written documentation, it is clear that every administration of metoclopramide was immediately (within s) followed by asystole. The asystole lasted 15-30 s on four occasions, on one occasion it lasted 2 min. The patient received atropine 0.5-1 mg and chest compressions, before sinus rhythm again took over. We interpret this as episodes of cardiac arrest caused by metoclopramide. The rapid injection via the central venous route and the concomitant tapering of dopamine infusion might have contributed in precipitating the adverse drug reaction.

Cardiac arrest

metoclopramide

metoclopramide

cardiac arrest

metoclopramide

asystole

metoclopramide

metoclopramide

asystole

asystole

atropine

cardiac arrest

metoclopramide

dopamine


Severe immune hemolytic anemia associated with prophylactic use of cefotetan in obstetric and gynecologic procedures.

Second- and third-generation cephalosporins, especially cefotetan, are increasingly associated with severe, sometimes fatal immune hemolytic anemia. We noticed that 10 of our 35 cases of cefotetan-induced hemolytic anemias were in patients who had received cefotetan prophylactically for obstetric and gynecologic procedures. Eight of these cases of severe immune hemolytic anemia are described.

hemolytic anemia

cefotetan

cephalosporins

cefotetan

hemolytic anemia

cefotetan

hemolytic anemias

cefotetan

hemolytic anemia


Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of cauda equina syndrome reported to the Swedish Pharmaceutical Insurance 1993-1997.

Six cases of cauda equina syndrome with varying severity were reported to the Swedish Pharmaceutical Insurance during the period 1993-1997. All were associated with spinal anaesthesia using hyperbaric 5% lignocaine. Five cases had single-shot spinal anaesthesia and one had a repeat spinal anaesthetic due to inadequate block. The dose of hyperbaric 5% lignocaine administered ranged from 60 to 120 mg. Three of the cases were most likely caused by direct neurotoxicity of hyperbaric 5% lignocaine. In the other 3 cases, direct neurotoxicity was also probable, but unfortunately radiological investigations were not done to definitely exclude a compressive aetiology. All cases sustained permanent neurological deficits. We recommend that hyperbaric lignocaine should be administered in concentrations not greater than 2% and at a total dose preferably not exceeding 60 mg.

Cauda equina syndrome

lignocaine

cauda equina syndrome

cauda equina syndrome

lignocaine

lignocaine

neurotoxicity

lignocaine

neurotoxicity

neurological deficits

lignocaine


Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia.

We have studied the regional cerebral blood flow (rCBF) changes induced by the execution of a finger-to-thumb opposition motor task in the supplementary and primary motor cortex of two groups of parkinsonian patients on L-dopa medication, the first one without L-dopa induced dyskinesia (n = 23) and the other with moderate peak-dose dyskinesia (n = 15), and of a group of 14 normal subjects. Single photon emission tomography with i.v. 133Xe was used to measure the rCBF changes. The dyskinetic parkinsonian patients exhibited a pattern of response which was markedly different from those of the normal subjects and non-dyskinetic parkinsonian patients, with a significant overactivation in the supplementary motor area and the ipsi- and contralateral primary motor areas. These results are compatible with the hypothesis that an hyperkinetic abnormal involuntary movement, like L-dopa-induced peak dose dyskinesia, is due to a disinhibition of the primary and associated motor cortex secondary to an excessive outflow of the pallidothalamocortical motor loop.

parkinsonian

L-dopa

dyskinesia

parkinsonian

L-dopa

L-dopa

dyskinesia

dyskinesia

dyskinetic

parkinsonian

dyskinetic

parkinsonian

hyperkinetic

abnormal involuntary movement

L-dopa

dyskinesia


Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes.

PURPOSE: Glucocorticoid administration can lead to the development of ocular hypertension and corticosteroid glaucoma in a subset of the population through a decrease in the aqueous humor outflow facility. The purpose of this study was to determine whether glucocorticoid treatment can directly affect the outflow facility of isolated, perfusion-cultured human eyes. METHODS: The anterior segments of human donor eyes from regional eye banks were placed in a constant flow, variable pressure perfusion culture system. Paired eyes were perfused in serum-free media with or without 10(-7) M dexamethasone for 12 days. Intraocular pressure was monitored daily. After incubation, the eyes were morphologically characterized by light microscopy, transmission and scanning electron microscopy, and scanning laser confocal microscopy. RESULTS: A significant increase in intraocular pressure developed in 13 of the 44 pairs of eyes perfused with dexamethasone with an average pressure rise of 17.5 +/- 3.8 mm Hg after 12 days of dexamethasone exposure. The contralateral control eyes, which did not receive dexamethasone, maintained a stable intraocular pressure during the same period. The outflow pathway of the untreated eyes appeared morphologically normal. In contrast, the dexamethasone-treated hypertensive eyes had thickened trabecular beams, decreased intertrabecular spaces, thickened juxtacanalicular tissue, activated trabecular meshwork cells, and increased amounts of amorphogranular extracellular material, especially in the juxtacanalicular tissue and beneath the endothelial lining of the canal of Schlemm. The dexamethasone-treated nonresponder eyes appeared to be morphologically similar to the untreated eyes, although several subtle dexamethasone-induced morphologic changes were evident. CONCLUSION: Dexamethasone treatment of isolated, perfusion-cultured human eyes led to the generation of ocular hypertension in approximately 30% of the dexamethasone-treated eyes. Steroid treatment resulted in morphologic changes in the trabecular meshwork similar to those reported for corticosteroid glaucoma and open angle glaucoma. This system may provide an acute model in which to study the pathogenic mechanisms involved in steroid glaucoma and primary open angle glaucoma.

Dexamethasone

ocular hypertension

ocular hypertension

corticosteroid glaucoma

dexamethasone

dexamethasone

dexamethasone

dexamethasone

dexamethasone

hypertensive eyes

dexamethasone

dexamethasone

Dexamethasone

ocular hypertension

dexamethasone

Steroid

corticosteroid glaucoma

open angle glaucoma

steroid glaucoma

primary open angle glaucoma


Cognitive deterioration from long-term abuse of dextromethorphan: a case report.

Dextromethorphan (DM), the dextrorotatory isomer of 3-hydroxy-N-methylmorphinan, is the main ingredient in a number of widely available, over-the-counter antitussives. Initial studies (Bornstein 1968) showed that it possessed no respiratory suppressant effects and no addiction liability. Subsequently, however, several articles reporting abuse of this drug have appeared in the literature. The drug is known to cause a variety of acute toxic effects, ranging from nausea, restlessness, insomnia, ataxia, slurred speech and nystagmus to mood changes, perceptual alterations, inattention, disorientation and aggressive behavior (Rammer et al 1988; Katona and Watson 1986; Isbell and Fraser 1953; Devlin et al 1985; McCarthy 1971; Dodds and Revai 1967; Degkwitz 1964; Hildebrand et al 1989). There have also been two reported fatalities from DM overdoses (Fleming 1986). However, there are no reports describing the effects of chronic abuse. This report describes a case of cognitive deterioration resulting from prolonged use of DM.

Cognitive deterioration

dextromethorphan

Dextromethorphan

DM

nausea

restlessness

insomnia

ataxia

nystagmus

aggressive behavior

DM

cognitive deterioration

DM


Long-term lithium treatment and the kidney. Interim report on fifty patients.

This is a report on the first part of our study of the effects of long-term lithium treatment on the kidney. Creatinine clearance, maximum urinary osmolality and 24 hour urine volume have been tested in 50 affectively ill patients who have been on long-term lithium for more than one year. These findings have been compared with norms and with values of the same tests from screening prior to lithium, available for most of our patients. No evidence was found for any reduction of glomerular filtration during lithium treatment. Low clearance values found in several patients could be accounted for by their age and their pre-lithium values. Urinary concentration defect appeared frequent but the extent of the impairment is difficult to assess because of the uncertainty about the norms applicable to this group of patients. The concentration defect appeared reversible, at least in part. Polyuria above 3 litres/24 hours was found in 10% of patients. An attempt is made to draw practical conclusions from the preliminary findings.

lithium

lithium

Creatinine

lithium

lithium

lithium

lithium

Polyuria


Complete heart block following a single dose of trazodone.

Forty minutes after receiving a single starting dose of trazodone, a patient developed complete heart block. The case illustrates that, despite the results of earlier studies, trazodone's effect on cardiac conduction may be severe in individuals at risk for conduction delay.

heart block

trazodone

trazodone

heart block

trazodone


Quinidine phenylethylbarbiturate-induced fulminant hepatitis in a pregnant woman. A case report.

We report the case of a 19-year-old Laotian patient affected by fulminant hepatitis during the third trimester of her pregnancy after a 1-month administration of quinidine phenylethylbarbiturate. After delivery, the patient underwent orthotopic liver transplantation. The patient was in good condition 16 months after liver transplantation. Quinidine itself or phenylethylbarbiturate may be responsible for fulminant hepatitis in this patient.

Quinidine phenylethylbarbiturate

hepatitis

hepatitis

quinidine phenylethylbarbiturate

Quinidine

phenylethylbarbiturate

hepatitis


The epidemiology of the acute flank pain syndrome from suprofen.

Suprofen, a new nonsteroidal anti-inflammatory drug, was marketed in early 1986 as an analgesic agent. Until physicians began reporting an unusual acute flank pain syndrome to the spontaneous reporting system, 700,000 persons used the drug in the United States. Through August 1986, a total of 163 cases of this syndrome were reported. To elucidate the epidemiology of the syndrome, a case-control study was performed, comparing 62 of the case patients who had been reported to the spontaneous reporting system to 185 suprofen-exposed control subjects who did not have the syndrome. Case patients were more likely to be men (odds ratio, 3.8; 95% confidence interval, 1.2-12.1), suffer from hay fever and asthma (odds ratio, 3.4; 95% confidence interval, 1.0-11.9); to participate in regular exercise (odds ratio, 5.9; 95% confidence interval, 1.1-30.7), especially in the use of Nautilus equipment (p = 0.02); and to use alcohol (odds ratio, 4.4; 95% confidence interval, 1.1-17.5). Possible risk factors included young age, concurrent use of other analgesic agents (especially ibuprofen), preexisting renal disease, a history of kidney stones, a history of gout, a recent increase in activity, a recent increase in sun exposure, and residence in the Sunbelt. These were findings that were suggestive but did not reach conventional statistical significance. These findings are consistent with the postulated mechanism for this unusual syndrome: acute diffuse crystallization of uric acid in renal tubules.

flank pain

suprofen

Suprofen

flank pain

suprofen

hay fever

asthma

alcohol

ibuprofen

renal disease

kidney stones

gout

uric acid


Hemolytic-uremic syndrome associated with ingestion of quinine.

Hemolytic-uremic syndrome following quinine ingestion is a newly described phenomenon, with just two previous descriptions of 4 cases in the literature. We describe a 5th case. The reaction may be mediated by the presence of antibodies reactive against platelets in the presence of quinine. Treatment has included use of plasma exchange, prednisone, aspirin, and dipyridamole. The patients have all regained some degree of renal function. However, it is unclear whether pharmacological treatment or spontaneous resolution is responsible for the improvement. Quinine-associated hemolytic-uremic syndrome probably occurs more often than is recognized. It is important to recognize this reaction when it occurs and to avoid further quinine exposure, since the reaction seems to be recurrent.

Hemolytic-uremic syndrome

quinine

Hemolytic-uremic syndrome

quinine

quinine

prednisone

aspirin

dipyridamole

Quinine

hemolytic-uremic syndrome

quinine


Pyeloureteral filling defects associated with systemic anticoagulation: a case report.

The etiology of pyeloureteritis cystica has long been attributed to chronic infection and inflammation. A case is presented that is unique in that the acute onset and the rapid resolution of pyeloureteral filling defects in this patient were documented by radiography. There is no evidence of antecedent or concurrent infection in this patient. The disease occurred subsequent to the initiation of heparin therapy for suspected pelvic thrombophlebitis and cleared rapidly subsequent to its discontinuation. The rate of resolution of the radiographic findings may be helpful in distinguishing between true pyeloureteritis cystica and submucosal hemorrhage.

pyeloureteritis cystica

infection

inflammation

infection

heparin

thrombophlebitis

pyeloureteritis cystica

submucosal hemorrhage


Changes in peroxisomes in preneoplastic liver and hepatoma of mice induced by alpha-benzene hexachloride.

Peroxisomes in hepatomas and hyperplastic preneoplastic liver lesions induced in mice by 500 ppm alpha-benzene hexachloride were examined histochemically and electron microscopically. Although most of the hepatomas were well-differentiated tumors and contained a considerable number of peroxisomes, the tumor cells did not respond to ethyl-alpha-p-chlorophenoxyisobutyrate with proliferation of peroxisomes. At the 16th week of carcinogen feeding, hyperplastic nodules appeared and advanced to further stages. A majority of the nodules showed a considerable number of peroxisomes and the inductive proliferation of peroxisomes. Within the nodules, foci of proliferation of the cells that showed no inducibility of proliferation of peroxisomes appeared. These cells proliferated further, replacing the most part of the nodules, and with this process hepatomas appeared to have been formed. No abnormal matrical inclusions of peroxisomes were formed in the cells of hyperplastic nodules by ethyl-alpha-p-chlorophenoxyisobutyrate unlike in the case of rats.

hepatoma

alpha-benzene hexachloride

hepatomas

liver lesions

alpha-benzene hexachloride

hepatomas

tumors

tumor

ethyl-alpha-p-chlorophenoxyisobutyrate

hepatomas

ethyl-alpha-p-chlorophenoxyisobutyrate


Quinidine hepatitis.

Long-term administration of quinidine was associated with persistent elevation of serum concentrations of SGOT, lactic acid dehydrogenase, and alkaline phosphatase. Liver biopsy showed active hepatitis. Discontinuance of quinidine therapy led to normalization of liver function tests. A challenge dose of quinidine caused clinical symptoms and abrupt elevation of SGOT, alkaline phosphatase, and lactic acid dehydrogenase values. We concluded that this patient had quinidine hepatotoxicity and believe that this is the first case reported with liver biopsy documentation. This report also suggests that, even after long-term administration, the hepatic toxicity is reversible.

Quinidine

hepatitis

quinidine

lactic acid

hepatitis

quinidine

quinidine

lactic acid

quinidine

hepatotoxicity

hepatic toxicity


Cholesteryl hemisuccinate treatment protects rodents from the toxic effects of acetaminophen, adriamycin, carbon tetrachloride, chloroform and galactosamine.

In addition to its use as a stabilizer/rigidifier of membranes, cholesteryl hemisuccinate, tris salt (CS) administration has also been shown to protect rats from the hepatotoxic effects of carbon tetrachloride (CCl4). To further our understanding of the mechanism of CS cytoprotection, we examined in rats and mice the protective abilities of CS and the non-hydrolyzable ether form of CS, gamma-cholesteryloxybutyric acid, tris salt (CSE) against acetaminophen-, adriamycin-, carbon tetrachloride-, chloroform- and galactosamine-induced toxicity. The results of these studies demonstrated that CS-mediated protection is not selective for a particular species, organ system or toxic chemical. A 24-h pretreatment of both rats and mice with a single dose of CS (100mg/kg, i.p.), resulted in significant protection against the hepatotoxic effects of CCl4, CHCl3, acetaminophen and galactosamine and against the lethal (and presumably cardiotoxic) effect of adriamycin administration. Maximal CS-mediated protection was observed in experimental animals pretreated 24 h prior to the toxic insult. These data suggest that CS intervenes in a critical cellular event that is an important common pathway to toxic cell death. The mechanism of CS protection does not appear to be dependent on the inhibition of chemical bioactivation to a toxic reactive intermediate (in light of the protection observed against galactosamine hepatotoxicity). However, based on the data presented, we can not exclude the possibility that CS administration inhibits chemical bioactivation. Our findings do suggest that CS-mediated protection is dependent on the action of the intact anionic CS molecule (non-hydrolyzable CSE was as protective as CS), whose mechanism has yet to be defined.

Cholesteryl hemisuccinate

acetaminophen

adriamycin

carbon tetrachloride

chloroform

galactosamine

cholesteryl hemisuccinate

tris salt

CS

hepatotoxic

carbon tetrachloride

CS

CS

CS

gamma-cholesteryloxybutyric acid

tris salt

CSE

acetaminophen

adriamycin

carbon tetrachloride

chloroform

galactosamine

toxicity

CS

CS

hepatotoxic

acetaminophen

galactosamine

cardiotoxic

adriamycin

CS

CS

CS

galactosamine

hepatotoxicity

CS

CS

CS

CSE

CS


DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.

A clinical trial was initiated to evaluate the recommended dose of cyclophosphamide in combination with bortezomib and dexamethasone as induction treatment before stem cell transplantation for younger patients with newly diagnosed multiple myeloma (MM). Thirty patients were treated with three 21-day cycles of bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 plus dexamethasone 40 mg on the day of bortezomib injection and the day after plus cyclophosphamide at 900, 1,200, or 1,500 mg/m(2) on day 1. The maximum tolerated dose of cyclophosphamide was defined as 900 mg/m(2). At this dose level, 92% of patients achieved at least a partial response. The overall response rate [complete response (CR) plus partial response (PR)] across all dose levels was 77%, with a 10% CR rate. No patient experienced progressive disease. The most frequent adverse events were hematological and gastrointestinal toxicities as well as neuropathy. The results suggest that bortezomib in combination with cyclophosphamide at 900 mg/m(2) and dexamethasone is an effective induction treatment for patients with newly diagnosed MM that warrants further investigation.

cyclophosphamide

bortezomib

dexamethasone

myeloma

cyclophosphamide

bortezomib

dexamethasone

multiple myeloma

MM

bortezomib

dexamethasone

bortezomib

cyclophosphamide

cyclophosphamide

hematological toxicities

gastrointestinal toxicities

neuropathy

bortezomib

cyclophosphamide

dexamethasone

MM


Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of a new fixed-dose combination (FDC) of telmisartan 40 mg + amlodipine 5 mg (T+A) compared with amlodipine 5-mg monotherapy (A) in adult Indian patients with stage II hypertension. METHODS: This comparative, Phase III, 12-week, multicenter, prospective, randomized, double-blind study was conducted in Indian patients aged 18 to 65 years with established stage II hypertension. Patients were treated with oral FDC of T+A or A QD before breakfast for 12 weeks; blood pressure (BP) and heart rate were measured in the sitting position. Primary efficacy end points were reduction in clinical systolic BP (SBP)/ diastolic BP (DBP) from baseline to study end and number of responders (ie, patients who achieved target SBP/ DBP <130/<80 mm Hg) at end of study. Tolerability was assessed by treatment-emergent adverse events, identified using physical examination, laboratory analysis, and electrocardiography. RESULTS: A total of 210 patients were enrolled in the study; 203 patients (143 men, 60 women) completed the study while 7 were lost to follow-up (4 patients in the T+A group and 3 in the A group) and considered with-drawn. At study end, statistically significant percentage reductions from baseline within groups and between groups were observed in SBP (T+A [-27.4%]; A [-16.6%]) and DBP (T+A [-20.1%]; A [-13.3%]) (all, P < 0.05). Response rates were 87.3% (89/102) in the T+A group and 69.3% (70/101) in the A group (P < 0.05). The prevalences of adverse events were not significantly different between the 2 treatment groups (T+A, 16.0% [17/106]; A, 15.4% [16/104]). Peripheral edema was reported in 8.5% patients (9/106) in the T+A group compared with 13.5% (14/104) in the A group, and cough was reported in 3.8% patients (4/106) in the T+A group and 1.0% (1/104) patients in the A group; these differences did not reach statistical significance. The incidences of headache, dizziness, and diarrhea were similar between the 2 groups. CONCLUSIONS: Among these Indian patients with stage II hypertension, the FDC of T+A was found to be significantly more effective, with regard to BP reductions, than A, and both treatments were well tolerated.

telmisartan

amlodipine

amlodipine

hypertension

telmisartan

amlodipine

amlodipine

hypertension

hypertension

edema

cough

headache

dizziness

diarrhea

hypertension


Cutaneous leucocytoclastic vasculitis associated with oxacillin.

A 67-year-old man who was treated with oxacillin for one week because of Staphylococcus aureus bacteremia, developed renal failure and diffuse, symmetric, palpable purpuric lesions on his feet. Necrotic blisters were noted on his fingers. Skin biopsies showed findings diagnostic of leucocytoclastic vasculitis. Oxacillin was discontinued and patient was treated with corticosteroids. The rash disappeared after three weeks and renal function returned to normal. Leucocytoclastic vasculitis presents as palpable purpura of the lower extremities often accompanied by abdominal pain, arthralgia, and renal involvement. Etiologic factors or associated disorders include infections, medications, collagen vascular disease and neoplasia. However, in half of the cases no etiologic factor is identified. Usually it is a self-limited disorder, but corticosteroid therapy may be needed in life-threatening cases since early treatment with corticosteroids in severe cases can prevent complications. Oxacillin should be included among the drugs that can cause leucocytoclastic vasculitis.

Cutaneous leucocytoclastic vasculitis

oxacillin

oxacillin

Staphylococcus aureus bacteremia

Staphylococcus aureus bacteremia

bacteremia

renal failure

purpuric lesions

Necrotic blisters

Necrotic

blisters

leucocytoclastic vasculitis

Oxacillin

corticosteroids

rash

Leucocytoclastic vasculitis

purpura

abdominal pain

arthralgia

renal involvement

infections

collagen vascular disease

neoplasia

corticosteroid

corticosteroids

Oxacillin

leucocytoclastic vasculitis


Naloxazone pretreatment modifies cardiorespiratory, temperature, and behavioral effects of morphine.

Behavioral and cardiorespiratory responses to a lethal dose of morphine were evaluated in rats pretreated with saline or naloxazone, an antagonist of high-affinity mu 1 opioid receptors. Pretreatment with naloxazone significantly blocked morphine analgesia, catalepsy and hypothermia at a dose which completely eliminated high-affinity binding in brain membranes. Moreover, naloxazone significantly attenuated the morphine-induced hypotension and respiratory depression, whereas morphine-induced bradycardia was less affected. Results indicate that subpopulations of mu receptors may mediate selective behavioral and cardiorespiratory responses to morphine.

Naloxazone

morphine

morphine

naloxazone

naloxazone

morphine

analgesia

catalepsy

hypothermia

naloxazone

morphine

hypotension

respiratory depression

morphine

bradycardia

morphine


Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin.

PURPOSE: The anthracyclines daunorubicin and doxorubicin and the epipodophyllotoxin etoposide are potent DNA cleavage-enhancing drugs that are widely used in clinical oncology; however, myelosuppression and cardiac toxicity limit their use. Dexrazoxane (ICRF-187) is recommended for protection against anthracycline-induced cardiotoxicity. EXPERIMENTAL DESIGN: Because of their widespread use, the hematologic toxicity following coadministration of dexrazoxane and these three structurally different DNA cleavage enhancers was investigated: Sensitivity of human and murine blood progenitor cells to etoposide, daunorubicin, and doxorubicin +/- dexrazoxane was determined in granulocyte-macrophage colony forming assays. Likewise, in vivo, B6D2F1 mice were treated with etoposide, daunorubicin, and doxorubicin, with or without dexrazoxane over a wide range of doses: posttreatment, a full hematologic evaluation was done. RESULTS: Nontoxic doses of dexrazoxane reduced myelosuppression and weight loss from daunorubicin and etoposide in mice and antagonized their antiproliferative effects in the colony assay; however, dexrazoxane neither reduced myelosuppression, weight loss, nor the in vitro cytotoxicity from doxorubicin. CONCLUSION: Although our findings support the observation that dexrazoxane reduces neither hematologic activity nor antitumor activity from doxorubicin clinically, the potent antagonism of daunorubicin activity raises concern; a possible interference with anticancer efficacy certainly would call for renewed attention. Our data also suggest that significant etoposide dose escalation is perhaps possible by the use of dexrazoxane. Clinical trials in patients with brain metastases combining dexrazoxane and high doses of etoposide is ongoing with the aim of improving efficacy without aggravating hematologic toxicity. If successful, this represents an exciting mechanism for pharmacologic regulation of side effects from cytotoxic chemotherapy.

Dexrazoxane

myelosuppression

etoposide

daunorubicin

doxorubicin

anthracyclines

daunorubicin

doxorubicin

epipodophyllotoxin

etoposide

myelosuppression

cardiac toxicity

Dexrazoxane

anthracycline

cardiotoxicity

hematologic toxicity

dexrazoxane

etoposide

daunorubicin

doxorubicin

dexrazoxane

etoposide

daunorubicin

doxorubicin

dexrazoxane

dexrazoxane

myelosuppression

weight loss

daunorubicin

etoposide

dexrazoxane

myelosuppression

weight loss

cytotoxicity

doxorubicin

dexrazoxane

doxorubicin

daunorubicin

etoposide

dexrazoxane

metastases

dexrazoxane

etoposide

hematologic toxicity


Effects of the novel compound aniracetam (Ro 13-5057) upon impaired learning and memory in rodents.

The effect of aniracetam (Ro 13-5057, 1-anisoyl-2-pyrrolidinone) was studied on various forms of experimentally impaired cognitive functions (learning and memory) in rodents and produced the following effects: (1) almost complete prevention of the incapacity to learn a discrete escape response in rats exposed to sublethal hypercapnia immediately before the acquisition session; (2) partial (rats) or complete (mice) prevention of the scopolamine-induced short-term amnesia for a passive avoidance task; (3) complete protection against amnesia for a passive avoidance task in rats submitted to electroconvulsive shock immediately after avoidance acquisition; (4) prevention of the long-term retention- or retrieval-deficit for a passive avoidance task induced in rats and mice by chloramphenicol or cycloheximide administered immediately after acquisition; (5) reversal, when administered as late as 1 h before the retention test, of the deficit in retention or retrieval of a passive avoidance task induced by cycloheximide injected 2 days previously; (6) prevention of the deficit in the retrieval of an active avoidance task induced in mice by subconvulsant electroshock or hypercapnia applied immediately before retrieval testing (24 h after acquisition). These improvements or normalizations of impaired cognitive functions were seen at oral aniracetam doses of 10-100 mg/kg. Generally, the dose-response curves were bell-shaped. The mechanisms underlying the activity of aniracetam and its 'therapeutic window' are unknown. Piracetam, another pyrrolidinone derivative was used for comparison. It was active only in six of nine tests and had about one-tenth the potency of aniracetam. The results indicate that aniracetam improves cognitive functions which are impaired by different procedure and in different phases of the learning and memory process.

aniracetam

Ro 13-5057

impaired learning and memory

impaired learning

impaired memory

aniracetam

Ro 13-5057

impaired cognitive functions

hypercapnia

scopolamine

amnesia

amnesia

chloramphenicol

cycloheximide

cycloheximide

hypercapnia

impaired cognitive functions

aniracetam

aniracetam

Piracetam

pyrrolidinone

aniracetam

aniracetam


Nicotine potentiation of morphine-induced catalepsy in mice.

In the present study, effects of nicotine on catalepsy induced by morphine in mice have been investigated. Morphine but not nicotine induced a dose-dependent catalepsy. The response of morphine was potentiated by nicotine. Intraperitoneal administration of atropine, naloxone, mecamylamine, and hexamethonium to mice reduced catalepsy induced by a combination of morphine with nicotine. Intracerebroventricular injection of atropine, hexamethonium, and naloxone also decreased catalepsy induced by morphine plus nicotine. Intraperitoneal administration of atropine, but not intraperitoneal or intracerebroventricular injection of hexamethonium, decreased the effect of a single dose of morphine. It was concluded that morphine catalepsy can be elicited by opioid and cholinergic receptors, and the potentiation of morphine induced by nicotine may also be mediated through cholinergic receptor mechanisms.

Nicotine

morphine

catalepsy

nicotine

catalepsy

morphine

Morphine

nicotine

catalepsy

morphine

nicotine

atropine

naloxone

mecamylamine

hexamethonium

catalepsy

morphine

nicotine

atropine

hexamethonium

naloxone

catalepsy

morphine

nicotine

atropine

hexamethonium

morphine

morphine

catalepsy

morphine

nicotine


Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

cardiotoxicity

doxorubicin

cyclophosphamide

doxorubicin

cyclophosphamide

breast cancer

Myocet

doxorubicin

cyclophosphamide

doxorubicin

cardiotoxicity

breast cancer

MBC

MBC

Myocet

doxorubicin

cyclophosphamide

toxicity

Cardiotoxicity

congestive heart failure

CHF

tumor

CHF

cardiotoxicity

doxorubicin

neutropenia

Myocet

doxorubicin

cardiotoxicity

neutropenia

cyclophosphamide

MBC


Protective effect of a specific platelet-activating factor antagonist, BN 52021, on bupivacaine-induced cardiovascular impairments in rats.

Administration of the local anaesthetic bupivacaine (1.5 or 2 mg/kg, i.v.) to rats elicited a marked decrease of mean arterial blood pressure (MBP) and heart rate (HR) leading to death (in 67% or 90% of animals respectively). Intravenous injection of the specific platelet-activating factor (PAF) antagonist BN 52021 (10 mg/kg), 30 min before bupivacaine administration (2 mg/kg i.v.) suppressed both the decrease of MBP and HR. In contrast, doses of 1 mg/kg BN 52021 given 30 min before or 10 mg/kg administered 5 min before i.v. injection of bupivacaine were ineffective. When BN 52021 (20 mg/kg i.v.) was injected immediately after bupivacaine (2 mg/kg), a partial reversion of the decrease of MBP and HR was observed, whereas the dose of 10 mg/kg was ineffective. A partial recovery of bupivacaine-induced ECG alterations was observed after pretreatment of the rats with BN 52021. Since the administration of BN 52021, at all doses studied, did not alter MBP and HR at the doses used, the bulk of these results clearly demonstrate a protective action of BN 52021, a specific antagonist of PAF, against bupivacaine-induced cardiovascular toxicity. Thus, consistent with its direct effect on heart, PAF appears to be implicated in bupivacaine-induced cardiovascular alterations.

BN 52021

bupivacaine

cardiovascular impairments

bupivacaine

decrease of
heart rate (HR)

BN 52021

bupivacaine

decrease of MBP and HR

decrease of MBP

decrease of
HR

BN 52021

bupivacaine

BN 52021

bupivacaine

decrease of MBP and HR

decrease of MBP

decrease of
HR

bupivacaine

BN 52021

BN 52021

BN 52021

bupivacaine

cardiovascular toxicity

bupivacaine

cardiovascular alterations


Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity.

Increased extracellular concentrations of uridine (Urd) have been reported to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration, the ability of benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo, increases the plasma concentration of Urd in a dose-dependent manner, without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL), the continued administration of AZT plus daily BAU (300 mg/kg, orally) partially reversed AZT-induced anemia and leukopenia (P less than .05), increased peripheral reticulocytes (to 4.9%, P less than .01), increased cellularity in the marrow, and improved megaloblastosis. When coadministered with AZT from the onset of drug administration, BAU reduced AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L, BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.

Benzylacyclouridine

azidothymidine

marrow suppression

immunodeficiency

uridine

Urd

azidothymidine

AZT

immunodeficiency

toxicities

Urd

benzylacyclouridine

BAU

AZT

anemia

leukopenia

Urd

Urd

Urd

toxicity

anemic

leukopenic

AZT

AZT

BAU

AZT

anemia

leukopenia

megaloblastosis

AZT

BAU

AZT

marrow toxicity

BAU

AZT


Cyclophosphamide-induced cystitis in freely-moving conscious rats: behavioral approach to a new model of visceral pain.

PURPOSE: To develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis. MATERIALS AND METHODS: CP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v. RESULTS: CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all. CONCLUSIONS: Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.

Cyclophosphamide

cystitis

visceral pain

visceral pain

Cyclophosphamide

CP

acrolein

cystitis

CP

morphine

CP

naloxone

CP

morphine

CP

CP

acrolein

CP

Morphine

behavioral disorders

CP

naloxone

morphine

edema

CP

CP

acrolein

CP

acrolein

CP

cystitis

visceral pain

painful syndromes


Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine.

Eight cancer patients in the terminal stages of the disease treated with high doses of intravenous morphine developed hyperalgesia. All cases were retrospectively sampled from three different hospitals in Copenhagen. Five patients developed universal hyperalgesia and hyperesthesia which in 2 cases were accompanied by myoclonus. In 3 patients a pre-existing neuralgia increased to excruciating intensity and in 2 of these cases myoclonus occurred simultaneously. Although only few clinical descriptions of the relationship between hyperalgesia/myoclonus and high doses of morphine are available, experimental support from animal studies indicates that morphine, or its metabolites, plays a causative role for the observed behavioural syndrome. The possible mechanisms are discussed and treatment proposals given suggesting the use of more efficacious opioids with less excitatory potency in these situations.

Hyperalgesia

myoclonus

cancer

morphine

cancer

morphine

hyperalgesia

hyperalgesia

hyperesthesia

myoclonus

neuralgia

myoclonus

hyperalgesia

myoclonus

morphine

morphine


A prospective study of adverse reactions associated with vancomycin therapy.

A prospective evaluation of the efficacy and safety of vancomycin was conducted in 54 consecutive patients over a 16-month period. Vancomycin was curative in 95% of 43 patients with proven infection. Drugs were ceased in six patients because of adverse reactions; in three of these vancomycin was considered the likely cause. Reactions included thrombophlebitis (20 of 54 patients), rash (4 of 54), nephrotoxicity (4 of 50), proteinuria (1 of 50) and ototoxicity (1 of 11 patients tested by audiometry). Thrombophlebitis occurred only with infusion through peripheral cannulae; nephrotoxicity and ototoxicity were confined to patients receiving an aminoglycoside plus vancomycin. We conclude that vancomycin, administered appropriately, constitutes safe, effective therapy for infections caused by susceptible bacteria.

vancomycin

vancomycin

Vancomycin

infection

vancomycin

thrombophlebitis

rash

nephrotoxicity

proteinuria

ototoxicity

Thrombophlebitis

nephrotoxicity

ototoxicity

aminoglycoside

vancomycin

vancomycin

infections


Blockade of both D-1 and D-2 dopamine receptors may induce catalepsy in mice.

1. The catalepsy induced by dopamine antagonists has been tested and the possible dopamine subtypes involved in catalepsy was determined. 2. Dopamine antagonist fluphenazine, D-1 antagonist SCH 23390 or D-2 antagonist sulpiride induced catalepsy. The effect of fluphenazine and sulpiride was dose-dependent. Combination of SCH 23390 with sulpiride did not induce catalepsy potentiation. 3. D-1 agonist SKF 38393 or D-2 agonist quinpirole decreased the catalepsy induced by fluphenazine, SCH 23390 or sulpiride. 4. Combination of SKF 38393 with quinpirole did not cause potentiated inhibitory effect on catalepsy induced by dopamine antagonists. 5. The data may indicate that although D-2 receptor blockade is involved in catalepsy, the D-1 receptor may plan a role.

dopamine

catalepsy

catalepsy

dopamine

dopamine

catalepsy

Dopamine

fluphenazine

SCH 23390

sulpiride

catalepsy

fluphenazine

sulpiride

SCH 23390

sulpiride

catalepsy

SKF 38393

quinpirole

catalepsy

fluphenazine

SCH 23390

sulpiride

SKF 38393

quinpirole

catalepsy

dopamine

catalepsy


Dextran-etodolac conjugates: synthesis, in vitro and in vivo evaluation.

Etodolac (E), is a non-narcotic analgesic and antiinflammatory drug. A biodegradable polymer dextran has been utilized as a carrier for synthesis of etodolac-dextran conjugates (ED) to improve its aqueous solubility and reduce gastrointestinal side effects. An activated moiety, i.e. N-acylimidazole derivative of etodolac (EAI), was condensed with the polysaccharide polymer dextran of different molecular weights (40000, 60000, 110000 and 200000). IR spectral data confirmed formation of ester bonding in the conjugates. Etodolac contents were evaluated by UV-spectrophotometric analysis. The molecular weights were determined by measuring viscosity using the Mark-Howink-Sakurada equation. In vitro hydrolysis of ED was done in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (v/v) human plasma (pH 7.4). At pH 9, a higher rate of etodolac release from ED was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. In vivo investigations were performed in animals. Acute analgesic and antiinflammatory activities were ascertained using acetic acid induced writhing model (mice) and carrageenan-induced rat paw edema model, respectively. In comparison to control, E and ED1-ED4 showed highly significant analgesic and antiinflammatory activities (p <0.001). Biological evaluation suggested that conjugates (ED1-ED4) retained comparable analgesic and antiinflammatory activities with remarkably reduced ulcerogenicity as compared to their parent drug--etodolac.

Dextran

etodolac

Etodolac

E

dextran

etodolac

dextran

N-acylimidazole

etodolac

EAI

dextran

Etodolac

etodolac

acetic acid

writhing

carrageenan

edema

E

etodolac


Hypersensitivity myocarditis complicating hypertrophic cardiomyopathy heart.

The present report describes a case of eosinophilic myocarditis complicating hypertrophic cardiomyopathy. The 47-year-old female patient, known to have hypertrophic cardiomyopathy, was admitted with biventricular failure and managed aggressively with dobutamine infusion and other drugs while being assessed for heart transplantation. On transthoracic echocardiogram, she had moderate left ventricular dysfunction with regional variability and moderate mitral regurgitation. The recipient's heart showed the features of apical hypertrophic cardiomyopathy and myocarditis with abundant eosinophils. Myocarditis is rare and eosinophilic myocarditis is rarer. It is likely that the hypersensitivity (eosinophilic) myocarditis was related to dobutamine infusion therapy. Eosinophilic myocarditis has been reported with an incidence of 2.4% to 7.2% in explanted hearts and may be related to multidrug therapy.

Hypersensitivity

myocarditis

hypertrophic cardiomyopathy

eosinophilic myocarditis

eosinophilic

myocarditis

hypertrophic cardiomyopathy

hypertrophic cardiomyopathy

biventricular failure

dobutamine

left ventricular dysfunction

mitral regurgitation

hypertrophic cardiomyopathy

myocarditis

Myocarditis

eosinophilic myocarditis

eosinophilic

myocarditis

hypersensitivity

eosinophilic

myocarditis

dobutamine

Eosinophilic myocarditis

Eosinophilic

myocarditis


All- trans-retinoic acid-induced erythema nodosum in patients with acute promyelocytic leukemia.

Erythema nodosum associated with all- trans-retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is very rare. We describe four patients with classic APL who developed erythema nodosum during ATRA therapy. Fever and subsequent multiple painful erythematous nodules over extremities developed on D11, D16, D17, and D19, respectively, after ATRA therapy. The skin biopsy taken from each patient was consistent with erythema nodosum. All patients received short course of steroids. Fever subsided rapidly and the skin lesions regressed completely. All patients achieved complete remission without withdrawal of ATRA. ATRA seemed to be the most possible etiology of erythema nodosum in our patients. Short-term use of steroid is very effective in ATRA-induced erythema nodosum.

All- trans-retinoic acid

erythema nodosum

acute promyelocytic leukemia

Erythema nodosum

all- trans-retinoic acid

ATRA

acute promyelocytic leukemia

APL

APL

erythema nodosum

ATRA

Fever

painful

erythematous nodules

ATRA

erythema nodosum

steroids

Fever

ATRA

ATRA

erythema nodosum

steroid

ATRA

erythema nodosum


Delayed-onset heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia presents 5 to 12 days after heparin exposure, with or without arterial or venous thromboemboli. Delayed recognition and treatment of heparin-induced thrombocytopenia contribute to poor patient outcomes. OBJECTIVE: To describe and increase awareness of a clinical scenario in which the onset or manifestations of heparin-induced thrombocytopenia are delayed. DESIGN: Retrospective case series. SETTING: Three large urban hospitals (with active cardiovascular surgery programs). PATIENTS: 14 patients seen over a 3-year period in whom heparin-induced thrombocytopenia became apparent on delayed presentation with thromboembolic complications. MEASUREMENTS: Platelet counts, onset of objectively determined thromboembolism, results of heparin-induced platelet factor 4 antibody tests, and outcomes. RESULTS: Patients went home after hospitalizations that had included heparin exposure--in most cases, with no thrombocytopenia recognized--only to return to the hospital (median, day 14) with thromboembolic complications. Thromboemboli were venous (12 patients, 7 with pulmonary emboli) or arterial (4 patients) or both. Platelet counts were mildly decreased in all but 2 patients on second presentation. On readmission, 11 patients received therapeutic heparin, which worsened the patients' clinical condition and, in all 11 cases, decreased the platelet count (mean at readmission, 143 x 10(9) cells/L; mean nadir after heparin re-exposure, 39 x 10(9) cells/L). Results of serologic tests for heparin-induced antibodies were positive in all patients. Subsequent treatments included alternative anticoagulants (11 patients), thrombolytic drugs (3 patients), inferior vena cava filters (3 patients) and, eventually, warfarin (11 patients). Three patients died. CONCLUSIONS: Delayed-onset heparin-induced thrombocytopenia is increasingly being recognized. To avoid disastrous outcomes, physicians must consider heparin-induced thrombocytopenia whenever a recently hospitalized patient returns with thromboembolism; therapy with alternative anticoagulants, not heparin, should be initiated.

heparin

thrombocytopenia

Heparin

thrombocytopenia

heparin

arterial or venous thromboemboli

arterial thromboemboli

venous thromboemboli

heparin

thrombocytopenia

heparin

thrombocytopenia

heparin

thrombocytopenia

thromboembolic

thromboembolism

heparin

heparin

thrombocytopenia

thromboembolic

Thromboemboli

pulmonary emboli

heparin

heparin

heparin

warfarin

heparin

thrombocytopenia

heparin

thrombocytopenia

thromboembolism

heparin


Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine.

OBJECTIVE: To compare the antihypertensive efficacy of a new angiotensin II antagonist, valsartan, with a reference therapy, amlodipine. METHODS: One hundred sixty-eight adult outpatients with mild to moderate hypertension were randomly allocated in double-blind fashion and equal number to receive 80 mg valsartan or 5 mg amlodipine for 12 weeks. After 8 weeks of therapy, in patients whose blood pressure remained uncontrolled, 5 mg amlodipine was added to the initial therapy. Patients were assessed at 4, 8, and 12 weeks. The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure at 8 weeks. Secondary variables included change in sitting systolic blood pressure and responder rates. RESULTS: Both valsartan and amlodipine were effective at lowering blood pressure at 4, 8, and 12 weeks. Similar decreases were observed in both groups, with no statistically significant differences between the groups for any variable analyzed. For the primary variable the difference was 0.5 mm Hg in favor of valsartan (p = 0.68; 95% confidence interval, -2.7 to 1.7). Responder rates at 8 weeks were 66.7% for valsartan and 60.2% for amlodipine (p = 0.39). Both treatments were well tolerated. The incidence of drug-related dependent edema was somewhat higher in the amlodipine group, particularly at a dose of 10 mg per day (2.4% for 80 mg valsartan; 3.6% for 5 mg amlodipine; 0% for valsartan plus 5 mg amlodipine; 14.3% for 10 mg amlodipine). CONCLUSIONS: The data show that valsartan is at least as effective as amlodipine in the treatment of mild to moderate hypertension. The results also show valsartan to be well tolerated and suggest that it is not associated with side effects characteristic of this comparator class, dihydropyridine calcium antagonists.

Valsartan

angiotensin II

hypertension

amlodipine

angiotensin II

valsartan

amlodipine

hypertension

valsartan

amlodipine

amlodipine

valsartan

amlodipine

valsartan

valsartan

amlodipine

edema

amlodipine

valsartan

amlodipine

valsartan

amlodipine

amlodipine

valsartan

amlodipine

hypertension

valsartan

dihydropyridine

calcium


KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity.

KF17837 is a novel selective adenosine A2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680 (10 micrograms), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.

adenosine

adenosine

cataleptic

adenosine

CGS 21680

catalepsy

haloperidol

reserpine

L-DOPA

benserazide

adenosine

adenosine

parkinsonism


Some central effects of repeated treatment with fluvoxamine.

We investigated the effect of repeated treatment with fluvoxamine, a selective serotonin uptake inhibitor, on behavioral effects of dopaminomimetics and methoxamine and on the animal behavior in the "behavioral despair" test. A repeated treatment with fluvoxamine (twice daily for 14 days) potentiated in mice and in rats (weaker) the amphetamine-induced hyperactivity. The hyperactivity induced by nomifensine in mice remained unaffected by fluvoxamine. The stimulation of locomotor activity by intracerebroventricularly administered methoxamine was not affected by repeated treatment with fluvoxamine. Given three times fluvoxamine had no effect on the immobilization time in the "behavioral despair" test in rats. The results indicate that fluvoxamine given repeatedly acts differently than citalopram, another selective serotonin uptake inhibitor, and differs also from other antidepressant drugs.

fluvoxamine

fluvoxamine

serotonin

methoxamine

fluvoxamine

amphetamine

hyperactivity

hyperactivity

nomifensine

fluvoxamine

methoxamine

fluvoxamine

fluvoxamine

fluvoxamine

citalopram

serotonin


Severe congestive heart failure patient on amiodarone presenting with myxedemic coma: a case report.

This is a case report of myxedema coma secondary to amiodarone-induced hypothyroidism in a patient with severe congestive heart failure (CHF). To our knowledge and after reviewing the literature there is one case report of myxedema coma during long term amiodarone therapy. Myxedema coma is a life threatening condition that carries a mortality reaching as high as 20% with treatment. The condition is treated with intravenous thyroxine (T4) or intravenous tri-iodo-thyronine (T3). Patients with CHF on amiodarone may suffer serious morbidity and mortality from hypothyroidism, and thus may deserve closer follow up for thyroid stimulating hormone (TSH) levels. This case report carries an important clinical application given the frequent usage of amiodarone among CHF patients. The myriad clinical presentation of myxedema coma and its serious morbidity and mortality stresses the need to suspect this clinical syndrome among CHF patients presenting with hypotension, weakness or other unexplained symptoms.

congestive heart failure

amiodarone

myxedemic coma

myxedemic

coma

myxedema coma

myxedema

coma

amiodarone

hypothyroidism

congestive heart failure

CHF

myxedema coma

myxedema

coma

amiodarone

Myxedema coma

Myxedema

coma

thyroxine

tri-iodo-thyronine

CHF

amiodarone

hypothyroidism

amiodarone

CHF

myxedema coma

myxedema

coma

CHF

hypotension

weakness


Fear-potentiated startle, but not light-enhanced startle, is enhanced by anxiogenic drugs.

RATIONALE AND OBJECTIVES: The light-enhanced startle paradigm (LES) is suggested to model anxiety, because of the non-specific cue and the long-term effect. In contrast, the fear-potentiated startle (FPS) is suggested to model conditioned fear. However, the pharmacological profiles of these two paradigms are very similar. The present study investigated the effects of putative anxiogenic drugs on LES and FPS and aimed at determining the sensitivity of LES for anxiogenic drugs and to potentially showing a pharmacological differentiation between these two paradigms. METHODS: Male Wistar rats received each dose of the alpha(2)-adrenoceptor antagonist yohimbine (0.25-1.0mg/kg), the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP, 0.5-2.0mg/kg) or the GABA(A) inverse receptor agonist pentylenetetrazole (PTZ, 3-30mg/kg) and were subsequently tested in either LES or FPS. RESULTS: None of the drugs enhanced LES, whereas mCPP increased percentage FPS and yohimbine increased absolute FPS values. Furthermore, yohimbine increased baseline startle amplitude in the LES, while mCPP suppressed baseline startle in both the LES and FPS and PTZ suppressed baseline startle in the FPS. CONCLUSIONS: In contrast to findings in the FPS paradigm, none of the drugs were able to exacerbate the LES response. Thus, a clear pharmacological differentiation was found between LES and FPS.

startle

startle

startle

anxiety

startle

yohimbine

m-chlorophenylpiperazine

mCPP

GABA

pentylenetetrazole

PTZ

mCPP

yohimbine

yohimbine

startle

mCPP

startle

PTZ

startle


Proteinase 3-antineutrophil cytoplasmic antibody-(PR3-ANCA) positive necrotizing glomerulonephritis after restarting sulphasalazine treatment.

A 59-year-old woman with ulcerative colitis developed red eyes, pleural effusion, eosinophilia and urinary abnormalities after restarting of sulphasalazine treatment. Light microscopy of a kidney biopsy revealed segmental necrotizing glomerulonephritis without deposition of immunoglobulin or complement. Proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) titer was elevated at 183 ELISA units (EU) in sera (normal range less than 10 EU), myeloperoxidase-ANCA was negative. PR3-ANCA titer was 250 and 1,070 EU in pleural effusions on right and left side, respectively. Although cessation of sulphasalazine treatment resulted in improvements in fever, red eyes, chest pain, titer of C-reactive protein and volume of the pleural effusions, we initiated steroid therapy, because PR3-ANCA titer rose to 320 EU, eosinophil count increased to 1,100 cells/microl, and the pleural effusion remained. One month after steroid therapy, the pleural effusion disappeared, and PR3-ANCA titer normalized 3 months later. This case suggests that sulphasalazine can induce PR3-ANCA-positive necrotizing glomerulonephritis.

glomerulonephritis

sulphasalazine

ulcerative colitis

red eyes

pleural effusion

eosinophilia

urinary abnormalities

sulphasalazine

pleural effusions

sulphasalazine

fever

red eyes

chest pain

pleural effusions

steroid

pleural effusion

steroid

pleural effusion

sulphasalazine

glomerulonephritis


Is phenytoin administration safe in a hypothermic child?

A male neonate with a Chiari malformation and a leaking myelomeningocoele underwent ventriculoperitoneal shunt insertion followed by repair of myelomeningocoele. During anaesthesia and surgery, he inadvertently became moderately hypothermic. Intravenous phenytoin was administered during the later part of the surgery for seizure prophylaxis. Following phenytoin administration, the patient developed acute severe bradycardia, refractory to atropine and adrenaline. The cardiac depressant actions of phenytoin and hypothermia can be additive. Administration of phenytoin in the presence of hypothermia may lead to an adverse cardiac event in children. As phenytoin is a commonly used drug, clinicians need to be aware of this interaction.

phenytoin

hypothermic

Chiari malformation

hypothermic

phenytoin

seizure

phenytoin

bradycardia

atropine

adrenaline

phenytoin

hypothermia

phenytoin

hypothermia

phenytoin


Amisulpride related tic-like symptoms in an adolescent schizophrenic.

Tic disorders can be effectively treated by atypical antipsychotics such as risperidone, olanzapine and ziprasidone. However, there are two case reports that show tic-like symptoms, including motor and phonic variants, occurring during treatment with quetiapine or clozapine. We present a 15-year-old girl schizophrenic who developed frequent involuntary eye-blinking movements after 5 months of amisulpride treatment (1000 mg per day). The tic-like symptoms resolved completely after we reduced the dose of amisulpride down to 800 mg per day. However, her psychosis recurred after the dose reduction. We then placed her on an additional 100 mg per day of quetiapine. She has been in complete remission under the combined medications for more than one year and maintains a fair role function. No more tic-like symptoms or other side effects have been reported. Together with previously reported cases, our patient suggests that tic-like symptoms might occur in certain vulnerable individuals during treatment with atypical antipsychotics such as quetiapine, clozapine, or amisulpride.

Amisulpride

tic-like symptoms

schizophrenic

Tic disorders

risperidone

olanzapine

ziprasidone

tic-like symptoms

quetiapine

clozapine

schizophrenic

involuntary eye-blinking movements

amisulpride

tic-like symptoms

amisulpride

psychosis

quetiapine

tic-like symptoms

tic-like symptoms

quetiapine

clozapine

amisulpride


Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.

BACKGROUND: Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15-24, 1971). There are no published ASA studies using the multiple dosing paradigm of GDs 6 to 17. Objectives of the current study were to compare results between Sprague-Dawley (SD) and Wistar strains when ASA is administered on GD 9, 10, or 11; to compare the malformation patterns following single and multiple dosings during organogenesis in SD rats; and to test the hypothesis that maternal gastrointestinal toxicity confounds the detection of low incidence malformations with ASA when a multiple dosing paradigm is used. METHODS: ASA was administered as a single dose on GD 9 (0, 250, 500, or 625 mg/kg), 10 (0, 500, 625, or 750 mg/kg), or 11 (0, 500, 750, or 1000 mg/kg) and from GD 6 to GD 17 (0, 50, 125, or 250 mg/kg a day) in the multiple dose study to SD rats. Animals were killed on GD 21, and fetuses were examined viscerally. RESULTS: The literature evaluation suggested that NSAIDs induce ventricular septal defects (VSDs) and midline defects (MDs) in rats and diaphragmatic hernia (DH), MDs, and VSDs in rabbits (Cook JC et al., 2003); hence, the present study focused on these malformations, even though ASA induces several other low-incidence malformations. In single dose studies, DH, MD, and VSD were induced on GDs 9 and 10. VSD also was noted following treatment on GD 11. In contrast, DH and MD were noted in the multiple dose study design only in the high-dose group, and VSD was noted across all dose groups. CONCLUSIONS: High concordance in major developmental anomalies between Wistar and SD rats were noted with the exception of VSD in the SD rats and hydrocephalus in the Wistar rats. Variations and malformations were similar when ASA was administered as a single dose or during the period of organogenesis (GDs 6 to 17). It was also evident that, by titrating the dose to achieve a maximum tolerated dose, malformations that normally occur at low incidence, as reported from previous single dose studies, could also be induced with ASA given at multiple doses.

aspirin

acetylsalicylic acid

developmental anomalies

Aspirin

acetylsalicylic acid

ASA

developmental anomalies

ASA

ASA

gastrointestinal toxicity

malformations

ASA

ASA

ventricular septal defects

VSDs

midline defects

MDs

diaphragmatic hernia

DH

MDs

VSDs

malformations

ASA

malformations

DH

MD

VSD

VSD

DH

MD

VSD

developmental anomalies

VSD

hydrocephalus

malformations

ASA

malformations

ASA


Torsade de pointes induced by metoclopramide in an elderly woman with preexisting complete left bundle branch block.

There is a growing list of drugs implicated in acquired long QT syndrome and torsade de pointes. However, the torsadogenic potential of metoclopramide, a commonly used antiemetic and prokinetic drug, has not been reported in the literature, despite its chemical similarity to procainamide. We report on a 92-year-old woman with preexisting complete left bundle branch block who developed torsade de pointes after intravenous and oral administration of metoclopramide. This patient also developed torsade de pointes when cisapride and erythromycin were given simultaneously. These two episodes were suppressed successfully after discontinuing the offending drugs and administering class IB drugs. This is the first documentation that metoclopramide provokes torsade de pointes clinically. Metoclopramide should be used cautiously in patients with a risk of torsade de pointes.

Torsade de pointes

metoclopramide

left bundle branch block

long QT syndrome

torsade de pointes

metoclopramide

procainamide

left bundle branch block

torsade de pointes

metoclopramide

torsade de pointes

cisapride

erythromycin

metoclopramide

torsade de pointes

Metoclopramide

torsade de pointes


Apomorphine: an underutilized therapy for Parkinson's disease.

Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study. A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings. Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy. In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias. The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.

Apomorphine

Parkinson's disease

Apomorphine

Parkinson's disease

Parkinson's disease

apomorphine

apomorphine

levodopa

apomorphine

apomorphine

dopamine

apomorphine

apomorphine

levodopa

dyskinesias

apomorphine

psychiatric

apomorphine

Parkinson's disease


Fatal excited delirium following cocaine use: epidemiologic findings provide new evidence for mechanisms of cocaine toxicity.

We describe an outbreak of deaths from cocaine-induced excited delirium (EDDs) in Dade County, Florida between 1979 and 1990. From a registry of all cocaine-related deaths in Dade County, Florida, from 1969-1990, 58 EDDs were compared with 125 victims of accidental cocaine overdose without excited delirium. Compared with controls, EDDs were more frequently black, male, and younger. They were less likely to have a low body mass index, and more likely to have died in police custody, to have received medical treatment immediately before death, to have survived for a longer period, to have developed hyperthermia, and to have died in summer months. EDDs had concentrations of cocaine and benzoylecgonine in autopsy blood that were similar to those for controls. The epidemiologic findings are most consistent with the hypothesis that chronic cocaine use disrupts dopaminergic function and, when coupled with recent cocaine use, may precipitate agitation, delirium, aberrant thermoregulation, rhabdomyolysis, and sudden death.

delirium

cocaine

cocaine

toxicity

cocaine

delirium

EDDs

cocaine

EDDs

cocaine

overdose

delirium

EDDs

hyperthermia

EDDs

cocaine

benzoylecgonine

cocaine

cocaine

agitation

delirium

rhabdomyolysis

sudden death


Heparin-induced thrombocytopenia, thrombosis, and hemorrhage.

Sixty-two patients with a heparin-induced thrombocytopenia are reported. Clinical manifestations of this disorder include hemorrhage or, more frequently, thromboembolic events in patients receiving heparin. Laboratory testing has revealed a falling platelet count, increased resistance to heparin, and aggregation of platelets by the patient's plasma when heparin is added. Immunologic testing has demonstrated the presence of a heparin-dependent platelet membrane antibody. The 20 deaths, 52 hemorrhagic and thromboembolic complications, and 21 surgical procedures to manage the complications confirm the seriousness of the disorder. Specific risk factors have not been identified; therefore, all patients receiving heparin should be monitored. If the platelet count falls to less than 100,000/mm3, while the patient is receiving heparin, platelet aggregation testing, using the patient's plasma, is indicated. Management consists of cessation of heparin, platelet anti-aggregating agents, and alternate forms of anticoagulation when indicated.

Heparin

thrombocytopenia

thrombosis

hemorrhage

heparin

thrombocytopenia

hemorrhage

thromboembolic

heparin

a falling platelet count

heparin

heparin

heparin

hemorrhagic complications

thromboembolic complications

heparin

heparin

platelet aggregation

heparin


Cardiac toxicity of 5-fluorouracil. Report of a case of spontaneous angina.

We report a case of a patient with colon carcinoma and liver metastasis who presented chest pain after 5-fluorouracil (5-FU) administration. Clinical electrocardiographic evolution was similar to that observed in Prinzmetal's angina, and chest pain promptly resolved with nifedipine. These data suggest that coronary spasm may be the cause of cardiotoxicity due to 5-FU, and that calcium antagonists may probably be used in the prevention or treatment of 5-FU cardiotoxicity.

Cardiac toxicity

angina

colon carcinoma

metastasis

chest pain

Prinzmetal's angina

chest pain

nifedipine

coronary spasm

cardiotoxicity

calcium

cardiotoxicity