Serotonin syndrome from venlafaxine-tranylcypromine interaction.

Excessive stimulation of serotonin 5HT1A receptors causes a syndrome of serotonin excess that consists of shivering, muscle rigidity, salivation, confusion, agitation and hyperthermia. The most common cause of this syndrome is an interaction between a monoamine oxidase inhibitor (MAOI) and a specific serotonin reuptake inhibitor. Venlafaxine is a new antidepressant agent that inhibits the reuptake of serotonin and norepinephrine. We report a venlafaxine-MAOI interaction that resulted in the serotonin syndrome in a 23-y-old male who was taking tranylcypromine for depression. He had been well until the morning of presentation when he took 1/2 tab of venlafaxine. Within 2 h he became confused with jerking movements of his extremities, tremors and rigidity. He was brought directly to a hospital where he was found to be agitated and confused with shivering, myoclonic jerks, rigidity, salivation and diaphoresis. His pupils were 7 mm and sluggishly reactive to light. Vital signs were: blood pressure 120/67 mm Hg, heart rate 127/min, respiratory rate 28/min, and temperature 97 F. After 180 mg of diazepam i.v. he remained tremulous with muscle rigidity and clenched jaws. He was intubated for airway protection and because of hypoventilation, and was paralyzed to control muscle rigidity. His subsequent course was remarkable for non-immune thrombocytopenia which resolved. The patient's maximal temperature was 101.2 F and his CPK remained < 500 units/L with no other evidence of rhabdomyolysis. His mental status normalized and he was transferred to a psychiatry ward. This patient survived without sequelae due to the aggressive sedation and neuromuscular paralysis.

Serotonin syndrome

venlafaxine

tranylcypromine

serotonin

serotonin

muscle rigidity

salivation

confusion

agitation

hyperthermia

serotonin

Venlafaxine

serotonin

norepinephrine

venlafaxine

serotonin syndrome

tranylcypromine

depression

venlafaxine

tremors

rigidity

myoclonic jerks

rigidity

salivation

diazepam

muscle rigidity

hypoventilation

paralyzed

muscle rigidity

thrombocytopenia

rhabdomyolysis

paralysis


Effect of nondopaminergic drugs on L-dopa-induced dyskinesias in MPTP-treated monkeys.

A group of four monkeys was rendered parkinsonian with the toxin MPTP. They were then treated chronically with L-DOPA/benserazide 50/12.5 mg/kg given orally daily for 2 months. This dose produced a striking antiparkinsonian effect, but all animals manifested dyskinesia. A series of agents acting primarily on neurotransmitters other than dopamine were then tested in combination with L-DOPA to see if the dyskinetic movements would be modified. Several drugs, including clonidine, physostigmine, methysergide, 5-MDOT, propranolol, and MK-801, markedly reduced the dyskinetic movements but at the cost of a return of parkinsonian symptomatology. However, yohimbine and meperidine reduced predominantly the dyskinetic movements. Baclofen was also useful in one monkey against a more dystonic form of dyskinesia. Atropine converted the dystonic movements into chorea.

L-dopa

dyskinesias

MPTP

parkinsonian

MPTP

L-DOPA/benserazide

dyskinesia

dopamine

L-DOPA

dyskinetic

clonidine

physostigmine

methysergide

propranolol

dyskinetic

parkinsonian

yohimbine

meperidine

dyskinetic

Baclofen

dystonic

dyskinesia

Atropine

dystonic

chorea


CCNU (lomustine) toxicity in dogs: a retrospective study (2002-07).

OBJECTIVE: To describe the incidence of haematological, renal, hepatic and gastrointestinal toxicities in tumour-bearing dogs receiving 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). DESIGN: The medical records of 206 dogs that were treated with CCNU at the Melbourne Veterinary Specialist Centre between February 2002 and December 2007 were retrospectively evaluated. RESULTS: Of the 206 dogs treated with CCNU, 185 met the inclusion criteria for at least one class of toxicity. CCNU was used most commonly in the treatment of lymphoma, mast cell tumour, brain tumour, histiocytic tumours and epitheliotropic lymphoma. Throughout treatment, 56.9% of dogs experienced neutropenia, 34.2% experienced anaemia and 14.2% experienced thrombocytopenia. Gastrointestinal toxicosis was detected in 37.8% of dogs, the most common sign of which was vomiting (24.3%). Potential renal toxicity and elevated alanine transaminase (ALT) concentration were reported in 12.2% and 48.8% of dogs, respectively. The incidence of hepatic failure was 1.2%. CONCLUSIONS: CCNU-associated toxicity in dogs is common, but is usually not life threatening.

CCNU

lomustine

toxicity

haematological toxicities

renal toxicities

hepatic toxicities

gastrointestinal toxicities

CCNU

CCNU

CCNU

toxicity

CCNU

lymphoma

mast cell tumour

brain tumour

histiocytic tumours

epitheliotropic lymphoma

neutropenia

anaemia

thrombocytopenia

Gastrointestinal toxicosis

vomiting

toxicity

alanine

hepatic failure

CCNU

toxicity


Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice.

Several structurally related metabolites of progesterone (3 alpha-hydroxy pregnane-20-ones) and deoxycorticosterone (3 alpha-hydroxy pregnane-21-diol-20-ones) and their 3 beta-epimers were evaluated for protective activity against pilocarpine-, kainic acid- and N-methyl-D-aspartate (NMDA)-induced seizures in mice. Steroids with the 3-hydroxy group in the alpha-position and 5-H in the alpha- or beta-configurations were highly effective in protecting against pilocarpine (416 mg/kg, s.c.)-induced limbic motor seizures and status epilepticus (ED50 values, 7.0-18.7 mg/kg, i.p.). The corresponding epimers with the 3-hydroxy group in the beta-position were also effective but less potent (ED50 values, 33.8-63.5, i.p.). Although the neuroactive steroids were considerably less potent than the benzodiazepine clonazepam in protecting against pilocarpine seizures, steroids with the 5 alpha,3 alpha-configuration had comparable or higher protective index values (TD50 for motor impairment divided by ED50 for seizure protection) than clonazepam, indicating that some neuroactive steroids may have lower relative toxicity. Steroids with the 5 alpha,3 alpha- or 5 beta,3 alpha-configurations also produced a dose-dependent delay in the onset of limbic seizures induced by kainic acid (32 mg/kg, s.c.), but did not completely protect against the seizures. However, when a second dose of the steroid was administered 1 hr after the first dose, complete protection from the kainic acid-induced limbic seizures and status epilepticus was obtained. The steroids also caused a dose-dependent delay in NMDA (257 mg/kg, s.c.)-induced lethality, but did not completely protect against NMDA seizures or lethality. We conclude that neuroactive steroids are highly effective in protecting against pilocarpine- and kainic acid-induced seizures and status epilepticus in mice, and may be of utility in the treatment of some forms of status epilepticus in humans.

steroids

pilocarpine

kainic acid

seizures

status epilepticus

progesterone

3 alpha-hydroxy pregnane-20-ones

deoxycorticosterone

pilocarpine

kainic acid

N-methyl-D-aspartate

NMDA

seizures

Steroids

pilocarpine

seizures

status epilepticus

steroids

benzodiazepine

clonazepam

pilocarpine

seizures

steroids

seizure

clonazepam

steroids

toxicity

Steroids

seizures

kainic acid

seizures

steroid

kainic acid

seizures

status epilepticus

steroids

NMDA

NMDA

seizures

steroids

pilocarpine

kainic acid

seizures

status epilepticus

status epilepticus


The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.

We conducted a double-blind, randomized phase II study to evaluate the safety and activity of combination therapy with N-butyl-deoxynojirimycin (SC-48334) (an alpha-glucosidase I inhibitor) and zidovudine versus zidovudine alone. Patients with 200 to 500 CD4 cells/mm3 who tolerated < or = 12 weeks of prior zidovudine therapy received SC-48334 (1000 mg every 8 h) and zidovudine (100 mg every 8 h) or zidovudine and placebo. Sixty patients received combination therapy and 58, zidovudine and placebo. Twenty-three patients (38%) and 15 (26%), in the combination and zidovudine groups, respectively, discontinued therapy (p = 0.15). The mean SC-48334 steady-state trough level (4.04 +/- 0.99 micrograms/ml) was below the in vitro inhibitory concentration for human immunodeficiency virus (HIV). The mean increase in CD4 cells at week 4 was 73.8 cells/mm3 and 52.4 cells/mm3 for the combination and zidovudine groups, respectively (p > 0.36). For patients with prior zidovudine therapy, the mean change in CD4 cells in the combination and zidovudine groups was 63.7 cells/mm3 and 4.9 cells/mm3 at week 8 and 6.8 cells/mm3 and -45.1 cells/mm3 at week 16, respectively. The number of patients with suppression of HIV p24 antigenemia in the combination and zidovudine groups was six (40%) and two (11%) at week 4 (p = 0.10) and five (45%) and two (14%) at week 24 (p = 0.08), respectively. Diarrhea, flatulence, abdominal pain, and weight loss were common for combination recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

N-butyl-deoxynojirimycin

zidovudine

HIV-1 infection

N-butyl-deoxynojirimycin

zidovudine

zidovudine

zidovudine

zidovudine

zidovudine

zidovudine

zidovudine

immunodeficiency

zidovudine

zidovudine

zidovudine

zidovudine

Diarrhea

flatulence

abdominal pain

weight loss


Recent preclinical and clinical studies with the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB 3717).

CB 3717, N10-propargyl-5,8-dideazafolic acid, is a tight-binding inhibitor of thymidylate synthase (TS) whose cytotoxicity is mediated solely through the inhibition of this enzyme. Recent preclinical studies have focused on the intracellular formation of CB 3717 polyglutamates. Following a 12-hour exposure of L1210 cells to 50 microM [3H]CB 3717, 30% of the extractable radioactivity could be accounted for as CB 3717 tetra- and pentaglutamate, as determined by high-pressure liquid chromatography (HPLC) analyses. As inhibitors of isolated L1210 TS, CB 3717 di-, tri-, tetra- and pentaglutamate are 26-, 87-, 119- and 114-fold more potent than CB 3717, respectively, and their formation may, therefore, be an important determinant of CB 3717 cytotoxicity. In early clinical studies with CB 3717, activity has been seen in breast cancer, ovarian cancer, hepatoma, and mesothelioma. Toxicities included hepatotoxicity, malaise, and dose-limiting nephrotoxicity. This latter effect is thought to be due to drug precipitation within the renal tubule as a result of the poor solubility of CB 3717 under acidic conditions. In an attempt to overcome this problem, a clinical trial of CB 3717 administered with alkaline diuresis is under way. Preliminary results at 400 and 500 mg/m2 suggest that a reduction in nephrotoxicity may have been achieved with only 1 instance of renal toxicity in 10 patients. Hepatotoxicity and malaise are again the most frequent side effects. Evidence of antitumor activity has been seen in 3 patients. Pharmacokinetic investigations have shown that alkaline diuresis does not alter CB 3717 plasma levels or urinary excretion and that satisfactory urinary alkalinization can be readily achieved.

N10-propargyl-5,8-dideazafolic acid

CB 3717

CB 3717

N10-propargyl-5,8-dideazafolic acid

cytotoxicity

CB 3717

CB 3717

CB 3717

CB 3717

CB 3717

cytotoxicity

CB 3717

breast cancer

ovarian cancer

hepatoma

mesothelioma

Toxicities

hepatotoxicity

malaise

nephrotoxicity

CB 3717

CB 3717

nephrotoxicity

renal toxicity

Hepatotoxicity

malaise

CB 3717


Ethopropazine and benztropine in neuroleptic-induced parkinsonism.

In a 12-week controlled study ethopropazine was compared to benztropine in the treatment of parkinsonism induced by fluphenazine enanthate in 60 schizophrenic outpatients. Ethopropazine and benztropine were found to be equally effective in controlling parkinsonian symptoms and were as efficacious as procyclidine, their previous antiparkinsonian drug. However, benztropine treated patients had a significant increase in tardive dyskinesia compared to their condition during procyclindine treatment, and significantly more anxiety and depression than ethopropazine treated patients. This suggests that benztropine is not the anticholinergic drug of choice in the treatment of neuroleptic-induced parkinsonian symptoms, because of its more toxic central and peripheral atropinic effect.

Ethopropazine

benztropine

parkinsonism

ethopropazine

benztropine

parkinsonism

fluphenazine enanthate

schizophrenic

Ethopropazine

benztropine

parkinsonian symptoms

procyclidine

benztropine

tardive dyskinesia

procyclindine

anxiety

depression

ethopropazine

benztropine

parkinsonian symptoms


Effect of alpha-tocopherol and deferoxamine on methamphetamine-induced neurotoxicity.

Methamphetamine (MA)-induced dopaminergic neurotoxicity is believed to be associated with the increased formation of free radicals. This study examined the effect of alpha-tocopherol (alpha-TC), a scavenger of reactive oxygen species, and deferoxamine (DFO), an iron chelator, on the MA-induced neurotoxicity. Male rats were treated with MA (10 mg/kg, every 2 h for four injections). The rat received either alpha-TC (20 mg/kg) intraperitoneally for 3 days and 30 min prior to MA administration or DFO (50 mg/kg) subcutaneously 30 min before MA administration. The concentrations of dopamine (DA), serotonin and their metabolites decreased significantly after MA administration, which was inhibited by the alpha-TC and DFO pretreatment. alpha-TC and DFO attenuated the MA-induced hyperthermia as well as the alterations in the locomotor activity. The level of lipid peroxidation was higher and the reduced glutathione concentration was lower in the MA-treated rats. These changes were significantly attenuated by alpha-TC and DFO. This suggests that alpha-TC and DFO ameliorate the MA-induced neuronal damage by decreasing the level of oxidative stress.

alpha-tocopherol

deferoxamine

methamphetamine

neurotoxicity

Methamphetamine

MA

neurotoxicity

alpha-tocopherol

alpha-TC

oxygen

deferoxamine

DFO

iron

MA

neurotoxicity

MA

alpha-TC

MA

DFO

MA

dopamine

DA

serotonin

MA

alpha-TC

DFO

alpha-TC

DFO

MA

hyperthermia

glutathione

MA

alpha-TC

DFO

alpha-TC

DFO

MA

neuronal damage


Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis.

AIM: Hemorrhagic cystitis (HC) is a limiting side-effect of chemotherapy with ifosfamide (IFS). In the study presented here, we investigated the use of dexamethasone in combination with mesna for the prevention of IFS-induced HC. METHODS: Male Wistar rats (150-200 g; 6 rats per group) were treated with saline or mesna 5 min (i.p.) before and 2 and 6 h after (v.o.) administration of IFS. One, two or three doses of mesna were replaced with dexamethasone alone or with dexamethasone plus mesna. Cystitis was evaluated 24 h after its induction by the changes in bladder wet weight and by macroscopic and microscopic analysis. RESULTS: The replacement of the last dose or the last two doses of mesna with dexamethasone reduced the increase in bladder wet weight induced by IFS by 84.79% and 89.13%, respectively. In addition, it almost abolished the macroscopic and microscopic alterations induced by IFS. Moreover, the addition of dexamethasone to the last two doses of mesna was more efficient than three doses of mesna alone when evaluated microscopically. CONCLUSION: Dexamethasone in combination with mesna was efficient in blocking IFS-induced HC. However, the replacement of last two doses of mesna with saline or all of the mesna doses with dexamethasone did not prevent HC.

dexamethasone

mesna

ifosfamide

hemorrhagic cystitis

hemorrhagic

cystitis

Hemorrhagic cystitis

Hemorrhagic

cystitis

HC

ifosfamide

IFS

dexamethasone

mesna

IFS

HC

mesna

IFS

mesna

dexamethasone

dexamethasone

mesna

Cystitis

mesna

dexamethasone

IFS

IFS

dexamethasone

mesna

mesna

Dexamethasone

mesna

IFS

HC

mesna

mesna

dexamethasone

HC


Behavioral effects of MK-801 on reserpine-treated mice.

The effects of dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, were studied on dopamine-related behaviors induced by reserpine treatments. This study focuses on behavioral syndromes that may used as models for Parkinson's disease, or tardive dyskinesia, and its response after glutamatergic blockage. Reserpine (1 mg/kg), administered once every other day for 4 days, produced increases in orofacial dyskinesia, tongue protrusion and vacuous chewing in mice, which are signs indicative of tardive dyskinesia. Reserpine also produced tremor and catalepsy, which are signs suggestive of Parkinson's disease. MK-801 (0.1 mg/kg), administered 30 min before the observation test, prevented the vacuous chewing movements, tongue protrusions and catalepsy induced by reserpine. However, MK-801 injection produced a significant increase of tremor in reserpine-treated mice. Reserpine (1 mg/kg), administered 90 min before the test and followed by apomophine injection (0.1 mg/kg) 5 min before the test, did not produce oral dyskinesia in mice. On the other hand, reserpine induced increases in tremor and catalepsy compared to control mice. MK-801 (0.1 mg/kg) administration attenuated the catalepsy and tremor induced by reserpine. Pretreatment with reserpine (1 mg/kg) 24 h before the observation test produced increases in vacuous chewing movements and tongue protrusion, as well as increases in tremor and catalepsy, whereas MK-801 (0.1 mg/kg) injection 90 min before the test reversed the effects of reserpine. These results show that reserpine produces different and abnormal movements, which are related to dose and schedule employed and can be considered as parkinsonian-like and tardive dsykinesia signs. The glutamatergic blockage produced by NMDA can restore these signs, such as vacuous chewing movements, tongue protrusions, catalepsy and tremor according to the employed model.

reserpine

dizocilpine

N-methyl-D-aspartate

NMDA

dopamine

reserpine

Parkinson's disease

tardive dyskinesia

Reserpine

orofacial dyskinesia

tardive dyskinesia

Reserpine

tremor

catalepsy

Parkinson's disease

catalepsy

reserpine

tremor

reserpine

Reserpine

apomophine

oral dyskinesia

reserpine

tremor

catalepsy

catalepsy

tremor

reserpine

reserpine

tremor

catalepsy

reserpine

reserpine

abnormal movements

parkinsonian

tardive dsykinesia

NMDA

catalepsy

tremor


Effect of glyceryl trinitrate on the sphincter of Oddi spasm evoked by prostigmine-morphine administration.

OBJECTIVE: In this study the effect of glyceryl trinitrate on the prostigmine-morphine-induced sphincter of Oddi spasm was evaluated in nine female patients with sphincter of Oddi dyskinesia. METHOD: Sphincter of Oddi spasm was induced by prostigmine-morphine administration (0.5 mg prostigmine intramuscularly and 10 mg morphine subcutaneously) and visualized by quantitative hepatobiliary scintigraphy. The entire procedure was repeated during glyceryl trinitrate infusion (Nitrolingual 1 microg/kg/min for 120 min). RESULTS: Prostigmine-morphine provocation caused significant increases in the time to peak activity (Tmax) over the hepatic hilum (HH: 34.33 +/- 5.05 vs. 22.77 +/- 3.26) and the common bile duct (CBD: 60.44 +/- 5.99 vs. 40.0 +/- 2.88) and in the half-time of excretion (T1/2) over the liver parenchyma (LP: 120.04 +/- 16.01 vs. 27.37 +/- 2.19), HH (117.61 +/- 14.71 vs. 31.85 +/- 3.99) and CBD (158.11 +/- 9.18 vs. 40.1 +/- 6.24), indicating a complete spasm at the level of the sphincter of Oddi. Glyceryl trinitrate infusion completely normalized the prostigmine-morphine-induced alterations in these quantitative parameters (TmaX over the LP: 11.33 +/- 1.13; over the HH: 18.88 +/- 1.48; and over the CBD: 36.22 +/- 1.92; and T1/2 over the LP: 28.21 +/- 1.83; over the HH: 33.42 +/- 3.10; and over the CBD: 41.66 +/- 6.33), suggesting an effective sphincter-relaxing effect of glyceryl trinitrate. CONCLUSION: These results provide the first evidence of the effectiveness of glyceryl trinitrate on the morphine-induced sphincter of Oddi spasm in humans. Since glyceryl trinitrate is able to overcome even the drastic effect of morphine, it might be of relevance in the treatment of sphincter of Oddi dyskinesia.

glyceryl trinitrate

sphincter of Oddi spasm

sphincter of Oddi spasm

spasm

prostigmine

morphine

glyceryl trinitrate

prostigmine

morphine

sphincter of Oddi spasm

sphincter of Oddi spasm

spasm

sphincter of Oddi dyskinesia

Sphincter of Oddi spasm

Sphincter of Oddi spasm

spasm

prostigmine

morphine

prostigmine

morphine

glyceryl trinitrate

Nitrolingual

Prostigmine

morphine

spasm

Glyceryl trinitrate

prostigmine

morphine

glyceryl trinitrate

glyceryl trinitrate

morphine

sphincter of Oddi spasm

sphincter of Oddi spasm

spasm

glyceryl trinitrate

morphine

sphincter of Oddi dyskinesia


Effects of acute steroid administration on ventilatory and peripheral muscles in rats.

Occasional case reports have shown that acute myopathy may occur in patients treated with massive doses of corticosteroids. The mechanism of this myopathy is poorly understood. Therefore, 60 male rats were randomly assigned to receive daily injection of saline (C), methylprednisolone (M), or triamcinolone (T) 80 mg/kg/d for 5 d. Nutritional intake, measured daily in 15 animals, showed a significant reduction of food intake in the steroid-treated groups (-50 and -79% in M and T, respectively). This was associated with a similar loss in body weight. In the 45 remaining animals, diaphragm contractility and histopathologic features of several muscles were studied. Weights of respiratory and peripheral muscles were similarly decreased after steroid treatment. Maximal twitches of the diaphragm were lower in the C group (653 +/- 174 g/cm(2)) than in the M group (837 +/- 171 g/cm(2); p < 0.05) and the T group (765 +/- 145 g/cm(2), NS). Half-relaxation time was prolonged in both steroid groups, and time to peak tension was longer with M, whereas tetanic tensions were similar. Steroid treatment also induced a leftward shift of the force-frequency curve at 25 and 50 Hz when compared with saline treatment (p < 0.05). ATPase staining of the diaphragm, scalenus medius, and gastrocnemius showed type IIb fiber atrophy in the steroid groups and also diaphragmatic type IIa atrophy with T, whereas histologic examinations revealed a normal muscular pattern with absence of necrosis. Finally, a pair-fed (PF) study, performed in 18 rats (C, T, and PF), showed that muscle atrophy was considerably less pronounced in PF animals than in T-treated animals. We conclude that (1) short-term treatment with massive doses of steroids induced severe respiratory and limb muscle wasting; (2) both types of steroids induced predominantly type IIb atrophy, resulting in the expected alterations in diaphragm contractile properties; (3) neither steroid caused muscle necrosis; (4) type IIb atrophy was not caused by acute nutritional deprivation alone.

steroid

myopathy

corticosteroids

myopathy

methylprednisolone

M

triamcinolone

T

reduction of food intake

steroid

M

T

loss in body weight

steroid

M

T

steroid

M

tetanic

Steroid

atrophy

steroid

atrophy

T

necrosis

T

muscle atrophy

T

steroids

steroids

atrophy

steroid

necrosis

atrophy


Refractory cardiogenic shock and complete heart block after verapamil SR and metoprolol treatment. A case report.

A seventy-eight-year-old woman presented with complete heart block and refractory hypotension two days after a therapeutic dose of sustained-release verapamil with concomitant use of metoprolol. The patient continued to remain hypotensive with complete heart block, even with multiple uses of intravenous atropine as well as high doses of pressor agents such as dopamine and dobutamine. However, shortly after the use of intravenous calcium chloride, the refractory hypotension and complete heart block resolved.

cardiogenic shock

heart block

verapamil

metoprolol

heart block

hypotension

verapamil

metoprolol

hypotensive

heart block

atropine

dopamine

dobutamine

calcium chloride

hypotension

heart block


A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid.

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

antipurine

lometrexol

DDATHF

folic acid

Lometrexol

glycinamide ribonucleotide

purine

lometrexol

tumours

methotrexate

lometrexol

toxicities

toxicity

lometrexol

folic acid

lometrexol

folic acid

toxicity

lometrexol

folic acid

Thrombocytopenia

mucositis

toxicities

toxicity

folate

lometrexol

folic acid

toxicity

lometrexol

cancer


Involvement of the mu-opiate receptor in peripheral analgesia.

The intradermal injection of mu (morphine, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and morphiceptin), kappa (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneactemide) and delta ([D-Pen2.5]-enkephalin and [D-Ser2]-[Leu]enkephalin-Thr) selective opioid-agonists, by themselves, did not significantly affect the mechanical nociceptive threshold in the hindpaw of the rat. Intradermal injection of mu, but not delta or kappa opioid-agonists, however, produced dose-dependent inhibition of prostaglandin E2-induced hyperalgesia. The analgesic effect of the mu-agonist morphine was dose-dependently antagonized by naloxone and prevented by co-injection of pertussis toxin. Morphine did not, however, alter the hyperalgesia induced by 8-bromo cyclic adenosine monophosphate. We conclude that the analgesic action of opioids on the peripheral terminals of primary afferents is via a binding site with characteristics of the mu-opioid receptor and that this action is mediated by inhibition of the cyclic adenosine monophosphate second messenger system.

analgesia

morphine

Tyr-D-Ala-Gly-NMe-Phe-Gly-ol

morphiceptin

prostaglandin E2

hyperalgesia

morphine

naloxone

Morphine

hyperalgesia

8-bromo cyclic adenosine monophosphate

cyclic adenosine monophosphate


Adequate timing of ribavirin reduction in patients with hemolysis during combination therapy of interferon and ribavirin for chronic hepatitis C.

BACKGROUND: Hemolytic anemia is one of the major adverse events of the combination therapy of interferon and ribavirin. Because of ribavirin-related hemolytic anemia, dose reduction is a common event in this therapy. In this clinical retrospective cohort study we have examined the suitable timing of ribavirin reduction in patients with hemolysis during combination therapy. METHODS: Thirty-seven of 160 patients who had HCV-genotype 1b, had high virus load, and received 24-week combination therapy developed anemia with hemoglobin level <10 g/dl or anemia-related signs during therapy. After that, these 37 patients were reduced one tablet of ribavirin (200 mg) per day. After reduction of ribavirin, 27 of 37 patients could continue combination therapy for a total of 24 weeks (group A). However, 10 of 37 patients with reduction of ribavirin could not continue combination therapy because their <8.5 g/dl hemoglobin values decreased to or anemia-related severe side effects occurred (group B). We assessed the final efficacy and safety after reduction of ribavirin in groups A and B. RESULTS: A sustained virological response (SVR) was 29.6% (8/27) in group A and 10% (1/10) in group B, respectively. A 34.4% (12/27) of SVR + biological response in group A was higher than 10% (1/10) in group B ( P = 0.051), with slight significance. With respect to hemoglobin level at the time of ribavirin reduction, a rate of continuation of therapy in patients with > or =10 g/dl hemoglobin was higher than that in patients with <10 g/dl ( P = 0.036). CONCLUSIONS: Reduction of ribavirin at hemoglobin level > or =10 g/dl is suitable in terms of efficacy and side effects.

ribavirin

hemolysis

interferon

ribavirin

chronic hepatitis C

Hemolytic anemia

interferon

ribavirin

ribavirin

hemolytic anemia

ribavirin

hemolysis

anemia

anemia

ribavirin

ribavirin

ribavirin

anemia

ribavirin

ribavirin

ribavirin


Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats.

Nephrotic syndrome is often accompanied by sodium retention and generalized edema. However, the molecular basis for the decreased renal sodium excretion remains undefined. We hypothesized that epithelial Na channel (ENaC) subunit dysregulation may be responsible for the increased sodium retention. An experimental group of rats was treated with puromycin aminonucleoside (PAN; 180 mg/kg iv), whereas the control group received only vehicle. After 7 days, PAN treatment induced significant proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and extensive ascites. The protein abundance of alpha-ENaC and beta-ENaC was increased in the inner stripe of the outer medulla (ISOM) and in the inner medulla (IM) but was not altered in the cortex. gamma-ENaC abundance was increased in the cortex, ISOM, and IM. Immunoperoxidase brightfield- and laser-scanning confocal fluorescence microscopy demonstrated increased targeting of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits to the apical plasma membrane in the distal convoluted tubule (DCT2), connecting tubule, and cortical and medullary collecting duct segments. Immunoelectron microscopy further revealed an increased labeling of alpha-ENaC in the apical plasma membrane of cortical collecting duct principal cells of PAN-treated rats, indicating enhanced apical targeting of alpha-ENaC subunits. In contrast, the protein abundances of Na(+)/H(+) exchanger type 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (BSC-1), and thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) were decreased. Moreover, the abundance of the alpha(1)-subunit of the Na-K-ATPase was decreased in the cortex and ISOM, but it remained unchanged in the IM. In conclusion, the increased or sustained expression of ENaC subunits combined with increased apical targeting in the DCT2, connecting tubule, and collecting duct are likely to play a role in the sodium retention associated with PAN-induced nephrotic syndrome. The decreased abundance of NHE3, BSC-1, TSC, and Na-K-ATPase may play a compensatory role to promote sodium excretion.

puromycin aminonucleoside

nephrotic syndrome

Nephrotic syndrome

sodium

edema

sodium

sodium

puromycin aminonucleoside

PAN

PAN

proteinuria

hypoalbuminemia

sodium

ascites

PAN

H

K

Cl

thiazide

Cl

K

sodium

PAN

nephrotic syndrome

K

sodium


Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study.

This pilot study examines whether hormone therapy for breast cancer affects cognition. Patients participating in a randomised trial of anastrozole, tamoxifen alone or combined (ATAC) (n=94) and a group of women without breast cancer (n=35) completed a battery of neuropsychological measures. Compared with the control group, the patients were impaired on a processing speed task (p=0.032) and on a measure of immediate verbal memory (p=0.026) after controlling for the use of hormone replacement therapy in both groups. Patient group performance was not significantly related to length of treatment or measures of psychological morbidity. The results showed specific impairments in processing speed and verbal memory in women receiving hormonal therapy for the treatment of breast cancer. Verbal memory may be especially sensitive to changes in oestrogen levels, a finding commonly reported in studies of hormone replacement therapy in healthy women. In view of the increased use of hormone therapies in an adjuvant and preventative setting their impact on cognitive functioning should be investigated more thoroughly.

breast cancer

detrimental effect on memory

detrimental effect on
cognition

breast cancer

anastrozole

tamoxifen

breast cancer

breast cancer

oestrogen


Association of nitric oxide production and apoptosis in a model of experimental nephropathy.

BACKGROUND: In recent studies increased amounts of nitric oxide (NO) and apoptosis have been implicated in various pathological conditions in the kidney. We have studied the role of NO and its association with apoptosis in an experimental model of nephrotic syndrome induced by a single injection of adriamycin (ADR). METHODS: The alteration in the NO pathway was assessed by measuring nitrite levels in serum/urine and by evaluating the changes in vascular reactivity of the isolated perfused rat kidney (IPRK) system. Rats were stratified into control groups and ADR-induced nephropathy groups. These two groups were then divided into: group 1, animals receiving saline; and group 2, animals receiving aminoguanidine (AG) which is a specific inhibitor of inducible-NO synthase. On day 21, rats were sacrificed after obtaining material for biochemical analysis. RESULTS: Histopathological examination of the kidneys of rats treated with ADR revealed focal areas of mesangial proliferation and mild tubulointerstitial inflammation. They also had significantly higher levels of proteinuria compared with control and treatment groups (P < 0.05). Urine nitrite levels were significantly increased in the ADR-nephropathy group (P < 0.05). In the IPRK phenylephrine and acetylcholine related responses were significantly impaired in the ADR-nephropathy group. Apoptosis was not detected in controls. However, in the ADR-nephropathy group, numerous apoptotic cells were identified in the tubulointerstitial areas. Double staining revealed numerous interstitial apoptotic cells to stain for ED1, a marker for monocytes/macrophages. Treatment with AG prevented the impairment of renal vascular bed responses and reduced both urine nitrite levels and apoptosis to control levels. CONCLUSION: We suggest that interactions between NO and apoptosis are important in the pathogenesis of the ADR-induced nephrosis.

nitric oxide

nephropathy

nitric oxide

NO

NO

nephrotic syndrome

adriamycin

ADR

NO

nitrite

ADR

nephropathy

aminoguanidine

AG

NO

ADR

mesangial proliferation

tubulointerstitial inflammation

proteinuria

nitrite

ADR

nephropathy

phenylephrine

acetylcholine

ADR

nephropathy

ADR

nephropathy

AG

nitrite

NO

ADR

nephrosis


The attenuating effect of carteolol hydrochloride, a beta-adrenoceptor antagonist, on neuroleptic-induced catalepsy in rats.

It is known that beta-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a beta-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its beta-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity.

carteolol hydrochloride

catalepsy

akathisia

catalepsy

akathisia

catalepsy

akathisia

carteolol

haloperidol

catalepsy

propranolol

biperiden

Carteolol

propranolol

biperiden

haloperidol

catalepsy

carteolol

propranolol

biperiden

Carteolol

dopamine

hyperlocomotion

Carteolol

haloperidol

apomorphine

carteolol

carteolol

physostigmine

carteolol

haloperidol

catalepsy

akathisia

dopamine


Penicillamine-induced rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis.

A 67-year-old woman with rheumatoid arthritis presented rapidly progressive glomerulonephritis (RPGN) after 5 months of D-penicillamine (250 mg/day) treatment. Light microscopy study showed severe glomerulonephritis with crescent formation in 60% of the glomeruli and infiltration of inflammatory cells in the wall of an arteriole. Immunofluorescence revealed scanty granular IgG, IgA and C3 deposits along the capillary walls and mesangium. The patient was treated with steroid pulse, plasmapheresis, cyclophosphamide and antiplatelet agents. A complete recovery of renal function was achieved in a few weeks. This new case of RPGN in the course of D-penicillamine treatment emphasizes the need for frequent monitoring of renal function and evaluation of urinary sediment and proteinuria in these patients. The prompt discontinuation of D-penicillamine and vigorous treatment measures could allow for a good prognosis as in this case.

Penicillamine

glomerulonephritis

rheumatoid arthritis

rheumatoid arthritis

glomerulonephritis

RPGN

D-penicillamine

glomerulonephritis

steroid

cyclophosphamide

antiplatelet agents

RPGN

D-penicillamine

proteinuria

D-penicillamine


Nature, time course and dose dependence of zidovudine-related side effects: results from the Multicenter Canadian Azidothymidine Trial.

To characterize the nature, time course and dose dependency of zidovudine-related side effects, we undertook a multicenter, prospective, dose-range finding study. Our study group consisted of 74 HIV-positive homosexual men belonging to groups II B, III and IV C2 from the Centers for Disease Control (CDC) classification of HIV disease. Following a 3-week observation period, volunteers were treated with zidovudine 600 mg/day for 18 weeks, 900 mg/day for 9 weeks and 1200 mg/day for 9 weeks, followed by a washout period of 6 weeks after which they were re-started on 1200 mg/day or the highest tolerated dose at 8-hourly intervals. Subjects were randomly assigned to 4-hourly or 8-hourly regimens within CDC groups while taking 600 and 1200 mg/day. Clinical and laboratory evaluations were performed at 3-week intervals. Symptomatic adverse effects were present in 96% of subjects, most commonly nausea (64%), fatigue (55%) and headache (49%). These were generally self-limited, reappearing briefly at each dose increment. A decrease in hemoglobin occurred shortly after initiation of therapy. This was not dose dependent and reversed rapidly upon discontinuation of treatment. A red blood cell count decrease, a mean cell volume increase and a granulocyte count decrease developed early in a dose-independent fashion, reverting at least partially during the washout phase. The decrease in reticulocyte count was dose related between 600 and 900 mg/day with no further change when the dose was escalated to 1200 mg/day. Bone marrow changes occurred rapidly as demonstrated by megaloblastosis in 95% of 65 specimens at week 18.(ABSTRACT TRUNCATED AT 250 WORDS)

zidovudine

Azidothymidine

zidovudine

HIV disease

zidovudine

nausea

fatigue

headache

megaloblastosis


Bilateral optic neuropathy due to combined ethambutol and isoniazid treatment.

The case of a 40-year-old patient who underwent an unsuccessful cadaver kidney transplantation and was treated with ethambutol and isoniazid is reported. A bilateral retrobulbar neuropathy with an unusual central bitemporal hemianopic scotoma was found. Ethambutol was stopped and only small improvement of the visual acuity followed. Isoniazid was discontinued later, followed by a dramatic improvement in the visual acuity. The hazards of optic nerve toxicity due to ethambutol are known. We emphasize the potential danger in the use of ethambutol and isoniazid.

Bilateral optic neuropathy

ethambutol

isoniazid

ethambutol

isoniazid

bilateral retrobulbar neuropathy

scotoma

Ethambutol

Isoniazid

toxicity

ethambutol

ethambutol

isoniazid


Progestational agents and blood coagulation. VII. Thromboembolic and other complications of oral contraceptive therapy in relationship to pretreatment levels of blood coagulation factors: summary report of a ten-year study.

During a ten-year period, 348 women were studied for a total of 5,877 patient months in four separate studies relating oral contraceptives to changes in hematologic parameters. Significant increases in certain factors of the blood coagulation and fibrinolysin systems (factors I,II,VII,VIII,IX, and X and plasminogen) were observed in the treated groups. Severe complications developed in four patients. All four had an abnormal blood coagulation profile, suggesting "hypercoagulability" before initiation of therapy. Some of these findings represented the most extreme abnormalities seen in the entire group of patients; some increased further during therapy. One of these patients developed a myocardial infarction before receiving any medication, shortly after the base-line values were obtained. One patient developed retinopathy 19 months after she began therapy, and another developed thrombophlebitis after 27 months of therapy. The fourth patient developed thrombophlebitis 14 days after initiation of contraceptive therapy. All four patients were of the A or AB blood group. Previous studies suggested the possiblility of increased propensity for thromboembolic episodes in patients possessing the A antigen. It appears from these data that hematologic work-ups may be useful in women who are about to start long-term oral contraceptive therapy.

blood coagulation

Thromboembolic

oral contraceptive

blood coagulation

oral contraceptives

blood coagulation

blood coagulation

hypercoagulability

myocardial infarction

retinopathy

thrombophlebitis

thrombophlebitis

thromboembolic episodes

oral contraceptive


Cardiac arrest in a child with cerebral palsy undergoing sevoflurane induction of anesthesia after preoperative clonidine.

Clonidine is a frequently administered alpha2-adrenergic agonist which can decrease heart rate and blood pressure. We present a case of a 5-year-old child with cerebral palsy and seizure disorder, receiving clonidine for restlessness, who presented for placement of a baclofen pump. Without the knowledge of the medical personnel, the patient's mother administered three doses of clonidine during the evening before and morning of surgery to reduce anxiety. During induction of anesthesia, the patient developed bradycardia and hypotension requiring cardiac resuscitation. There are no previous reports of clonidine-associated cardiac arrest in a child undergoing induction of anesthesia.

Cardiac arrest

cerebral palsy

sevoflurane

clonidine

Clonidine

cerebral palsy

seizure disorder

clonidine

restlessness

baclofen

clonidine

anxiety

bradycardia

hypotension

clonidine

cardiac arrest


Effects of UMB24 and (+/-)-SM 21, putative sigma2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice.

Earlier studies have demonstrated that antagonism of sigma1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of sigma2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (+/-)-SM 21 (3alpha-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (+/-)-SM 21 display preferential affinity for sigma2 over sigma1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (+/-)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (+/-)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that sigma2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.

SM 21

cocaine

convulsive

cocaine

SM 21

SM 21

SM 21

cocaine

convulsions

SM 21

cocaine


Methimazole-induced cholestatic jaundice.

Methimazole is a widely used and generally well-tolerated antithyroid agent. A 43-year-old woman had severe jaundice and itching 1 month after receiving methimazole (10 mg tid) and propranolol (20 mg tid) for treatment of hyperthyroidism. The patient continued treatment for another 4 days after the appearance of jaundice until she finished both medications. When seen at the emergency department 2 weeks later, she still had severe icterus, pruritus, and hyperbilirubinemia, formed mainly of the conjugated fraction. Methimazole-induced cholestasis was diagnosed, and propranolol therapy was resumed. Over the following 9 days, the symptoms improved and plasma bilirubin levels were normal after 12 weeks without methimazole. In rare cases within the first few weeks of therapy, this drug can cause severe and reversible cholestatic jaundice. Physicians and patients should be aware of this adverse effect so that, upon occurrence, they can discontinue methimazole therapy and avoid unnecessary invasive procedures.

Methimazole

cholestatic jaundice

Methimazole

jaundice

itching

methimazole

propranolol

hyperthyroidism

jaundice

icterus

pruritus

hyperbilirubinemia

Methimazole

cholestasis

propranolol

bilirubin

methimazole

cholestatic jaundice

methimazole


Ciprofloxacin-induced acute interstitial nephritis and autoimmune hemolytic anemia.

Ciprofloxacin has been associated with several side effects including interstitial nephritis and hemolytic anemia. The combination of both side effects is extremely rare. In this report, we describe a case of ciprofloxacin-induced interstitial nephritis and autoimmune hemolytic anemia. Hemolytic anemia improved after stopping the drug and initiation of steroid therapy. Unfortunately, acute interstitial nephritis was irreversible and the patient developed end-stage renal disease.

Ciprofloxacin

interstitial nephritis

autoimmune hemolytic anemia

Ciprofloxacin

interstitial nephritis

hemolytic anemia

ciprofloxacin

interstitial nephritis

autoimmune hemolytic anemia

Hemolytic anemia

steroid

interstitial nephritis

end-stage renal disease


Contribution of sodium valproate to the syndrome of inappropriate secretion of antidiuretic hormone.

We report the case of a 62-year-old man who was administered sodium valproate (VPA) and who subsequently developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). He had been taking VPA for treatment of idiopathic generalized tonic-clonic convulsions since he was 56 years old. After substituting VPA with zonisamide, the serum sodium level returned to normal. We consider this episode of SIADH to be the result of a combination of factors including a weakness of the central nervous system and the long-term administration of VPA.

sodium valproate

sodium valproate

VPA

SIADH

VPA

tonic-clonic convulsions

VPA

zonisamide

sodium

SIADH

weakness of the central nervous system

VPA


Vasopressin in the treatment of milrinone-induced hypotension in severe heart failure.

The use of phosphodiesterase inhibitors such as milrinone in the treatment of severe heart failure is frequently restricted because they cause vasodilation and hypotension. In patients with decompensated heart failure with hypotension after treatment with milrinone, low doses of vasopressin restored blood pressure without inhibiting the inotropic effect of milrinone.

Vasopressin

milrinone

hypotension

heart failure

milrinone

heart failure

hypotension

heart failure

hypotension

milrinone

vasopressin

milrinone


Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies.

Two halogenated anesthetics, enflurane and isoflurane, have been associated with an allergic-type hepatic injury both alone and following previous exposure to halothane. Halothane hepatitis appears to involve an aberrant immune response. An antibody response to a protein-bound biotransformation product (trifluoroacetyl adduct) has been detected on halothane hepatitis patients. This study was performed to determine cross-reactivity between enflurane and isoflurane with the hypersensitivity induced by halothane. The subcellular and lobular production of hepatic neoantigens recognized by halothane-induced antibodies following enflurane and isoflurane, and the biochemical nature of these neoantigens was investigated in two animal models. Enflurane administration resulted in neoantigens detected in both the microsomal and cytosolic fraction of liver homogenates and in the centrilobular region of the liver. In the same liver, biochemical analysis detected fluorinated liver adducts that were up to 20-fold greater in guinea pigs than in rats. This supports and extends previous evidence for a mechanism by which enflurane and/or isoflurane could produce a hypersensitivity condition similar to that of halothane hepatitis either alone or subsequent to halothane administration. The guinea pig would appear to be a useful model for further investigations of the immunological response to these antigens.

halothane

enflurane

isoflurane

hepatic injury

halothane

Halothane

hepatitis

trifluoroacetyl

halothane

hepatitis

enflurane

isoflurane

hypersensitivity

halothane

halothane

enflurane

isoflurane

Enflurane

enflurane

isoflurane

hypersensitivity

halothane

hepatitis

halothane


Induction by paracetamol of bladder and liver tumours in the rat. Effects on hepatocyte fine structure.

Groups of male and female inbred Leeds strain rats were fed diets containing either 0.5% or 1.0% paracetamol by weight for up to 18 months. At the 1.0% dosage level, 20% of rats of both sexes developed neoplastic nodules of the liver, a statistically significant incidence. These rats also showed gross enlargement of their livers and an increase in foci of cellular alteration, the latter also being observed in the low dosage male rats. Papillomas of the transitional epithelium of the bladder developed in all paracetamol-treated groups, and three rats bore bladder carcinomas. However, significant yields of bladder tumours were only obtained from low dosage females and high dosage males. Additionally, 20 to 25% of paracetamol-treated rats developed hyperplasia of the bladder epithelium, which was not coincident with the presence of bladder calculi. A low yield of tumours at various other sites also arose following paracetamol feeding. An electron microscope study of the livers of paracetamol-treated rats revealed ultrastructural changes in the hepatocytes that resemble those that result from exposure to a variety of known hepatocarcinogens.

paracetamol

bladder and liver tumours

bladder tumours

liver tumours

paracetamol

Papillomas

paracetamol

bladder carcinomas

bladder tumours

paracetamol

hyperplasia

bladder calculi

tumours

paracetamol

paracetamol

hepatocarcinogens


Rat extraocular muscle regeneration. Repair of local anesthetic-induced damage.

Local anesthetics that are commonly used in ophthalmic surgery (0.75% bupivacaine hydrochloride, 2.0% mepivacaine hydrochloride, and 2.0% lidocaine hydrochloride plus 1:100,000 epinephrine) were injected into the retrobulbar area of rat eyes. Controls were injected with physiological saline. All three anesthetics produced massive degeneration of the extraocular muscles. Muscle degeneration is followed by regeneration of the damaged muscle fibers. In addition to muscle damage, severe damage was also seen in harderian glands, especially after exposure to mepivacaine and lidocaine plus epinephrine. With these findings in rats, it is hypothesized that the temporary diplopia sometimes seen in patients after ophthalmic surgery might be due to anesthetic-induced damage to the extraocular muscles.

bupivacaine hydrochloride

mepivacaine hydrochloride

lidocaine hydrochloride

epinephrine

Muscle degeneration

muscle damage

mepivacaine

lidocaine

epinephrine

diplopia


Reversal of neuroleptic-induced catalepsy by novel aryl-piperazine anxiolytic drugs.

The novel anxiolytic drug, buspirone, reverses catalepsy induced by haloperidol. A series of aryl-piperazine analogues of buspirone and other 5-hydroxytryptaminergic agonists were tested for their ability to reverse haloperidol induced catalepsy. Those drugs with strong affinity for 5-hydroxytryptamine1a receptors were able to reverse catalepsy. Drugs with affinity for other 5-HT receptors or weak affinity were ineffective. However, inhibition of postsynaptic 5-HT receptors neither inhibited nor potentiated reversal of catalepsy and leaves open the question as to the site or mechanism for this effect.

catalepsy

aryl-piperazine

buspirone

catalepsy

haloperidol

aryl-piperazine

buspirone

5-hydroxytryptaminergic agonists

haloperidol

catalepsy

catalepsy

catalepsy


Diazepam facilitates reflex bradycardia in conscious rats.

The effects of diazepam on cardiovascular function were assessed in conscious rats. Intravenous administration of diazepam (1-30 mg kg-1) produced a dose-dependent decrease in both the mean arterial pressure and the heart rate. Also, reflex bradycardia was produced in rats by intravenous infusion of adrenaline (1.25-2.5 micrograms kg-1). Intravenous pretreatment of the rats with diazepam, although causing no change in the adrenaline-induced pressor effect, did enhance the adrenaline-induced reflex bradycardia. However, the diazepam enhancement of adrenaline-induced reflex bradycardia was antagonized by pretreatment of rats with an intravenous dose of picrotoxin (an agent blocks chloride channels by binding to sites associated with the benzodiazepine-GABA-chloride channel macromolecular complex). The data indicate that diazepam acts through the benzodiazepine-GABA-chloride channel macromolecular complex within the central nervous system to facilitate reflex bradycardia mediated through baroreceptor reflexes in response to an acute increase in arterial pressure.

Diazepam

bradycardia

diazepam

diazepam

bradycardia

adrenaline

diazepam

adrenaline

adrenaline

bradycardia

diazepam

adrenaline

bradycardia

picrotoxin

chloride

benzodiazepine

GABA

chloride

diazepam

benzodiazepine

GABA

chloride

bradycardia


Chronic carbamazepine inhibits the development of local anesthetic seizures kindled by cocaine and lidocaine.

The effects of carbamazepine (CBZ) treatment on local anesthetic-kindled seizures and lethality were evaluated in different stages of the kindling process and under different methods of CBZ administration. Chronic oral CBZ inhibited the development of both lidocaine- and cocaine-induced seizures, but had little effect on the fully developed local anesthetic seizures. Chronic CBZ also decreased the incidence of seizure-related mortality in the cocaine-injected rats. Acute CBZ over a range of doses (15-50 mg/kg) had no effect on completed lidocaine-kindled or acute cocaine-induced seizures. Repeated i.p. injection of CBZ (15 mg/kg) also was without effect on the development of lidocaine- or cocaine-kindled seizures. The differential effects of CBZ depending upon stage of seizure development suggest that distinct mechanisms underlie the development versus maintenance of local anesthetic-kindled seizures. The effectiveness of chronic but not repeated, intermittent injections of CBZ suggests that different biochemical consequences result from the different treatment regimens. The possible utility of chronic CBZ in preventing the development of toxic side effects in human cocaine users is suggested by these data, but remains to be directly evaluated.

carbamazepine

seizures

cocaine

lidocaine

carbamazepine

CBZ

seizures

CBZ

CBZ

lidocaine

cocaine

seizures

seizures

CBZ

seizure

cocaine

CBZ

lidocaine

cocaine

seizures

CBZ

lidocaine

cocaine

seizures

CBZ

seizure

seizures

CBZ

CBZ

cocaine


D-penicillamine in the treatment of localized scleroderma.

Localized scleroderma has no recognized internal organ involvement but may be disfiguring and disabling when the cutaneous lesions are extensive or affect children. There is no accepted or proven treatment for localized scleroderma. Case reports of 11 patients with severe, extensive localized scleroderma who were treated with D-penicillamine are summarized in this article. This drug was judged to have a favorable effect on the disease course in 7 (64%) of 11 patients. Improvement began within 3 to 6 months and consisted of cessation of active cutaneous lesions in all 7 patients, skin softening in 5, and more normal growth of the affected limb in 2 of 3 children. Joint stiffness and contractures also improved. The dose of D-penicillamine associated with a favorable response was as low as 2 to 5 mg/kg per day given over a period ranging from 15 to 53 months. D-Penicillamine caused nephrotic syndrome in 1 patient and milder reversible proteinuria in 3 other patients; none developed renal insufficiency. These data suggest that D-penicillamine may be effective in severe cases of localized scleroderma.

D-penicillamine

localized scleroderma

Localized scleroderma

localized scleroderma

localized scleroderma

D-penicillamine

contractures

D-penicillamine

D-Penicillamine

nephrotic syndrome

proteinuria

renal insufficiency

D-penicillamine

localized scleroderma


Preservation of renal blood flow during hypotension induced with fenoldopam in dogs.

The introduction of drugs that could induce hypotension with different pharmacological actions would be advantageous because side effects unique to a specific drug could be minimized by selecting appropriate therapy. Specific dopamine-1, (DA1) and dopamine-2 (DA2) receptor agonists are now under clinical investigation. Fenoldopam mesylate is a specific DA1 receptor agonist that lowers blood pressure by vasodilatation. The hypothesis that fenoldopam could be used to induce hypotension and preserve blood flow to the kidney was tested. Systemic aortic blood pressure and renal blood flow were measured continuously with a carotid arterial catheter and an electromagnetic flow probe respectively, in order to compare the cardiovascular and renal vascular effects of fenoldopam and sodium nitroprusside in ten dogs under halothane general anaesthesia. Mean arterial pressure was decreased 30 +/- 8 per cent from control with infusion of fenoldopam (3.4 +/- 2.0 micrograms.kg-1.min-1) and 34 +/- 4 per cent with infusion of sodium nitroprusside (5.9 micrograms.kg-1.min-1) (NS). Renal blood flow (RBF) increased during fenoldopam-induced hypotension 11 +/- 7 per cent and decreased 21 +/- 8 per cent during sodium nitroprusside-induced hypotension (P less than 0.01). Sodium nitroprusside is a non-selective arteriolar and venous vasodilator that can produce redistribution of blood flow away from the kidney during induced hypotension. Fenoldopam is a selective dopamine-1 (DA1) receptor agonist that causes vasodilatation to the kidney and other organs with DA1 receptors and preserves blood flow to the kidney during induced hypotension.

hypotension

fenoldopam

hypotension

dopamine

DA

dopamine

DA

Fenoldopam mesylate

fenoldopam

hypotension

fenoldopam

sodium

nitroprusside

halothane

fenoldopam

sodium

nitroprusside

fenoldopam

hypotension

sodium

nitroprusside

hypotension

nitroprusside

hypotension

dopamine

hypotension


Antiarrhythmic effects of optical isomers of cibenzoline on canine ventricular arrhythmias.

Antiarrhythmic effects of (+)-cibenzoline and (-)-cibenzoline were examined using two canine ventricular arrhythmia models. Digitalis arrhythmia, which is suppressed by Na channel blockers, was induced by intermittent intravenous (i.v.) injection of ouabain in pentobarbital-anesthetized dogs. Adrenaline arrhythmia, which is suppressed by Ca channel blockers, was induced by adrenaline infusion in halothane-anesthetized dogs. Ten and 5 mg/kg i.v. (+)-cibenzoline suppressed digitalis- and adrenaline-induced arrhythmias, respectively. The minimum effective plasma concentrations of (+)-cibenzoline for digitalis- and adrenaline-induced arrhythmias were 1.4 +/- 0.4 and 2.0 +/- 0.6 micrograms/ml, respectively (mean +/- SD, n = 6). A lower dose of 1 mg/kg i.v. of (-)-cibenzoline suppressed the digitalis-induced arrhythmia, whereas 5 mg/kg i.v. was needed to suppress adrenaline-induced arrhythmias. The minimum effective plasma concentrations of (-)-cibenzoline for digitalis- and adrenaline-induced arrhythmia were 0.06 +/- 0.04 and 0.7 +/- 0.1 micrograms/ml, respectively (mean +/- SD, n = 6). The stronger antiarrhythmic effect of (-)-cibenzoline indicates that (-)-isomer may have an effect nearly 5-20 times stronger in suppressing Na channels, but effects of both drugs on Ca channels may be almost equipotent.

cibenzoline

ventricular arrhythmias

cibenzoline

cibenzoline

ventricular arrhythmia

Digitalis

arrhythmia

ouabain

pentobarbital

Adrenaline arrhythmia

Ca

adrenaline

halothane

cibenzoline

digitalis

adrenaline

arrhythmias

cibenzoline

digitalis

adrenaline

arrhythmias

cibenzoline

digitalis

arrhythmia

adrenaline

arrhythmias

cibenzoline

digitalis

adrenaline

arrhythmia

cibenzoline

Ca


Effect of Hibiscus rosa sinensis on reserpine-induced neurobehavioral and biochemical alterations in rats.

Effect of methanolic extract of Hibiscus rosa sinensis (100-300 mg/kg) was studied on reserpine-induced orofacial dyskinesia and neurochemical alterations. The rats were treated with intraperitoneal reserpine (1 mg/kg, ip) for 3 days every other day. On day 5, vacuous chewing movements and tongue protrusions were counted for 5 min. Reserpine treated rats significantly developed vacuous chewing movements and tongue protrusions however, coadministration of Hibiscus rosa sinensis roots extract (100, 200 and 300 mg/kg, per orally) attenuated the effects. Biochemical analysis of brain revealed that the reserpine treatment significantly increased lipid peroxidation and decreased levels of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH), an index of oxidative stress process. Coadministration of extract significantly reduced the lipid peroxidation and reversed the decrease in brain SOD, CAT and GSH levels. The results of the present study suggested that Hibiscus rosa sinensis had a protective role against reserpine-induced orofacial dyskinesia and oxidative stress.

Hibiscus rosa sinensis

reserpine

Hibiscus rosa sinensis

reserpine

dyskinesia

reserpine

Reserpine

Hibiscus rosa sinensis

reserpine

superoxide

glutathione

Hibiscus rosa sinensis

reserpine

dyskinesia


Comparison of aqueous and gellan ophthalmic timolol with placebo on the 24-hour heart rate response in patients on treatment for glaucoma.

PURPOSE: Topical beta-blocker treatment is routine therapy in the management of patients with glaucoma. Therapy results in systemic absorption, however, the degree of reduction of resting and peak heart rate has not been quantified. DESIGN: This trial evaluated the effect of placebo, 0.5% aqueous timolol (timolol solution) and a 0.5% timolol suspension that forms a gel on application to the conjunctiva (timolol gellan) on the 24-hour heart rate in patients currently being treated for glaucoma to quantify the reduction in mean heart rate. METHODS: Forty-three Caucasian patients with primary open-angle glaucoma or ocular hypertension with a mean (+/-SD) age of 63 (+/-8) years were randomized and crossed over in a double-masked manner to 14 days of treatment with placebo (morning and evening in both eyes), timolol solution (morning and evening in both eyes), or timolol gellan (morning in both eyes with placebo in the evening). On the 13th day of each period, heart rate was recorded continuously during a typical, ambulant 24-hour period. RESULTS: Both timolol solution and timolol gellan reduced the mean 24-hour heart rate compared with placebo (P < or = .001), and this reduction was most pronounced during the daytime (-7.5% change in mean heart rate, -5.7 beats/min). Timolol gellan showed a numerically but not significantly smaller reduction in 24-hour heart rate, compared with timolol solution. During the night, the mean 12-hour heart rate on placebo and timolol gellan were both significantly less than on timolol solution; the difference between solution and gellan treatments was statistically significant (P = .01). CONCLUSIONS: Both timolol solution and timolol gellan decrease the mean 24-hour heart rate compared with placebo. This response was most pronounced during the active daytime period. These data quantify the modest bradycardia associated with ophthalmic beta-blocker therapy in a typical patient population on therapy for glaucoma. Although exercise performance was not assessed in this trial, reductions of this magnitude should not have substantial clinical consequences.

timolol

glaucoma

glaucoma

timolol

timolol

timolol

timolol

glaucoma

open-angle glaucoma

ocular hypertension

timolol

timolol

timolol

timolol

Timolol

timolol

timolol

timolol

timolol

timolol

bradycardia

glaucoma


5 flourouracil-induced apical ballooning syndrome: a case report.

The apical ballooning syndrome (ABS) is a recently described stress-mediated acute cardiac syndrome characterized by transient wall-motion abnormalities involving the apex and midventricle with hyperkinesis of the basal left ventricular (LV) segments without obstructive epicardial coronary disease. Cardiotoxicity is not an uncommon adverse effect of chemotherapeutic agents. However, there are no reports of ABS secondary to chemotherapeutic agents. We describe the case of a woman who developed the syndrome after chemotherapy for metastatic cancer. A 79-year-old woman presented with typical ischemic chest pain, elevated cardiac enzymes with significant ST-segment abnormalities on her electrocardiogram. She underwent recent chemotherapy with fluorouracil for metastatic colorectal cancer. Echocardiography revealed a wall-motion abnormality involving the apical and periapical segments which appeared akinetic. Coronary angiography revealed no obstructive coronary lesions. The patient was stabilized with medical therapy. Four weeks later she remained completely asymptomatic. Echocardiogram revealed a normal ejection fraction and a resolution of the apical akinesis. Pathogenetic mechanisms of cardiac complications in cancer patients undergoing chemotherapy include coronary vasospasm, endothelial damage and consequent thrombus formation. In our patient, both supraphysiologic levels of plasma catecholamines and stress related neuropeptides caused by cancer diagnosis as well as chemotherapy may have contributed the development of ABS.

5 flourouracil

apical ballooning syndrome

apical ballooning syndrome

ABS

acute cardiac syndrome

hyperkinesis

epicardial coronary disease

Cardiotoxicity

ABS

cancer

ischemic

chest pain

fluorouracil

colorectal cancer

akinetic

akinesis

cardiac complications

cancer

coronary vasospasm

thrombus

catecholamines

cancer

ABS


Reduction of pain during induction with target-controlled propofol and remifentanil.

BACKGROUND: Pain on injection of propofol is unpleasant. We hypothesized that propofol infusion pain might be prevented by infusing remifentanil before starting the propofol infusion in a clinical setting where target-controlled infusions (TCI) of both drugs were used. A prospective, randomized, double-blind, placebo-controlled trial was performed to determine the effect-site concentration (Ce) of remifentanil to prevent the pain without producing complications. METHODS: A total of 128 patients undergoing general surgery were randomly allocated to receive normal saline (control) or remifentanil to a target Ce of 2 ng ml(-1) (R2), 4 ng ml(-1) (R4), or 6 ng ml(-1) (R6) administered via TCI. After the target Ce was achieved, the infusion of propofol was started. Remifentanil-related complications were assessed during the remifentanil infusion, and pain caused by propofol was evaluated using a four-point scale during the propofol infusion. RESULTS: The incidence of pain was significantly lower in Groups R4 and R6 than in the control and R2 groups (12/32 and 6/31 vs 26/31 and 25/32, respectively, P<0.001). Pain was less severe in Groups R4 and R6 than in the control and R2 groups (P<0.001). However, both incidence and severity of pain were not different between Groups R4 and R6. No significant complications were observed during the study. CONCLUSIONS: During induction of anaesthesia with TCI of propofol and remifentanil, a significant reduction in propofol infusion pain was achieved without significant complications by prior administration of remifentanil at a target Ce of 4 ng ml(-1).

pain

propofol

remifentanil

Pain

propofol

propofol

pain

remifentanil

propofol

remifentanil

pain

remifentanil

propofol

Remifentanil

remifentanil

pain

propofol

propofol

pain

Pain

pain

propofol

remifentanil

propofol

pain

remifentanil


Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat.

RATIONALE: Fluoxetine is a selective serotonin reuptake inhibitor antidepressant widely used by pregnant women. Epidemiological data suggest that fluoxetine exposure prenatally increases the prevalence of persistent pulmonary hypertension syndrome of the newborn. The mechanism responsible for this effect is unclear and paradoxical, considering the current evidence of a pulmonary hypertension protective fluoxetine effect in adult rodents. OBJECTIVES: To evaluate the fluoxetine effect on fetal rat pulmonary vascular smooth muscle mechanical properties and cell proliferation rate. METHODS: Pregnant rats were treated with fluoxetine (10 mg/kg) from Day 11 through Day 21 of gestation. MEASUREMENTS AND MAIN RESULTS: Fetuses were delivered by cesarean section. As compared with controls, fluoxetine exposure resulted in fetal pulmonary hypertension as evidenced by an increase in the weight ratio of the right ventricle to the left ventricle plus septum (P = 0.02) and by an increase in pulmonary arterial medial thickness (P < 0.01). Postnatal mortality was increased among experimental animals, and arterial oxygen saturation was 96 +/- 1% in 1-day-old control animals and significantly lower (P < 0.01) in fluoxetine-exposed pups (79 +/- 2%). In vitro, fluoxetine induced pulmonary arterial muscle contraction in fetal, but not adult, animals (P < 0.01) and reduced serotonin-induced contraction at both ages (P < 0.01). After in utero exposure to a low fluoxetine concentration the pulmonary arterial smooth muscle cell proliferation rate was significantly increased in fetal, but not adult, cells (P < 0.01). CONCLUSIONS: In contrast to the adult, fluoxetine exposure in utero induces pulmonary hypertension in the fetal rat as a result of a developmentally regulated increase in pulmonary vascular smooth muscle proliferation.

fluoxetine

fetal pulmonary hypertension

fetal pulmonary hypertension

pulmonary hypertension

Fluoxetine

serotonin

fluoxetine

pulmonary hypertension syndrome

pulmonary hypertension

fluoxetine

fluoxetine

fluoxetine

fluoxetine

fetal pulmonary hypertension

fetal pulmonary hypertension

pulmonary hypertension

oxygen

fluoxetine

fluoxetine

serotonin

fluoxetine

fluoxetine

pulmonary hypertension


Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen.

BACKGROUND: Methadone is prescribed to heroin addicts to decrease illicit opioid use. Prolongation of the QT interval in the ECG of patients with torsade de pointes (TdP) has been reported in methadone users. As heroin addicts sometimes faint while using illicit drugs, doctors might attribute too many episodes of syncope to illicit drug use and thereby underestimate the incidence of TdP in this special population, and the high mortality in this population may, in part, be caused by the proarrhythmic effect of methadone. METHODS: In this cross-sectional study interview, ECGs and blood samples were collected in a population of adult heroin addicts treated with methadone or buprenorphine on a daily basis. Of the patients at the Drug Addiction Service in the municipal of Copenhagen, 450 (approximately 52%) were included. The QT interval was estimated from 12 lead ECGs. All participants were interviewed about any experience of syncope. The association between opioid dose and QT, and methadone dose and reporting of syncope was assessed using multivariate linear regression and logistic regression, respectively. RESULTS: Methadone dose was associated with longer QT interval of 0.140 ms/mg (p = 0.002). No association between buprenorphine and QTc was found. Among the subjects treated with methadone, 28% men and 32% women had prolonged QTc interval. None of the subjects treated with buprenorphine had QTc interval >0.440 s((1/2)). A 50 mg higher methadone dose was associated with a 1.2 (95% CI 1.1 to 1.4) times higher odds for syncope. CONCLUSIONS: Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts.

Syncope

QT prolongation

methadone

heroin

Methadone

heroin

torsade de pointes

TdP

methadone

heroin

syncope

TdP

methadone

heroin

methadone

buprenorphine

syncope

methadone

syncope

Methadone

buprenorphine

methadone

prolonged QTc interval

buprenorphine

methadone

syncope

Methadone

QT prolongation

syncope

heroin


Peripheral neuropathy caused by high-dose cytosine arabinoside treatment in a patient with acute myeloid leukemia.

The central nervous system toxicity of high-dose cytosine arabinoside is well recognized, but the toxicity of cytosine arabinoside in the peripheral nervous system has been infrequently reported. A 49-year-old Japanese man was diagnosed with acute myeloid leukemia. After he achieved complete remission, he received high-dose cytosine arabinoside treatment (2 g/m2 twice a day for 5 days; total, 20 g/m2) as consolidation therapy. The first course of high-dose cytosine arabinoside resulted in no unusual symptoms, but on day 21 of the second course of treatment, the patient complained of numbness in his right foot. Electromyogram and nerve-conduction studies showed peripheral neuropathy in both peroneal nerves. This neuropathy was gradually resolving; however, after the patient received allogeneic bone marrow transplantation, the symptoms worsened, with the development of graft-versus-host disease, and the symptoms subsequently responded to methylprednisolone. Although the mechanisms of peripheral neuropathy are still unclear, high-dose cytosine arabinoside is a therapy that is potentially toxic to the peripheral nervous system, and auto/alloimmunity may play an important role in these mechanisms.

Peripheral neuropathy

cytosine arabinoside

acute myeloid leukemia

toxicity

cytosine arabinoside

toxicity

cytosine arabinoside

acute myeloid leukemia

cytosine arabinoside

cytosine arabinoside

numbness

peripheral neuropathy

neuropathy

graft-versus-host disease

methylprednisolone

peripheral neuropathy

cytosine arabinoside


Atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.

To assess the antioxidant effects of atorvastatin (atorva) on dexamethasone (dex)-induced hypertension, 60 male Sprague-Dawley rats were treated with atorva 30 mg/kg/day or tap water for 15 days. Dex increased systolic blood pressure (SBP) from 109 +/- 1.8 to 135 +/- 0.6 mmHg and plasma superoxide (5711 +/- 284.9 saline, 7931 +/- 392.8 U/ml dex, P < 0.001). In this prevention study, SBP in the atorva + dex group was increased from 115 +/- 0.4 to 124 +/- 1.5 mmHg, but this was significantly lower than in the dex-only group (P' < 0.05). Atorva reversed dex-induced hypertension (129 +/- 0.6 mmHg, vs. 135 +/- 0.6 mmHg P' < 0.05) and decreased plasma superoxide (7931 +/- 392.8 dex, 1187 +/- 441.2 atorva + dex, P < 0.0001). Plasma nitrate/nitrite (NOx) was decreased in dex-treated rats compared to saline-treated rats (11.2 +/- 1.08 microm, 15.3 +/- 1.17 microm, respectively, P < 0.05). Atorva affected neither plasma NOx nor thymus weight. Thus, atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.

Atorvastatin

dexamethasone

hypertension

atorvastatin

atorva

dexamethasone

dex

hypertension

atorva

Dex

superoxide

dex

atorva

dex

dex

Atorva

dex

hypertension

superoxide

dex

atorva

dex

nitrate

nitrite

dex

Atorva

atorvastatin

dexamethasone

hypertension


Two prodrugs of potent and selective GluR5 kainate receptor antagonists actives in three animal models of pain.

Amino acids 5 and 7, two potent and selective competitive GluR5 KA receptor antagonists, exhibited high GluR5 receptor affinity over other glutamate receptors. Their ester prodrugs 6 and 8 were orally active in three models of pain: reversal of formalin-induced paw licking, carrageenan-induced thermal hyperalgesia, and capsaicin-induced mechanical hyperalgesia.

kainate

pain

KA

glutamate

pain

formalin

carrageenan

thermal hyperalgesia

capsaicin

mechanical hyperalgesia


Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients.

Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been available for almost 20 years. Although these drugs are highly effective and represent the mainstay of transplant immunosuppression, they are associated with acute and chronic nephrotoxicity. Acute nephrotoxicity, which occurs in the early period after transplantation, leads to a higher rate of dialysis, and chronic nephrotoxicity may eventually result in graft loss. Acute and chronic nephrotoxicity is becoming more common as the use of marginal kidneys for transplantation increases. Two recently available immunosuppressive agents, mycophenolate mofetil and sirolimus (rapamycin), have no nephrotoxicity. The use of these drugs in combination with other agents has led to the development of new paradigms of immunosuppressive therapy. This paper reviews the results of clinical trials that have investigated these new approaches to immunosuppression in renal transplant recipients.

Sirolimus

mycophenolate mofetil

cyclosporine

tacrolimus

nephrotoxicity

nephrotoxicity

nephrotoxicity

nephrotoxicity

mycophenolate mofetil

sirolimus

rapamycin

nephrotoxicity


Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors.

The aim of this study was to examine the impact of anemia prevention by recombinant human erythropoietin (rHuEPO) treatment on the cytotoxicity of cyclophosphamide in solid experimental tumors. Anemia was induced using a single dose of carboplatin (50 mg/kg i.v.) resulting in a long-lasting reduction (30%) of the hemoglobin concentration. In a second group, the development of anemia was prevented by rHuEPO (1000 IU/kg) administered s.c. three times/week starting 7 days before carboplatin application. Four days after carboplatin treatment, tumors (DS-sarcoma of the rat) were implanted s.c. onto the hind food dorsum. Neither carboplatin nor rHuEPO treatment influenced tumor growth rate per se. When tumors were treated with a single dose of cyclophosphamide (60 mg/kg i.p.) 5 days after implantation, a growth delay with a subsequent regrowth of the tumors was observed. In the anemia group, the growth delay was significantly shorter compared with nonanemic controls (13.3 days versus 8.6 days). In the group where anemia was prevented by rHuEPO treatment, growth delay was comparable with that of nonanemic controls (13.3 days). These results suggest that chemotherapy-induced anemia reduces cytotoxicity of cyclophosphamide in tumors, whereas correction of anemia by rHuEPO treatment (epoetin alpha) increases the sensitivity, probably as a result of an improved oxygen supply to tumor tissue.

anemia

cyclophosphamide

cytotoxicity

tumors

anemia

cytotoxicity

cyclophosphamide

tumors

Anemia

carboplatin

anemia

carboplatin

carboplatin

tumors

sarcoma

carboplatin

tumor

tumors

cyclophosphamide

tumors

anemia

anemia

anemia

cytotoxicity

cyclophosphamide

tumors

anemia

oxygen

tumor


The role of nitrergic system in lidocaine-induced convulsion in the mouse.

The effects of N-nitro-L-arginine-methyl ester (L-NAME) a nitric oxide (NO) synthase inhibitor and L-arginine, a NO precursor, were investigated on lidocaine-induced convulsions. In the first experiment, four groups of mice received physiological saline (0.9%), L-arginine (300 mg/kg, i.p.), L-NAME (100 mg/kg, i.p.) and diazepam (2 mg/kg), respectively. Thirty minutes after these injections, all mice received lidocaine (50 mg/kg, i.p.). In the second experiment, four groups of mice received similar treatment in the first experiment, and 30 min after these injections, all mice received a higher dose of lidocaine (80 mg/kg). L-NAME (100 mg/kg, i.p.) and diazepam (2 mg/kg) significantly decreased the incidence of lidocaine (50 mg/kg)-induced convulsions. In contrast, the L-arginine treatment increased the incidence of lidocaine (80 mg/kg, i.p.)-induced convulsions significantly. These results may suggest that NO is a proconvulsant mediator in lidocaine-induced convulsions.

lidocaine

convulsion

N-nitro-L-arginine-methyl ester

L-NAME

nitric oxide

NO

L-arginine

NO

lidocaine

convulsions

L-arginine

L-NAME

diazepam

lidocaine

lidocaine

L-NAME

diazepam

lidocaine

convulsions

L-arginine

lidocaine

convulsions

NO

lidocaine

convulsions


Effect of intravenous metoprolol or intravenous metoprolol plus glucagon on dobutamine-induced myocardial ischemia.

STUDY OBJECTIVE: To determine the effect of metoprolol on dobutamine stress testing with technetium-99m sestamibi single-photon emission computed tomography imaging and ST-segment monitoring, and to assess the impact of intravenous glucagon on metoprolol's effects. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Community hospital. PATIENTS: Twenty-two patients with known reversible perfusion defects. INTERVENTION: Patients underwent dobutamine stress tests per standard protocol. Before dobutamine was begun, no therapy was given during the first visit, and patients were randomized on subsequent visits to receive metoprolol or metoprolol plus glucagon 1 mg. Metoprolol was dosed to achieve a resting predobutamine heart rate below 65 beats/minute or a total intravenous dose of 20 mg. MEASUREMENTS AND MAIN RESULTS: Metoprolol reduced maximum heart rate 31%, summed stress scores 29%, and summed difference scores 43% versus control. Metoprolol plus glucagon also reduced the maximum heart rate 29% versus control. Summed stress and summed difference scores were not significantly reduced, although they were 18% and 30% lower, respectively, than control. No significant differences were found in any parameter between metoprolol and metoprolol-glucagon. CONCLUSION: During dobutamine stress testing, metoprolol attenuates or eliminates evidence of myocardial ischemia. Glucagon 1 mg, although somewhat effective, does not correct this effect to the extent that it can be administered clinically.

metoprolol

metoprolol

dobutamine

myocardial ischemia

metoprolol

dobutamine

technetium-99m sestamibi

metoprolol

dobutamine

dobutamine

metoprolol

metoprolol

Metoprolol

predobutamine

Metoprolol

Metoprolol

metoprolol

metoprolol

dobutamine

metoprolol

myocardial ischemia


Prednisolone-induced muscle dysfunction is caused more by atrophy than by altered acetylcholine receptor expression.

Large doses of glucocorticoids can alter muscle physiology and susceptibility to neuromuscular blocking drugs by mechanisms not clearly understood. We investigated the effects of moderate and large doses of prednisolone on muscle function and pharmacology, and their relationship to changes in muscle size and acetylcholine receptor (AChR) expression. With institutional approval, 35 Sprague-Dawley rats were randomly allocated to receive daily subcutaneous doses of 10 mg/kg prednisolone (P10 group), 100 mg/kg prednisolone (P100 group), or an equal volume of saline (S group) for 7 days. A fourth group of rats was pair fed (food restricted) with the P100 rats for 7 days (FR group). On Day 8, the nerve-evoked peak twitch tensions, tetanic tensions, and fatigability, and the dose-response curves of d-tubocurarine in the tibialis cranialis muscle were measured in vivo and related to muscle mass or expression of AChRs. Rate of body weight gain was depressed in the P100, FR, and P10 groups compared with the S group. Tibialis muscle mass was smaller in the P100 group than in the P10 or S groups. The evoked peak twitch and tetanic tensions were less in the P100 group than in the P10 or S groups, however, tension per milligram of muscle mass was greater in the P100 group than in the S group. The 50% effective dose of d-tubocurarine (microg/kg) in the tibialis muscle was smaller in the P10 (33.6 +/- 5.4) than in the S (61.9 +/- 5.0) or the P100 (71.3 +/- 9.6) groups. AChR expression was less in the P10 group than in the S group. The evoked tensions correlated with muscle mass (r(2) = 0.32, P < 0.001), however, not with expression of AChR. The 50% effective dose of d-tubocurarine did not correlate with muscle mass or AChR expression. Our results suggest that the neuromuscular dysfunction after prednisolone is dose-dependent, and derives primarily from muscle atrophy and derives less so from changes in AChR expression. IMPLICATIONS: The mechanisms by which chronic glucocorticoid therapy alters neuromuscular physiology and pharmacology are unclear. We suggest that the observed effects are dose-dependent and derive primarily from muscle atrophy and derive less from changes in acetylcholine receptor expression.

Prednisolone

muscle dysfunction

atrophy

acetylcholine

prednisolone

acetylcholine

prednisolone

prednisolone

tetanic

d-tubocurarine

tetanic

d-tubocurarine

d-tubocurarine

neuromuscular dysfunction

prednisolone

muscle atrophy

muscle atrophy

acetylcholine


Rapid reversal of life-threatening diltiazem-induced tetany with calcium chloride.

We describe a patient who developed tetany with sudden respiratory arrest after the infusion of intravenous diltiazem. The administration of calcium chloride rapidly resolved the patient's tetany with prompt recovery of respiratory function, averting the need for more aggressive airway management and ventilatory support. The emergency physician should be aware that life-threatening tetany may accompany the administration of intravenous diltiazem and that calcium chloride may be a rapid and effective remedy.

diltiazem

tetany

calcium chloride

tetany

respiratory arrest

diltiazem

calcium chloride

tetany

tetany

diltiazem

calcium chloride


Effects of nonsteroidal anti-inflammatory drugs on hemostasis in patients with aneurysmal subarachnoid hemorrhage.

Platelet function is impaired by nonsteroidal anti-inflammatory drugs (NSAIDs) with prominent anti-inflammatory properties. Their safety in patients undergoing intracranial surgery is under debate. Patients with aneurysmal subarachnoid hemorrhage (SAH) were randomized to receive either ketoprofen, 100 mg, three times a day (ketoprofen group, n = 9) or a weak NSAID, acetaminophen, 1 g, three times a day (acetaminophen group, n = 9) starting immediately after the diagnosis of aneurysmal SAH. Treatment was continued for 3 days postoperatively. Test blood samples were taken before treatment and surgery as well as on the first, third, and fifth postoperative mornings. Maximal platelet aggregation induced by 6 microM of adenosine diphosphate decreased after administration of ketoprofen. Aggregation was lower (P < .05) in the ketoprofen group than in the acetaminophen group just before surgery and on the third postoperative day. In contrast, maximal platelet aggregation increased in the acetaminophen group on the third postoperative day as compared with the pretreatment platelet aggregation results (P < .05). One patient in the ketoprofen group developed a postoperative intracranial hematoma. Coagulation (prothrombin time [PT], activated partial thromboplastin time [APPT], fibrinogen concentration, and antithrombin III [AT III]) was comparable between the two groups. Ketoprofen but not acetaminophen impaired platelet function in patients with SAH. If ketoprofen is used before surgery on cerebral artery aneurysms, it may pose an additional risk factor for hemorrhage.

aneurysmal subarachnoid hemorrhage

aneurysmal subarachnoid hemorrhage

SAH

ketoprofen

ketoprofen

acetaminophen

acetaminophen

aneurysmal

SAH

platelet aggregation

adenosine diphosphate

ketoprofen

ketoprofen

acetaminophen

platelet aggregation

acetaminophen

platelet aggregation

ketoprofen

hematoma

Ketoprofen

acetaminophen

SAH

ketoprofen

artery aneurysms

hemorrhage


Value of methylprednisolone in prevention of the arthralgia-myalgia syndrome associated with the total dose infusion of iron dextran: a double blind randomized trial.

The safety and efficacy of total dose infusion (TDI) of iron dextran has been well documented. In 40% of treated patients, an arthralgia-myalgia syndrome develops. The purpose of this randomized, double-blind, prospective study was to investigate whether intravenous (i.v.) administration of methylprednisolone (MP) prevents this complication. Sixty-five patients, 34 women and 31 men, ages 36 to 80 years, received either normal saline before and after TDI (group 1), 125 mg i.v. MP before and saline after TDI (group 2), or 125 mg i.v. MP before and after TDI (group 3). Patients were observed for 72 hours and reactions were recorded and graded according to severity. Fifty-eight percent of group 1 patients, 33% of group 2, and 26% of group 3 had reactions to TDI. The severity of reactions (minimal, mild, and moderate, respectively) was as follows: group 1--6, 6, and 2; group 2--1, 5, and 0; group 3--5, 1, and 0. Data were analyzed by the two-sided Fisher's exact test using 95% confidence intervals with the approximation of Woolf. These data demonstrate that administration of MP before and after TDI reduces the frequency and severity of the arthralgia-myalgia syndrome. We conclude that 125 mg i.v. MP should be given routinely before and after TDI of iron dextran.

methylprednisolone

arthralgia

myalgia

iron dextran

iron dextran

arthralgia

myalgia

methylprednisolone

MP

MP

MP

MP

arthralgia

myalgia

MP

iron dextran


Long-term effects of vincristine on the peripheral nervous system.

Forty patients with Non-Hodgkin's Lymphoma treated with vincristine between 1984 and 1990 (cumulative dose 12 mg in 18-24 weeks) were investigated in order to evaluate the long term effects of vincristine on the peripheral nervous system. The patients were interviewed with emphasis on neuropathic symptoms. Physical and quantitative sensory examination with determination of vibratory perception and thermal discrimination thresholds were performed, four to 77 months (median 34 months) after vincristine treatment. Twenty-seven patients reported neuropathic symptoms. In 13 of these 27 patients symptoms were still present at the time of examination. In these patients sensory signs and symptoms predominated. In the other 14 patients symptoms had been present in the past. Symptoms persisted maximally 40 months since cessation of therapy. There was no age difference between patients with and without complaints at the time of examination. Normal reflexes were found in two third of patients. Neuropathic complaints were not very troublesome on the long term. It is concluded that with the above mentioned vincristine dose schedule signs and symptoms of vincristine neuropathy are reversible for a great deal and prognosis is fairly good.

vincristine

Non-Hodgkin's Lymphoma

vincristine

vincristine

neuropathic symptoms

vincristine

neuropathic symptoms

vincristine

vincristine

neuropathy


A case of polymyositis in a patient with primary biliary cirrhosis treated with D-penicillamine.

Although D-penicillamine has been used for many rheumatologic diseases, toxicity limits its usefulness in many patients. Polymyositis/dermatomyositis can develop as one of the autoimmune complications of D-penicillamine treatment, but its exact pathogenesis remains unclear. We report a patient with primary biliary cirrhosis, who developed polymyositis while receiving D-penicillamine therapy. We described the special clinical course of the patient. Patients receiving D-penicillamine therapy should be followed carefully for the development of autoimmune complications like polymyositis/dermatomyositis.

polymyositis

primary biliary cirrhosis

D-penicillamine

D-penicillamine

rheumatologic diseases

toxicity

Polymyositis

dermatomyositis

D-penicillamine

primary biliary cirrhosis

polymyositis

D-penicillamine

D-penicillamine

polymyositis

dermatomyositis


Photodistributed nifedipine-induced facial telangiectasia.

Five months after starting nifedipine (Adalat), two patients developed photodistributed facial telangiectasia, which became more noticeable with time. Neither patient complained of photosensitivity or flushing. Both patients reported a significant cosmetic improvement after discontinuing the drug. One commenced the closely related drug amlodipine 3 years later, with recurrence of telangiectasia. The photodistribution of the telangiectasia suggests a significant drug/light interaction.

nifedipine

telangiectasia

nifedipine

Adalat

telangiectasia

flushing

amlodipine

telangiectasia

telangiectasia


Nephrotoxicity of cyclosporin A and FK506: inhibition of calcineurin phosphatase.

Cyclosporin A (CsA; 50 mg/kg) and Fujimycine (FK506; 5 mg/kg), but not the related macrolide immunosuppressant rapamycin (5 mg/kg), caused a reduction of glomerular filtration rate, degenerative changes of proximal tubular epithelium, and hypertrophy of the juxtaglomerular apparatus in male Wistar rats when given for 10 days. The molecular mechanisms of CsA and FK506 toxicity were investigated. Cyclophilin A and FK506-binding protein, the main intracytoplasmic receptors for CsA and FK506, respectively, were each detected in renal tissue extract. In the kidney, high levels of immunoreactive and enzymatically active calcineurin were found which were inhibited by the immunosuppressants CsA and FK506, but not by rapamycin. Finally, specific immunophilin-drug-calcineurin complexes formed only in the presence of CsA and FK506, but not rapamycin. These results suggest that the nephrotoxic effects of CsA and FK506 is likely mediated through binding to renal immunophilin and inhibiting calcineurin phosphatase.

Nephrotoxicity

cyclosporin A

Cyclosporin A

CsA

Fujimycine

macrolide

rapamycin

hypertrophy

CsA

toxicity

CsA

CsA

rapamycin

CsA

rapamycin

nephrotoxic

CsA


Massive cerebral edema associated with fulminant hepatic failure in acetaminophen overdose: possible role of cranial decompression.

Cerebral edema may complicate the course of fulminant hepatic failure. Response to conventional therapy has been disappointing. We present a patient with fatal acetaminophen-induced fulminant hepatic failure, with signs and symptoms of cerebral edema, unresponsive to conventional medical therapy. Cranial decompression was carried out. A justification of the need for further evaluation of cranial decompression in such patients is presented.

cerebral edema

hepatic failure

acetaminophen

overdose

Cerebral edema

fulminant hepatic failure

acetaminophen

fulminant hepatic failure

cerebral edema


Gentamicin nephropathy in a neonate.

The clinical and autopsy findings in a premature baby who died of acute renal failure after therapy with gentamicin (5 mg/kg/day) and penicillin are presented. The serum gentamicin concentration had reached toxic levels when anuria developed. Numerous periodic acid Schiff (PAS) positive, diastase resistant cytoplasmic inclusion bodies which appeared as myelin figures in cytosegresomes under the electron microscope were identified in the proximal convoluted tubules. The pathological changes induced by gentamicin in the human neonatal kidneys have not been previously reported.

Gentamicin

nephropathy

acute renal failure

gentamicin

penicillin

gentamicin

anuria

periodic acid

gentamicin