Effects of ouabain on myocardial oxygen supply and demand in patients with chronic coronary artery disease. A hemodynamic, volumetric, and metabolic study in patients without heart failure.

The effects of digitalis glycosides on myocardial oxygen supply and demand are of particular interest in the presence of obstructive coronary artery disease, but have not been measured previously in man. We assessed the effects of ouabain (0.015 mg/kg body weight) on hemodynamic, volumetric, and metabolic parameters in 11 patients with severe chronic coronary artery disease without clinical congestive heart failure. Because the protocol was long and involved interventions which might affect the determinations, we also studied in nine patients using an identical protocol except that ouabain administration was omitted. Left ventricular end-diastolic pressure and left ventricular end-diastolic volume fell in each patient given ouabain, even though they were initially elevated in only two patients. Left ventricular end-diastolic pressure fell from 11.5+/-1.4 (mean+/-SE) to 5.6+/-0.9 mm Hg (P less than 0.001) and left ventricular end-diastolic volume fell from 100+/-17 to 82+/-12 ml/m2 (P less than 0.01) 1 h after ouabain infusion was completed. The maximum velocity of contractile element shortening increased from 1.68+/-0.11 ml/s to 2.18+/-0.21 muscle-lengths/s (P less than 0.05) and is consistent with an increase in contractility. No significant change in these parameters occurred in the control patients. No significant change in myocardial oxygen consumption occurred after ouabain administration but this may be related to a greater decrease in mean arterial pressure in the ouabain patients than in the control patients. We conclude that in patients with chronic coronary artery disease who are not in clinical congestive heart failure left ventricular end-diastolic volume falls after ouabain administration even when it is initially normal. Though this fall would be associated with a decrease in wall tension, and, therefore, of myocardial oxygen consumption, it may not be of sufficient magnitude to prevent a net increase in myocardial oxygen consumption. Nevertheless, compensatory mechanisms prevent a deterioration of resting myocardial metabolism.

ouabain

oxygen

coronary artery disease

heart failure

digitalis glycosides

oxygen

coronary artery disease

ouabain

coronary artery disease

congestive heart failure

ouabain

ouabain

ouabain

oxygen

ouabain

ouabain

coronary artery disease

congestive heart failure

ouabain

oxygen

oxygen


Prolongation of the QT interval related to cisapride-diltiazem interaction.

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.

Prolongation of the QT interval

cisapride

diltiazem

Cisapride

gastrointestinal motility disorders

Prolongation of QT interval

torsades de pointes

sudden cardiac death

erythromycin

azole

cisapride

gastroesophageal reflux disorder

diltiazem

hypertension

syncope

QT-interval prolongation

cisapride

cisapride

diltiazem


Paclitaxel combined with carboplatin in the first-line treatment of advanced ovarian cancer.

In a phase I study to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in combination with carboplatin administered every 21 days to women with advanced ovarian cancer, paclitaxel doses were escalated as follows: level 1, 135 mg/m2; level 2, 160 mg/m2; level 3, 185 mg/m2; and level 4,210 mg/m2. The fixed dose of carboplatin at levels 1 through 4 was given to achieve an area under the concentration-time curve (AUC) of 5 using the Calvert formula. In levels 5 and 6 the carboplatin dose was targeted at AUCs of 6 and 7.5, respectively, combined with a fixed paclitaxel dose of 185 mg/m2. To date, 30 previously untreated patients, all with a good performance status (Eastern Cooperative Oncology Group 0 to 2) have been entered into this ongoing study. The dose-limiting toxicity of the combination was myelosuppression (leukopenia, granulocytopenia, and thrombocytopenia). Neurotoxicity was largely moderate. So far, 14 patients are evaluable for response; of these, eight (57%) showed objective (complete or partial) response and disease stabilized in six patients. No patient had disease progression. We conclude that the combination of paclitaxel 185 mg/m2 administered as a 3-hour infusion followed immediately by a 1-hour infusion of carboplatin at an AUC of 6 can be administered safely in a 21-day schedule in the outpatient setting. The recommended dose for phase III studies is paclitaxel 185 mg/m2 and carboplatin AUC 6.

Paclitaxel

carboplatin

ovarian cancer

paclitaxel

Taxol

carboplatin

ovarian cancer

paclitaxel

carboplatin

carboplatin

paclitaxel

toxicity

myelosuppression

leukopenia

granulocytopenia

thrombocytopenia

Neurotoxicity

paclitaxel

carboplatin

paclitaxel

carboplatin


Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients.

When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4%) and late in 41 (58.6%). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritus (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2%) had improvement/resolution; in 4 (9.8%), adverse effects persisted. The overall rejection rate was 30%. Sixty-two patients (88.6%) are alive with functioning grafts 686 +/- 362 days (range, 154-1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome.

tacrolimus

cyclosporine

tacrolimus

cyclosporine

tacrolimus

tacrolimus

tacrolimus

neurotoxicity

(insulin-dependent) diabetes mellitus

IDDM

nephrotoxicity

gastrointestinal (GI) toxicity

cardiomyopathy

neurotoxicity

IDDM

nephrotoxicity

GI toxicity

hepatotoxicity

PTLD

cardiomyopathy

hemolytic anemia

pruritus

tacrolimus


Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

toxicity

netilmicin

tobramycin

netilmicin sulfate

tobramycin sulfate

piperacillin sodium

infections

Nephrotoxicity

netilmicin

tobramycin

Ototoxicity

netilmicin

piperacillin

tobramycin

piperacillin

netilmicin

piperacillin

tobramycin

piperacillin

netilmicin

piperacillin

tobramycin

piperacillin

aminoglycoside

ototoxicity

netilmicin

tobramycin


Effect of prostaglandin synthetase inhibitors on experimentally induced convulsions in rats.

To investigate the relationship of prostaglandins (PGs) to seizure induction, the effects of six PG synthetase inhibitors on convulsions induced by flurothyl, picrotoxin, pentetrazol (PTZ), electroshock or bicuculline were evaluated. Ibuprofen, sulindac, mefenamic acid, and low dose meclofenamic acid increased the latency-to-onset in the flurothyl and/or PTZ models; the electroshock, picrotoxin and bicuculline models were not significantly affected by any of the pretreatment agents. These results suggest that PGs are involved in the mechanism(s) underlying fluorthyl- and PTZ-induced convulsions, but not picrotoxin-, electroshock-, or bicuculline-induced convulsions.

prostaglandin

convulsions

prostaglandins

PGs

seizure

convulsions

flurothyl

picrotoxin

pentetrazol

PTZ

bicuculline

Ibuprofen

sulindac

mefenamic acid

meclofenamic acid

flurothyl

PTZ

picrotoxin

bicuculline

PGs

fluorthyl

PTZ

convulsions

picrotoxin

bicuculline

convulsions


Angiotensin-converting enzyme (ACE) inhibitor-associated angioedema of the stomach and small intestine: a case report.

This is a case report on a 45-year old African-American female with newly diagnosed hypertension, who was started on a combination pill of amlodipine/benazapril 10/5 mg. The very next day, she presented at the emergency room (ER) with abdominal pain, nausea and vomiting. Physical exam, complete metabolic panel, and hemogram were in the normal range. She was discharged from the ER after a few hours of treatment with fluid and analgesics. However, she returned to the ER the next day with the same complaints. This time the physical exam was significant for a distended abdomen with dullness to percussion. CT scan of the abdomen revealed markedly thickened antrum of the stomach, duodenum and jejunum, along with fluid in the abdominal and pelvic cavity. Angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema was suspected, and anti-hypertensive medications were discontinued. Her symptoms improved within the next 24 hours, and repeat CT after 72 hours revealed marked improvement in stomach and small bowel thickening and resolution of ascites. The recognition of angiotensin-converting enzyme (ACE) and angiotensin receptor blocker (ARB) intestinal angioedema constitutes a challenge to primary care physicians, internists, emergency room personal and surgeons.

angioedema

hypertension

amlodipine

benazapril

abdominal pain

nausea

vomiting

angioedema

hypertensive

ascites

angiotensin

angiotensin

intestinal angioedema

intestinal

angioedema


Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats.

A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.

Valproic acid

liver toxicity

valproic acid

valproic acid

VPA

VPA

hepatotoxicity

VPA

lipid hydroperoxides

LPO

thiobarbituric acid reactive substances

TBARs

VPA

LPO

TBARs

Liver toxicity

glutathione

hepatotoxicity

inflammation

necrosis

steatosis

VPA

VPA

necrosis

steatosis


Pheochromocytoma unmasked by amisulpride and tiapride.

OBJECTIVE: To describe the unmasking of pheochromocytoma in a patient treated with amisulpride and tiapride. CASE SUMMARY: A 42-year-old white man developed acute hypertension with severe headache and vomiting 2 hours after the first doses of amisulpride 100 mg and tiapride 100 mg. Both drugs were immediately discontinued, and the patient recovered after subsequent nicardipine and verapamil treatment. Abdominal ultrasound showed an adrenal mass, and postoperative histologic examination confirmed the diagnosis of pheochromocytoma. DISCUSSION: Drug-induced symptoms of pheochromocytoma are often associated with the use of substituted benzamide drugs, but the underlying mechanism is unknown. In our case, use of the Naranjo probability scale indicated a possible relationship between the hypertensive crisis and amisulpride and tiapride therapy. CONCLUSIONS: As of March 24, 2005, this is the first reported case of amisulpride- and tiapride-induced hypertensive crisis in a patient with pheochromocytoma. Physicians and other healthcare professionals should be aware of this potential adverse effect of tiapride and amisulpride.

Pheochromocytoma

amisulpride

tiapride

pheochromocytoma

amisulpride

tiapride

hypertension

headache

vomiting

amisulpride

tiapride

nicardipine

verapamil

pheochromocytoma

pheochromocytoma

benzamide

hypertensive

amisulpride

tiapride

amisulpride

tiapride

hypertensive

pheochromocytoma

tiapride

amisulpride


Quantitative drug levels in stimulant psychosis: relationship to symptom severity, catecholamines and hyperkinesia.

To examine the relationship between quantitative stimulant drug levels, catecholamines, and psychotic symptoms, nineteen patients in a psychiatric emergency service with a diagnosis of amphetamine- or cocaine-induced psychosis were interviewed, and plasma and urine were collected for quantitative assays of stimulant drug and catecholamine metabolite levels. Methamphetamine or amphetamine levels were related to several psychopathology scores and the global hyperkinesia rating. HVA levels were related to global hyperkinesia but not to psychopathology ratings. Although many other factors such as sensitization may play a role, intensity of stimulant-induced psychotic symptoms and stereotypies appears to be at least in part dose-related.

psychosis

catecholamines

hyperkinesia

catecholamines

psychotic symptoms

psychiatric

amphetamine

cocaine

psychosis

catecholamine

Methamphetamine

amphetamine

hyperkinesia

hyperkinesia

psychotic symptoms

stereotypies


Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium.

A 51 year old man took a mixed overdose including 1.8-3.6 g of diltiazem, paracetamol, aspirin, isosorbide nitrate, and alcohol. He initially presented to hospital after six hours with mild hypotension and was treated with activated charcoal and intravenous fluids. Eighteen hours after the overdose he had two generalised tonic-clonic seizures. The patient remained unresponsive with junctional bradycardia, unrecordable blood pressure, and then became asystolic. He was resuscitated with high dose (13.5 g) intravenous calcium and adrenaline (epinephrine). He required inotropic support and temporary pacing over the next 48 hours. This case suggests there is a role for aggressive high dose intravenous calcium therapy in severe diltiazem overdose, particularly with the onset of asystole. It should be considered early in cases of cardiac arrest after diltiazem overdose. The case also highlights the problems with delayed toxicity when whole bowel irrigation is not administered.

asystolic

cardiac arrest

diltiazem

overdose

calcium

overdose

diltiazem

paracetamol

aspirin

isosorbide

nitrate

alcohol

hypotension

overdose

tonic-clonic seizures

bradycardia

asystolic

calcium

adrenaline

epinephrine

calcium

diltiazem

overdose

asystole

cardiac arrest

diltiazem

overdose

toxicity


Renal papillary necrosis due to naproxen.

A 31-year-old man with rheumatoid arthritis, who had previously been treated with sulindac, fenoprofen calcium, high dose salicylates and gold salts, developed renal papillary necrosis (RPN) 4 months after institution of naproxen therapy. No other factor predisposing to RPN could be discovered. Sulindac was substituted for naproxen and no further adverse renal effects occurred over the next 12 months. We review previous reports linking RPN to antiinflammatory drug use and discuss possible advantages of sulindac in patients who have experienced renal toxicity from other antiinflammatory agents.

Renal papillary necrosis

naproxen

rheumatoid arthritis

sulindac

fenoprofen calcium

salicylates

gold

renal papillary necrosis

RPN

naproxen

RPN

Sulindac

naproxen

RPN

sulindac

renal toxicity


Adverse interaction between beta-adrenergic blocking drugs and verapamil--report of three cases.

Three patients with ischaemic heart disease developed profound cardiac failure, hypotension and bradycardia during combined therapy with verapamil and beta-adrenergic blocking drugs. This clinical picture resolved completely with cessation of the combined therapy. Baseline left ventricular function, assessed by cardiac catheterisation or nuclear angiography, was normal in two patients and only mildly reduced in the other. Simultaneously administration of beta-adrenergic blocking drugs and verapamil may result in profound adverse interactions and should only be administered with great caution.

beta-adrenergic blocking drugs

verapamil

ischaemic heart disease

cardiac failure

hypotension

bradycardia

verapamil

beta-adrenergic blocking drugs

beta-adrenergic blocking drugs

verapamil


Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension.

Participants in the Medical Research Council treatment trial for mild hypertension are randomly allocated to one of four treatment groups: bendrofluazide, propranolol, or a placebo for either of these drugs. The trial is single-blind. 23 582 patient-years of observation have been completed so far, 10 684 on active drugs and 12 898 on placebos. The results show an association between bendrofluazide treatment and impotence, and impotence also occurred more frequently in patients taking propranolol than in those taking placebos. Other adverse reactions significantly linked with active drugs include impaired glucose tolerance in men and women and gout in men, associated with bendrofluazide treatment, and Raynaud's phenomenon and dyspnoea in men and women taking propranolol. No corneal disease is known to have occurred in the propranolol group. Mean serum potassium level fell, and urea and uric acid levels rose, in men and women taking bendrofluazide. In the propranolol group, serum potassium and uric acid levels rose in both sexes, but the urea level rose significantly in women only.

bendrofluazide

propranolol

hypertension

Hypertension

hypertension

bendrofluazide

propranolol

bendrofluazide

impotence

impotence

propranolol

impaired glucose tolerance

gout

bendrofluazide

Raynaud's phenomenon

dyspnoea

propranolol

corneal disease

propranolol

potassium

urea

uric acid

bendrofluazide

propranolol

potassium

uric acid

urea


Dexmedetomidine and cardiac protection for non-cardiac surgery: a meta-analysis of randomised controlled trials.

We conducted a systematic review of the effects of dexmedetomidine on cardiac outcomes following non-cardiac surgery. We included prospective, randomised peri-operative studies of dexmedetomidine that reported mortality, cardiac morbidity or adverse drug events. A PubMed Central and EMBASE search was conducted up to July 2007. The reference lists of identified papers were examined for further trials. Of 425 studies identified, 20 were included in the meta-analysis (840 patients). Dexmedetomidine was associated with a trend towards improved cardiac outcomes; all-cause mortality (OR 0.27, 95% CI 0.01-7.13, p = 0.44), non-fatal myocardial infarction (OR 0.26, 95% CI 0.04-1.60, p = 0.14), and myocardial ischaemia (OR 0.65, 95% CI 0.26-1.63, p = 0.36). Peri-operative hypotension (26%, OR 3.80, 95% CI 1.91-7.54, p = 0.0001) and bradycardia (17%, OR 5.45, 95% CI 2.98-9.95, p < 0.00001) were significantly increased. An anticholinergic did not reduce the incidence of bradycardia (p = 0.43). A randomised placebo-controlled trial of dexmedetomidine is warranted.

Dexmedetomidine

dexmedetomidine

dexmedetomidine

Dexmedetomidine

myocardial infarction

myocardial ischaemia

hypotension

bradycardia

bradycardia

dexmedetomidine


Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus.

We report the clinical and bioptic findings for a 57-year-old woman with severe chloroquine-induced myopathy. Since 1989, she had been suffering from systemic lupus erythematosus (SLE) with renal involvement and undergone periods of treatment with azathioprine and cyclophosphamide. Additional therapy with chloroquine (CQ) was started because of arthralgia. At the same time, slightly increased creatine kinase (CK) levels were noted. Myositis was suspected, and the patient was treated with steroids. The CK increase persisted, however, and she developed progressive muscular weakness and muscular atrophy. Routine controls revealed markedly elevated CK levels of 1,700 U/l. The neurological and electrophysiological findings were not typical of myositis. Thus, muscle biopsy of the deltoid muscle was performed in order to exclude polymyositis or toxic myopathy. As it revealed chloroquine-induced myopathy, medication was stopped. Discriminating between primary SLE-induced affection of the musculoskeletal system and drug-induced side effects is important for appropriate treatment of SLE patients.

creatine

systemic lupus erythematosus

chloroquine

myopathy

systemic lupus erythematosus

SLE

renal involvement

azathioprine

cyclophosphamide

chloroquine

CQ

arthralgia

creatine

Myositis

steroids

muscular weakness

muscular atrophy

myositis

polymyositis

myopathy

chloroquine

myopathy

SLE

affection of the musculoskeletal system

SLE


Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children.

BACKGROUND: Adenovirus is an important cause of morbidity and mortality in the immunocompromised host. The incidence of severe adenovirus disease in pediatrics is increasing in association with growing numbers of immunocompromised children, where case fatality rates as high as 50% to 80% have been reported. There are no approved antiviral agents with proven efficacy for the treatment of severe adenovirus disease, nor are there any prospective randomized, controlled trials of potentially useful anti-adenovirus therapies. Apparent clinical success in the treatment of severe adenovirus disease is limited to a few case reports and small series. Experience is greatest with intravenous ribavirin and cidofovir. Ribavirin, a guanosine analogue, has broad antiviral activity against both RNA and DNA viruses, including documented activity against adenovirus in vitro. Ribavirin is licensed in aerosol form for the treatment of respiratory syncytial virus infection, and orally in combination with interferon to treat hepatitis C. Intravenous ribavirin is the treatment of choice for infection with hemorrhagic fever viruses. The most common adverse effect of intravenous ribavirin is reversible mild anemia. The use of cidofovir in severe adenovirus infection has been limited by adverse effects, the most significant of which is nephrotoxicity. OBJECTIVE: We report our experience with intravenous ribavirin therapy for severe adenovirus disease in a series of immunocompromised children and review the literature. DESIGN/METHODS: We retrospectively reviewed the medical records of 5 children treated with intravenous ribavirin for documented severe adenovirus disease. Two patients developed adenovirus hemorrhagic cystitis after cardiac and bone marrow transplants, respectively. The bone marrow transplant patient also received intravenous cidofovir for progressive disseminated disease. An additional 3 children developed adenovirus pneumonia; 2 were neonates, 1 of whom had partial DiGeorge syndrome. The remaining infant had recently undergone a cardiac transplant. Intravenous ribavirin was administered on a compassionate-use protocol. RESULTS: Complete clinical recovery followed later by viral clearance was observed in 2 children: the cardiac transplant recipient with adenovirus hemorrhagic cystitis and the immunocompetent neonate with adenovirus pneumonia. The remaining 3 children died of adenovirus disease. Intravenous ribavirin therapy was well tolerated. Use of cidofovir in 1 child was associated with progressive renal failure and neutropenia. DISCUSSION: Our series of patients is representative of the spectrum of immunocompromised children at greatest risk for severe adenovirus disease, namely solid-organ and bone marrow transplant recipients, neonates, and children with immunodeficiency. Although intravenous ribavirin was not effective for all children with severe adenovirus disease in this series or in the literature, therapy is unlikely to be of benefit if begun late in the course of the infection. Early identification, eg by polymerase chain reaction of those patients at risk of disseminated adenovirus disease may permit earlier antiviral treatment and better evaluation of therapeutic response. CONCLUSIONS: Two of 5 children with severe adenovirus disease treated with intravenous ribavirin recovered. The availability of newer rapid diagnostic techniques, such as polymerase chain reaction, may make earlier, more effective treatment of adenovirus infection possible. Given the seriousness and increasing prevalence of adenovirus disease in certain hosts, especially children, a large, multicenter clinical trial of potentially useful anti-adenoviral therapies, such as intravenous ribavirin, is clearly required to demonstrate the most effective and least toxic therapy.

ribavirin

adenovirus disease

adenovirus disease

adenovirus disease

adenovirus disease

ribavirin

cidofovir

Ribavirin

guanosine

Ribavirin

respiratory syncytial virus infection

hepatitis C

ribavirin

ribavirin

anemia

cidofovir

adenovirus infection

nephrotoxicity

ribavirin

adenovirus disease

ribavirin

adenovirus disease

hemorrhagic cystitis

hemorrhagic

cystitis

cidofovir

adenovirus pneumonia

adenovirus

pneumonia

DiGeorge syndrome

ribavirin

hemorrhagic cystitis

hemorrhagic

cystitis

adenovirus pneumonia

adenovirus

pneumonia

adenovirus disease

ribavirin

cidofovir

progressive renal failure

neutropenia

adenovirus disease

immunodeficiency

ribavirin

adenovirus disease

infection

adenovirus disease

adenovirus disease

ribavirin

adenovirus infection

adenovirus disease

ribavirin


Hepatotoxicity of amiodarone.

Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. The use of amiodarone has, however, been limited due to its serious side-effects. A patient with cholestatic hepatitis due to amiodarone treatment is presented below and a review of the hepatotoxicity of amiodarone is given. It is concluded that solid evidence exists of hepatic injury due to amiodarone treatment, including steatosis, alterations resembling alcoholic hepatitis, cholestatic hepatitis and micronodular cirrhosis of the liver. Patients receiving amiodarone should be regularly screened with respect to hepatic enzyme levels. Therapy should be discontinued on the suspicion of cholestatic injury or hepatomegaly.

Hepatotoxicity

amiodarone

Amiodarone

tachyarrhythmias

amiodarone

cholestatic hepatitis

cholestatic

hepatitis

amiodarone

hepatotoxicity

amiodarone

hepatic injury

amiodarone

steatosis

alcoholic hepatitis

cholestatic hepatitis

cholestatic

hepatitis

cirrhosis of the liver

amiodarone

cholestatic injury

hepatomegaly


Catalepsy induced by combinations of ketamine and morphine: potentiation, antagonism, tolerance and cross-tolerance in the rat.

Previous studies demonstrated that both ketamine and morphine induced analgesia and catalepsy in the rat. Pre-treatment with ketamine produced cross-tolerance to morphine, whereas pretreatment with morphine did not induce cross-tolerance to ketamine but rather augmented the cataleptic response; this augmentation was attributed to residual morphine in the brain. The present studies explored the duration of the loss of righting reflex induced by sub-effective doses of ketamine and morphine, administered simultaneously. There was mutual potentiation between sub-effective doses of ketamine and morphine, but sub-effective doses of ketamine partly antagonized fully-effective doses of morphine. Latency to the loss of righting reflex, rigidity and behavior on recovery, reflected the relative predominance of ketamine or morphine in each combination. Naloxone inhibited the induced cataleptic effects. The degree and time course of development of tolerance to daily administration of sub-effective dose combinations of ketamine and morphine were similar. Rats, tolerant to ketamine-dominant combinations, were cross-tolerant to both drugs, while those tolerant to morphine-dominant combinations were cross-tolerant to morphine but showed either no cross-tolerance or an augmented response to ketamine. While the mutual potentiation, antagonism and tolerance suggest common mechanisms for the induced catalepsy, differences in latency, rigidity and behavior, asymmetry of cross-tolerance and a widely-different ID50 for naloxone would argue against an action at a single opioid site.

Catalepsy

ketamine

morphine

ketamine

morphine

analgesia

catalepsy

ketamine

morphine

morphine

ketamine

cataleptic

morphine

ketamine

morphine

ketamine

morphine

ketamine

morphine

rigidity

ketamine

morphine

Naloxone

cataleptic

ketamine

morphine

ketamine

morphine

morphine

ketamine

catalepsy

rigidity

naloxone


Acute renal failure in patients with AIDS on tenofovir while receiving prolonged vancomycin course for osteomyelitis.

Renal failure developed after a prolonged course of vancomycin therapy in 2 patients who were receiving tenofovir disoproxil fumarate as part of an antiretroviral regimen. Tenofovir has been implicated in the development of Fanconi syndrome and renal insufficiency because of its effects on the proximal renal tubule. Vancomycin nephrotoxicity is infrequent but may result from coadministration with a nephrotoxic agent. Clinicians should be aware that tenofovir may raise the risk of renal failure during prolonged administration of vancomycin.

Acute renal failure

AIDS

tenofovir

vancomycin

osteomyelitis

Renal failure

vancomycin

tenofovir disoproxil fumarate

Tenofovir

Fanconi syndrome

renal insufficiency

Vancomycin

nephrotoxicity

nephrotoxic

tenofovir

renal failure

vancomycin


Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients.

BACKGROUND: A transient leukoencephalopathy mimicking cerebrovascular accident has been described as a complication of chemotherapy, most commonly in recipients of intrathecal methotrexate for childhood leukaemia. Recently published neuroimaging data suggest a common pathophysiology associated with a variety of chemotherapy agents and modes of administration. METHODS: We reviewed the medical literature for single reports and case series of patients presenting with stroke-like episodes while receiving systemic or intrathecal chemotherapy. We only included studies providing detailed neuroimaging data. Patients with cerebrovascular accidents were excluded. RESULTS: We identified 27 reports of toxic leukoencephalopathy in patients treated with methotrexate (intrathecal, systemic), 5-fluorouracil and its derivative carmofur, and capecitabine. Diffusion weighted imaging (DWI) of all patients revealed well demarcated hyperintense lesions within the subcortical white matter of the cerebral hemispheres and the corpus callosum, corresponding to areas of decreased proton diffusion on apparent diffusion coefficient (ADC) maps (available in 21/27 patients). Lesions exceeded the confines of adjacent vascular territories. Complete resolution of symptoms within 1-4 days was accompanied by normalisation of ADC abnormalities. However, fluid attenuated inversion recovery (FLAIR) sequences frequently revealed persistent white matter abnormalities. CONCLUSIONS: Several pathophysiological models of delayed leukoencephalopathy after exposure to intrathecal or systemic chemotherapy have been proposed. DWI findings in this cohort are indicative of cytotoxic oedema within cerebral white matter and lend support to an at least partially reversible metabolic derangement as the basis for this syndrome.

leukoencephalopathy

stroke

leukoencephalopathy

cerebrovascular accident

methotrexate

leukaemia

stroke

cerebrovascular accidents

leukoencephalopathy

methotrexate

carmofur

capecitabine

white matter abnormalities

leukoencephalopathy


Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics.

Alterations of norepinephrine transporter (NET) function by chronic inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied in mice. Daily administration of desipramine, an inhibitor of the NET, for 5 days decreased [(3)H]norepinephrine uptake in the P2 fractions of hippocampus but not cortex, striatum or amygdalae. Co-administration of lidocaine, bupivacaine or tricaine with desipramine reversed this effect. Daily treatment of cocaine increased [(3)H]norepinephrine uptake into the hippocampus. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. Co-administration of lidocaine with desipramine reversed the changes of convulsive activity of lidocaine and cocaine induced by repeated administration of desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na(+) channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. Repeated administration of cocaine induces up-regulation of hippocampal NET function. Desipramine-induced sensitization of lidocaine seizures may have a mechanism distinct from kindling resulting from repeated administration of cocaine.

norepinephrine

desipramine

convulsions

norepinephrine

seizures

cocaine

desipramine

norepinephrine

lidocaine

bupivacaine

tricaine

desipramine

cocaine

norepinephrine

desipramine

lidocaine

convulsions

cocaine

convulsions

lidocaine

desipramine

convulsive

lidocaine

cocaine

desipramine

desipramine

desipramine

lidocaine

convulsions

desipramine

cocaine

Desipramine

lidocaine

seizures

cocaine


Definition and management of anemia in patients infected with hepatitis C virus.

Chronic infection with hepatitis C virus (HCV) can progress to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. The current best treatment for HCV infection is combination therapy with pegylated interferon and ribavirin. Although this regimen produces sustained virologic responses (SVRs) in approximately 50% of patients, it can be associated with a potentially dose-limiting hemolytic anemia. Hemoglobin concentrations decrease mainly as a result of ribavirin-induced hemolysis, and this anemia can be problematic in patients with HCV infection, especially those who have comorbid renal or cardiovascular disorders. In general, anemia can increase the risk of morbidity and mortality, and may have negative effects on cerebral function and quality of life. Although ribavirin-associated anemia can be reversed by dose reduction or discontinuation, this approach compromises outcomes by significantly decreasing SVR rates. Recombinant human erythropoietin has been used to manage ribavirin-associated anemia but has other potential disadvantages. Viramidine, a liver-targeting prodrug of ribavirin, has the potential to maintain the virologic efficacy of ribavirin while decreasing the risk of hemolytic anemia in patients with chronic hepatitis C.

anemia

infected with hepatitis C virus

cirrhosis

hepatocellular carcinoma

end-stage liver disease

HCV infection

interferon

ribavirin

hemolytic anemia

ribavirin

hemolysis

anemia

HCV infection

renal or cardiovascular disorders

renal disorders

cardiovascular disorders

anemia

ribavirin

anemia

ribavirin

anemia

Viramidine

ribavirin

ribavirin

hemolytic anemia

chronic hepatitis C


Calcium carbonate toxicity: the updated milk-alkali syndrome; report of 3 cases and review of the literature.

OBJECTIVE: To describe 3 patients with calcium carbonate-induced hypercalcemia and gain insights into the cause and management of the milk-alkali syndrome. METHODS: We report the clinical and laboratory data in 3 patients who presented with severe hypercalcemia (corrected serum calcium > or = 14 mg/dL) and review the pertinent literature on milk-alkali syndrome. RESULTS: The 3 patients had acute renal insufficiency, relative metabolic alkalosis, and low parathyroid hormone (PTH), PTH-related peptide, and 1,25-dihydroxyvitamin D concentrations. No malignant lesion was found. Treatment included aggressive hydration and varied amounts of furosemide. The 2 patients with the higher serum calcium concentrations received pamidronate intravenously (60 and 30 mg, respectively), which caused severe hypocalcemia. Of the 3 patients, 2 were ingesting acceptable doses of elemental calcium (1 g and 2 g daily, respectively) in the form of calcium carbonate. In addition to our highlighted cases, we review the history, classification, pathophysiologic features, and treatment of milk-alkali syndrome and summarize the cases reported from early 1995 to November 2003. CONCLUSION: Milk-alkali syndrome may be a common cause of unexplained hypercalcemia and can be precipitated by small amounts of orally ingested calcium carbonate in susceptible persons. Treatment with hydration, furosemide, and discontinuation of the calcium and vitamin D source is adequate. Pamidronate treatment is associated with considerable risk for hypocalcemia, even in cases of initially severe hypercalcemia.

Calcium carbonate

toxicity

milk-alkali syndrome

calcium carbonate

hypercalcemia

milk-alkali syndrome

hypercalcemia

calcium

milk-alkali syndrome

acute renal insufficiency

metabolic alkalosis

1,25-dihydroxyvitamin D

furosemide

calcium

pamidronate

hypocalcemia

calcium

calcium carbonate

milk-alkali syndrome

Milk-alkali syndrome

hypercalcemia

calcium carbonate

furosemide

calcium

vitamin D

Pamidronate

hypocalcemia

hypercalcemia


Management strategies for ribavirin-induced hemolytic anemia in the treatment of hepatitis C: clinical and economic implications.

OBJECTIVES: Recently published studies have demonstrated increased efficacy and cost-effectiveness of combination therapy with interferon and alpha-2b/ribavirin compared with interferon-alpha monotherapy in the treatment of chronic hepatitis C (CHC). Combination therapy is associated with a clinically important adverse effect: ribavirin-induced hemolytic anemia (RIHA). The objective of this study was to evaluate the direct health-care costs and management of RIHA during treatment of CHC in a clinical trial setting. METHODS: A systematic literature review was conducted to synthesize information on the incidence and management of RIHA. Decision-analytic techniques were used to estimate the cost of treating RIHA. Uncertainty was evaluated using sensitivity analyses. RESULTS: RIHA, defined as a reduction in hemoglobin to less than 100 g/L, occurs in approximately 7% to 9% of patients treated with combination therapy. The standard of care for management of RIHA is reduction or discontinuation of the ribavirin dosage. We estimated the direct cost of treating clinically significant RIHA to be  170 per patient receiving combination therapy per 48-week treatment course (range  68- 692). The results of the one-way sensitivity analyses ranged from  57 to  317. In comparison, the cost of 48 weeks of combination therapy is  16,459. CONCLUSIONS: The direct cost of treating clinically significant RIHA is 1% ( 170/ 16,459) of drug treatment costs. Questions remain about the optimal dose of ribavirin and the incidence of RIHA in a real-world population. Despite these uncertainties, this initial evaluation of the direct cost of treating RIHA provides an estimate of the cost and management implications of this clinically important adverse effect.

ribavirin

hemolytic anemia

hepatitis C

ribavirin

interferon-alpha

chronic hepatitis C

CHC

ribavirin

hemolytic anemia

RIHA

RIHA

CHC

RIHA

RIHA

RIHA

RIHA

ribavirin

RIHA

RIHA

ribavirin

RIHA

RIHA


Effects of amine pretreatment on ketamine catatonia in pinealectomized or hypophysectomized animals.

The present studies were designed to clarify the role of catecholamines and pineal idolamines on ketamine-induced catatonia in the intact, pinealectomized or hypophysectomized chick and rat. In the pinealectomized chick, pretreatment with dopamine increased the duration of catatonia (DOC) after ketamine, but pretreatment with norepinephrine did not. The pineal indolamines exhibited mixed actions. Serotonin and N-acetyl serotonin which augmented ketamine DOC, did not do so in the absence of the pineal gland, whereas melatonin potentiated the ketamine DOC in both the intact and pinealectomized chick. Ketamine was more potent in the hypophysectomized chick and the circadian rhythm noted in the intact chick was absent; furthermore, melatonin did not augment the ketamine DOC whereas dopamine continued to do so. This study did not demonstrate a species difference regarding the role of the amines on the pineal in spite of the immature blood-brain barrier in the young chick and the intact barrier in the rat. In addition, these data indicate a direct role of the pituitary in the augmentation of ketamine DOC induced by melatonin. Furthermore, dopamine appeared to act on systems more closely involved with the induction of ketamine catatonia rather than directly on the pituitary.

amine

ketamine

catatonia

catecholamines

ketamine

catatonia

dopamine

catatonia

ketamine

norepinephrine

Serotonin

N-acetyl serotonin

ketamine

melatonin

ketamine

Ketamine

melatonin

ketamine

dopamine

amines

ketamine

melatonin

dopamine

ketamine

catatonia


Multicenter, double-blind, multiple-dose, parallel-groups efficacy and safety trial of azelastine, chlorpheniramine, and placebo in the treatment of spring allergic rhinitis.

Azelastine, a novel antiallergic medication, was compared with chlorpheniramine maleate and placebo for efficacy and safety in the treatment of spring allergic rhinitis in a multicenter, double-blind, multiple-dose, parallel-groups study. One hundred fifty-five subjects participated. Subjects ranged in age from 18 to 60 years of age and had at least a 2-year history of spring allergic rhinitis, confirmed by positive skin test to spring aeroallergens. Medications were given four times daily; the azelastine groups received 0.5, 1.0, or 2.0 mg in the morning and evening with placebo in the early and late afternoon; the chlorpheniramine group received 4.0 mg four times daily. Daily subject symptom cards were completed during a screening period to assess pretreatment symptoms and during a 4-week treatment period while subjects received study medications. Individual symptoms, total symptoms, and major symptoms were compared to determine efficacy of medication. Elicited, volunteered, and observed adverse experiences were recorded for each subject and compared among groups. Vital signs, body weights, serum chemistry values, complete blood cell counts, urine studies, and electrocardiograms were obtained for each subject and compared among groups. Symptoms relief in the group receiving the highest concentration of azelastine (2.0 mg twice daily) was statistically greater than in the placebo group during all weeks of the study. Lower doses of azelastine were statistically more effective than placebo only during portions of the first 3 weeks of the study. In contrast, although the chlorpheniramine group did have fewer symptoms than the placebo group during the study, the difference never reached statistical significance during any week of the study. There were no serious side effects in any of the treatment groups. Drowsiness and altered taste perception were increased significantly over placebo only in the high-dose azelastine group. Azelastine appears to be a safe, efficacious medication for seasonal allergic rhinitis.

azelastine

chlorpheniramine

spring allergic rhinitis

Azelastine

chlorpheniramine maleate

spring allergic rhinitis

spring allergic rhinitis

azelastine

chlorpheniramine

azelastine

azelastine

chlorpheniramine

Drowsiness

altered taste perception

azelastine

Azelastine

seasonal allergic rhinitis


Obsolete but dangerous antacid preparations.

One case of acute hypercalcaemia and two of recurrent nephrolithiasis are reported in patients who had regularly consumed large amounts of calcium carbon-ate-sodium bicarbonate powders for more than 20 years. The powders had been obtained from pharmacists unknown to the patients' medical practitioners. It is suggested that these preparations were responsible for the patient's problems, and that such powders should no longer be freely obtainable.

hypercalcaemia

nephrolithiasis

calcium carbon-ate

sodium bicarbonate


Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids.

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37-52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors.

paralysis

corticosteroids

ND-NMBA

muscle weakness

respiratory insufficiency

weakness

ND-NMBAs

corticosteroids

acidosis

vecuronium

loss of thick, myosin filaments

weakness

ND-NMBA

corticosteroids

Hepatic dysfunction

acidosis


Prostaglandin E2-induced bladder hyperactivity in normal, conscious rats: involvement of tachykinins?

In normal conscious rats investigated by continuous cystometry, intravesically instilled prostaglandin (PG) E2 facilitated micturition and increased basal intravesical pressure. The effect was attenuated by both the NK1 receptor selective antagonist RP 67,580 and the NK2 receptor selective antagonist SR 48,968, given intra-arterially, suggesting that it was mediated by stimulation of both NK1 and NK2 receptors. Intra-arterially given PGE2 produced a distinct increase in bladder pressure before initiating a micturition reflex, indicating that the PG had a direct contractant effect on the detrusor smooth muscle. The effect of intra-arterial PGE2 could not be blocked by intra-arterial RP 67,580 or SR 48,968, which opens the possibility that the micturition reflex elicited by intra-arterial PGE2 was mediated by pathways other than the reflex initiated when the PG was given intravesically. The present results thus suggest that intra-arterial PGE2, given near the bladder, may initiate micturition in the normal rat chiefly by directly contracting the smooth muscle of the detrusor. However, when given intravesically, PGE2 may stimulate micturition by releasing tachykinins from nerves in and/or immediately below the urothelium. These tachykinins, in turn, initiate a micturition reflex by stimulating NK1 and NK2 receptors. Prostanoids may, via release of tachykinins, contribute to both urge and bladder hyperactivity seen in inflammatory conditions of the lower urinary tract.

Prostaglandin E2

bladder hyperactivity

tachykinins

prostaglandin (PG) E2

RP 67,580

SR 48,968

PG

RP 67,580

SR 48,968

PG

tachykinins

tachykinins

Prostanoids

tachykinins

bladder hyperactivity


Thiazide diuretics, hypokalemia and cardiac arrhythmias.

Thiazide diuretics are widely accepted as the cornerstone of antihypertensive treatment programs. Hypokalemia is a commonly encountered metabolic consequence of chronic thiazide therapy. We treated 38 patients (22 low renin, 16 normal renin) with moderate diastolic hypertension with hydrochlorothiazide (HCTC) administered on a twice daily schedule. Initial dose was 50 mg and the dose was increased at monthly intervals to 100 mg, 150 mg and 200 mg daily until blood pressure normalized. The serum K during the control period was 4.5 +/- 0.2 mEq/l an on 50, 100, 150 and 200 mg HCTZ daily 3.9 +/- 0.3, 3.4 +/- 0.2, 2.9 +/- 0.2, and 2.4 +/- 0.3 mEq/l, respectively. Corresponding figures for whole body K were 4107 +/- 208, 3722 +/- 319, 3628 +/- 257, 3551 +/- 336, and 3269 +/- 380 mEq, respectively. In 13 patients we observed the effects of HCTZ therapy (100 mg daily) on the occurrence of PVC's during rest as well as during static and dynamic exercise. During rest we observed 0.6 +/- 0.08 PVC beats/min +/- SEM and during static and dynamic exercise 0.6 +/- 0.06 and 0.8 +/- 0.15, respectively. Corresponding figures during HCTZ therapy 100 mg daily were 1.4 +/- 0.1, 3.6 +/- 0.7 and 5.7 4/- 0.8, respectively. The occurrence of PVC's correlated significantly with the fall in serum K+ observed r = 0.72, p less than 0.001. In conclusion we found that thiazide diuretics cause hypokalemia and depletion of body potassium. The more profound hypokalemia, the greater the propensity for the occurrence of PVC's.

Thiazide

hypokalemia

cardiac arrhythmias

Thiazide

Hypokalemia

thiazide

diastolic hypertension

hydrochlorothiazide

HCTC

K

HCTZ

K

HCTZ

HCTZ

K

thiazide

hypokalemia

potassium

hypokalemia


Diuretics, potassium and arrhythmias in hypertensive coronary disease.

It has been proposed that modest changes in plasma potassium can alter the tendency towards cardiac arrhythmias. If this were so, patients with coronary artery disease might be especially susceptible. Thus, myocardial electrical excitability was measured in patients with mild essential hypertension and known coronary artery disease after 8 weeks of treatment with a potassium-conserving diuretic (amiloride) and a similar period on a potassium-losing diuretic (chlorthalidone) in a randomised study. Plasma potassium concentrations were on average 1 mmol/L lower during the chlorthalidone phase compared to amiloride therapy. Blood pressure and volume states as assessed by bodyweight, plasma renin and noradrenaline (norepinephrine) concentrations were similar on the 2 regimens. Compared to amiloride treatment, the chlorthalidone phase was associated with an increased frequency of ventricular ectopic beats (24-hour Holter monitoring) and a higher Lown grading, increased upslope and duration of the monophasic action potential, prolonged ventricular effective refractory period, and increased electrical instability during programmed ventricular stimulation. The above results indicate that because potassium-losing diuretic therapy can increase myocardial electrical excitability in patients with ischaemic heart disease, even minor falls in plasma potassium concentrations are probably best avoided in such patients.

potassium

arrhythmias

hypertensive

coronary disease

potassium

cardiac arrhythmias

coronary artery disease

hypertension

coronary artery disease

potassium

amiloride

potassium

chlorthalidone

potassium

chlorthalidone

amiloride

noradrenaline

norepinephrine

amiloride

chlorthalidone

ventricular ectopic beats

potassium

ischaemic heart disease

potassium


GABA involvement in naloxone induced reversal of respiratory paralysis produced by thiopental.

No agent is yet available to reverse respiratory paralysis produced by CNS depressants, such as general anesthetics. In this study naloxone reversed respiratory paralysis induced by thiopental in rats. 25 mg/kg, i.v. thiopental produced anesthesia without altering respiratory rate, increased GABA, decreased glutamate, and had no effect on aspartate or glycine levels compared to controls in rat cortex and brain stem. Pretreatment of rats with thiosemicarbazide for 30 minutes abolished the anesthetic action as well as the respiratory depressant action of thiopental. 50 mg/kg, i.v. thiopental produced respiratory arrest with further increase in GABA and decrease in glutamate again in cortex and brain stem without affecting any of the amino acids studied in four regions of rat brain. Naloxone (2.5 mg/kg, i.v.) reversed respiratory paralysis, glutamate and GABA levels to control values in brain stem and cortex with no changes in caudate or cerebellum. These data suggest naloxone reverses respiratory paralysis produced by thiopental and involves GABA in its action.

GABA

naloxone

respiratory paralysis

thiopental

respiratory paralysis

naloxone

respiratory paralysis

thiopental

thiopental

GABA

glutamate

aspartate

glycine

thiosemicarbazide

thiopental

thiopental

respiratory arrest

GABA

glutamate

amino acids

Naloxone

respiratory paralysis

glutamate

GABA

naloxone

respiratory paralysis

thiopental

GABA


National project on the prevention of mother-to-infant infection by hepatitis B virus in Japan.

In Japan, a nationwide prevention program against mother-to-infant infection by hepatitis B virus (HBV) started in 1985. This program consists of double screenings of pregnant women and prophylactic treatment to the infants born to both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive mothers. These infants are treated with two injections of hepatitis B immune globulin (HBIG) and at least three injections of plasma derived hepatitis B vaccine. We sent questionnaires about the numbers of each procedure or examination during nine months of investigation period to each local government in 1986 and 1987. 93.4% pregnant women had the chance to be examined for HBsAg, and the positive rate was 1.4 to 1.5%. The HBeAg positive rate in HBsAg positive was 23 to 26%. The HBsAg positive rate in neonates and in infants before two months were 3% and 2% respectively. Some problems may arise, because 27 to 30% of infants need the fourth vaccination in some restricted areas.

infection by hepatitis B virus

infection by hepatitis B virus

hepatitis B surface antigen

HBsAg

hepatitis B e antigen

HBeAg

hepatitis B

hepatitis B vaccine

HBsAg

HBeAg

HBsAg

HBsAg


Nociceptive effects induced by intrathecal administration of prostaglandin D2, E2, or F2 alpha to conscious mice.

The effects of intrathecal administration of prostaglandins on pain responses in conscious mice were evaluated by using hot plate and acetic acid writhing tests. Prostaglandin D2 (0.5-3 ng/mouse) had a hyperalgesic action on the response to a hot plate during a 3-60 min period after injection. Prostaglandin E2 showed a hyperalgesic effect at doses of 1 pg to 10 ng/mouse, but the effect lasted shorter (3-30 min) than that of prostaglandin D2. Similar results were obtained by acetic acid writhing tests. The hyperalgesic effect of prostaglandin D2 was blocked by simultaneous injection of a substance P antagonist (greater than or equal to 100 ng) but not by AH6809, a prostanoid EP1-receptor antagonist. Conversely, prostaglandin E2-induced hyperalgesia was blocked by AH6809 (greater than or equal to 500 ng) but not by the substance P antagonist. Prostaglandin F2 alpha had little effect on pain responses. These results demonstrate that both prostaglandin D2 and prostaglandin E2 exert hyperalgesia in the spinal cord, but in different ways.

prostaglandin D2, E2, or F2 alpha

prostaglandin D2

prostaglandin

prostaglandin
F2 alpha

prostaglandins

pain

acetic acid

Prostaglandin D2

hyperalgesic

Prostaglandin E2

hyperalgesic

pg

prostaglandin D2

acetic acid

hyperalgesic

prostaglandin D2

prostaglandin E2

hyperalgesia

Prostaglandin F2 alpha

pain

prostaglandin D2

prostaglandin E2

hyperalgesia


Swallowing-induced atrial tachyarrhythmia triggered by salbutamol: case report and review of the literature.

CASE: A 49-year-old patient experienced chest discomfort while swallowing. On electrocardiogram, episodes of atrial tachyarrhythmia were recorded immediately after swallowing; 24-hour Holter monitoring recorded several events. The arrhythmia resolved after therapy with atenolol, but recurred a year later. The patient noticed that before these episodes he had been using an inhalator of salbutamol. After stopping the beta-agonist, and after a week with the atenolol, the arrhythmia disappeared. DISCUSSION: Swallowing-induced atrial tachyarrhythmia (SIAT) is a rare phenomenon. Fewer than 50 cases of SIAT have been described in the literature. This article summarizes all the cases published, creating a comprehensive review of the current knowledge and approach to SIAT. It discusses demographics, clinical characteristics and types of arrhythmia, postulated mechanisms of SIAT, and different treatment possibilities such as medications, surgery, and radiofrequency catheter ablation (RFCA). CONCLUSION: Salbutamol is presented here as a possible trigger for SIAT. Although it is difficult to define causality in a case report, it is logical to think that a beta-agonist like salbutamol (known to induce tachycardia) may be the trigger of adrenergic reflexes originating in the esophagus while swallowing and that a beta-blocker such as atenolol (that blocks the adrenergic activity) may relieve it.

atrial tachyarrhythmia

salbutamol

atrial tachyarrhythmia

arrhythmia

atenolol

salbutamol

atenolol

arrhythmia

atrial tachyarrhythmia

SIAT

SIAT

SIAT

arrhythmia

SIAT

Salbutamol

SIAT

salbutamol

tachycardia

atenolol


Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice.

The nephroprotective effect of coenzyme Q10 was investigated in mice with acute renal injury induced by a single i.p. injection of cisplatin (5 mg/kg). Coenzyme Q10 treatment (10 mg/kg/day, i.p.) was applied for 6 consecutive days, starting 1 day before cisplatin administration. Coenzyme Q10 significantly reduced blood urea nitrogen and serum creatinine levels which were increased by cisplatin. Coenzyme Q10 significantly compensated deficits in the antioxidant defense mechanisms (reduced glutathione level and superoxide dismutase activity), suppressed lipid peroxidation, decreased the elevations of tumor necrosis factor-alpha, nitric oxide and platinum ion concentration, and attenuated the reductions of selenium and zinc ions in renal tissue resulted from cisplatin administration. Also, histopathological renal tissue damage mediated by cisplatin was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the cisplatin-induced overexpression of inducible nitric oxide synthase, nuclear factor-kappaB, caspase-3 and p53 in renal tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect against acute cisplatin nephrotoxicity commonly encountered in clinical practice.

Coenzyme Q10

cisplatin

nephrotoxicity

coenzyme Q10

acute renal injury

cisplatin

Coenzyme Q10

cisplatin

Coenzyme Q10

blood urea nitrogen

creatinine

cisplatin

Coenzyme Q10

reduced glutathione

superoxide

tumor

necrosis

nitric oxide

platinum

selenium

zinc

cisplatin

renal tissue damage

cisplatin

coenzyme Q10

coenzyme Q10

cisplatin

nitric oxide

coenzyme Q10

cisplatin

nephrotoxicity


Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway.

The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis.

Metformin

gentamicin

nephropathy

metformin

vascular dysfunction

gentamicin

toxicity

oxygen

gentamicin

Metformin

gentamicin

acute renal failure

Metformin

gentamicin

kidney dysfunction

metformin

gentamicin

oxygen

metformin

metformin

gentamicin

nephrotoxicity


Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair.

OBJECTIVE: To determine whether limiting intraoperative sedation depth during spinal anesthesia for hip fracture repair in elderly patients can decrease the prevalence of postoperative delirium. PATIENTS AND METHODS: We performed a double-blind, randomized controlled trial at an academic medical center of elderly patients (>or=65 years) without preoperative delirium or severe dementia who underwent hip fracture repair under spinal anesthesia with propofol sedation. Sedation depth was titrated using processed electroencephalography with the bispectral index (BIS), and patients were randomized to receive either deep (BIS, approximately 50) or light (BIS, >or=80) sedation. Postoperative delirium was assessed as defined by Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) criteria using the Confusion Assessment Method beginning at any time from the second day after surgery. RESULTS: From April 2, 2005, through October 30, 2008, a total of 114 patients were randomized. The prevalence of postoperative delirium was significantly lower in the light sedation group (11/57 [19%] vs 23/57 [40%] in the deep sedation group; P=.02), indicating that 1 incident of delirium will be prevented for every 4.7 patients treated with light sedation. The mean +/- SD number of days of delirium during hospitalization was lower in the light sedation group than in the deep sedation group (0.5+/-1.5 days vs 1.4+/-4.0 days; P=.01). CONCLUSION: The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation. Limiting depth of sedation during spinal anesthesia is a simple, safe, and cost-effective intervention for preventing postoperative delirium in elderly patients that could be widely and readily adopted.

postoperative delirium

postoperative delirium

delirium

hip fracture

hip fracture

postoperative delirium

postoperative delirium

delirium

delirium

dementia

hip fracture

propofol

Postoperative delirium

Postoperative delirium

delirium

Mental Disorders

postoperative delirium

postoperative delirium

delirium

delirium

delirium

propofol

postoperative delirium

postoperative delirium

delirium

postoperative delirium

postoperative delirium

delirium


Sorafenib-induced acute myocardial infarction due to coronary artery spasm.

A 65-year-old man with advanced renal cell carcinoma was admitted due to continuing chest pain at rest. Two weeks before his admission, sorafenib had been started. He was diagnosed with non-ST-elevation myocardial infarction by laboratory data and electrocardiogram. Enhanced heart magnetic resonance imaging also showed subendocardial infarction. However, there was no stenosis in coronary arteries on angiography. Coronary artery spasm was induced by a provocative test. Cessation of sorafenib and administration of Ca-channel blocker and nitrates ameliorated his symptoms, but relapse occurred after resumption of sorafenib. Addition of oral nicorandil reduced his symptoms and maintained stable angina status. We report the first case of sorafenib-induced coronary artery spasm. Sorafenib is a multikinase inhibitor that targets signaling pathways necessary for cellular proliferation and survival. On the other hand, the Rho/ROCK pathway has an important role in the pathogenesis of coronary artery spasm. Our report may show an adverse effect on the Rho/ROCK pathway by sorafenib use.

Sorafenib

myocardial infarction

coronary artery spasm

renal cell carcinoma

chest pain

sorafenib

myocardial infarction

subendocardial infarction

Coronary artery spasm

sorafenib

Ca

nitrates

sorafenib

nicorandil

stable angina

sorafenib

coronary artery spasm

Sorafenib

coronary artery spasm

sorafenib


Anxiogenic potential of ciprofloxacin and norfloxacin in rats.

INTRODUCTION: The possible anxiogenic effects of fluoroquinolones, namely ciprofloxacin and norfloxacin, were investigated in adult Charles Foster albino rats of either sex, weighing 150-200 g. METHODS: The drugs were given orally, in doses of 50 mg/kg for five consecutive days and the experiments were performed on the fifth day. The tests included open-field exploratory behaviour, elevated plus maze and elevated zero maze, social interaction and novelty-suppressed feeding latency behaviour. RESULTS: The results indicate that ciprofloxacin- and norfloxacin-treated rats showed anxious behaviour in comparison to control rats in all the parameters studied. However, ciprofloxacin- and norfloxacin-treated rats did not differ significantly from each other in various behavioural parameters. CONCLUSION: The present experimental findings substantiate the clinically observed anxiogenic potential of ciprofloxacin and norfloxacin.

ciprofloxacin

norfloxacin

fluoroquinolones

ciprofloxacin

norfloxacin

ciprofloxacin

norfloxacin

anxious behaviour

ciprofloxacin

norfloxacin

ciprofloxacin

norfloxacin


Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. METHODS AND RESULTS: In order to investigate whether the HAART component zidovudine (3'-azido-2',3'-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. CONCLUSIONS: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.

AZT

cardiomyopathy

Dilated cardiomyopathy

DCM

myocarditis

HIV-infected

heart failure

acquired immunodeficiency syndrome

AIDS

cardiac and skeletal myopathies

zidovudine

AZT

DCM

AZT

AZT

cardiac dilation

cardiomyopathy

cardiac dilation and dysfunction

cardiac dilation

cardiac dysfunction


Valproate-induced chorea and encephalopathy in atypical nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is a disorder of amino acid metabolism in which a defect in the glycine cleavage system leads to an accumulation of glycine in the brain and other body compartments. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, followed by significant psychomotor retardation. An important subset of children with nonketotic hyperglycinemia are atypical variants who present in a heterogeneous manner. This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy.

Valproate

chorea

encephalopathy

nonketotic hyperglycinemia

Nonketotic hyperglycinemia

disorder of amino acid metabolism

glycine

glycine

apnea

seizures

hypotonia

psychomotor retardation

nonketotic hyperglycinemia

language delay

mental retardation

nonketotic hyperglycinemia

encephalopathy

chorea

valproate


Microinjection of ritanserin into the CA1 region of hippocampus improves scopolamine-induced amnesia in adult male rats.

The effect of ritanserin (5-HT2 antagonist) on scopolamine (muscarinic cholinergic antagonist)-induced amnesia in Morris water maze (MWM) was investigated. Rats were divided into eight groups and bilaterally cannulated into CA1 region of the hippocampus. One week later, they received repeatedly vehicles (saline, DMSO, saline+DMSO), scopolamine (2 microg/0.5 microl saline/side; 30 min before training), ritanserin (2, 4 and 8 microg/0.5 microl DMSO/side; 20 min before training) and scopolamine (2 microg/0.5 microl; 30 min before ritanserin injection)+ritanserin (4 microg/0.5 microl DMSO) through cannulae each day. Animals were tested for four consecutive days (4 trial/day) in MWM during which the position of hidden platform was unchanged. In the fifth day, the platform was elevated above the water surface in another position to evaluate the function of motor, motivational and visual systems. The results showed a significant increase in escape latencies and traveled distances to find platform in scopolamine-treated group as compared to saline group. Ritanserin-treated rats (4 microg/0.5 microl/side) showed a significant decrease in the mentioned parameters as compared to DMSO-treated group. However, scopolamine and ritanserin co-administration resulted in a significant decrease in escape latencies and traveled distances as compared to the scopolamine-treated rats. Our findings show that microinjection of ritanserin into the CA1 region of the hippocampus improves the scopolamine-induced amnesia.

ritanserin

scopolamine

amnesia

ritanserin

scopolamine

amnesia

DMSO

DMSO

scopolamine

ritanserin

DMSO

scopolamine

ritanserin

ritanserin

DMSO

scopolamine

Ritanserin

DMSO

scopolamine

ritanserin

scopolamine

ritanserin

scopolamine

amnesia


Hypoxia in renal disease with proteinuria and/or glomerular hypertension.

Despite the increasing need to identify and quantify tissue oxygenation at the cellular level, relatively few methods have been available. In this study, we developed a new hypoxia-responsive reporter vector using a hypoxia-responsive element of the 5' vascular endothelial growth factor untranslated region and generated a novel hypoxia-sensing transgenic rat. We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney. With this model, we were able to identify diffuse cortical hypoxia in the puromycin aminonucleoside-induced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model. Expression of the hypoxia-responsive transgene increased throughout the observation period, reaching 2.2-fold at 2 weeks in the puromycin aminonucleoside model and 2.6-fold at 4 weeks in the remnant kidney model, whereas that of vascular endothelial growth factor showed a mild decrease, reflecting distinct behaviors of the two genes. The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models. Finally, we identified the localization of proliferating cell nuclear antigen-positive, ED-1-positive, and terminal dUTP nick-end labeled-positive cells in the hypoxic cortical area in the remnant kidney model. We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases.

Hypoxia

renal disease

proteinuria

hypertension

hypoxia

hypoxia

hypoxia

hypoxia

diseased kidney

hypoxia

puromycin aminonucleoside

nephrotic syndrome

hypoxia

hypoxia

puromycin aminonucleoside

hypoxia

tubulointerstitial injury

hypoxic

hypoxia

glomerular diseases


Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference to systemic sclerosis and multiple sclerosis.

Autologous haematopoietic stem cell transplantation is now a feasible and effective treatment for selected patients with severe autoimmune diseases. Worldwide, over 650 patients have been transplanted in the context of phase I and II clinical trials. The results are encouraging enough to begin randomised phase III trials. However, as predicted, significant transplant-related morbidity and mortality have been observed. This is primarily due to complications related to either the stage of the disease at transplant or due to infections. The number of deaths related to cardiac toxicity is low. However, caution is required when cyclophosphamide or anthracyclines such as mitoxantrone are used in patients with a possible underlying heart damage, for example, systemic sclerosis patients. In November 2002, a meeting was held in Florence, bringing together a number of experts in various fields, including rheumatology, cardiology, neurology, pharmacology and transplantation medicine. The object of the meeting was to analyse existing data, both published or available, in the European Group for Blood and Marrow Transplantation autoimmune disease database, and to propose a safe approach to such patients. A full cardiological assessment before and during the transplant emerged as the major recommendation.

cardiotoxicity

autoimmune diseases

systemic sclerosis

multiple sclerosis

autoimmune diseases

infections

cardiac toxicity

cyclophosphamide

anthracyclines

mitoxantrone

heart damage

systemic sclerosis

autoimmune disease


Immunohistochemical study on inducible type of nitric oxide (iNOS), basic fibroblast growth factor (bFGF) and tumor growth factor-beta1 (TGF-beta1) in arteritis induced in rats by fenoldopam and theophylline, vasodilators.

Arteritis induced in rats by vasodilators, fenoldopam and theophylline, was examined immunohistochemically for expressions of inducible type of nitric oxide synthase (iNOS), basic fibroblast growth factor (bFGF) and tumor growth factor-beta1 (TGF-beta1). Rats were administered fenoldopam for 24 hours by intravenous infusion with or without following repeated daily oral administrations of theophylline. Irrespective of theophylline administration, iNOS antigens were remarkably abundant in ED-1-positive cells on day 5 and 8 post-fenoldopam-infusion (DPI); bFGF antigens were remarkably abundant in ED-1-positive cells on 1 and 3 DPI; TGF-beta1 antigens were observed in ED-1-positive cells on and after 5 DPI. These results suggest that the peak expression of iNOS antigen was followed by that of bFGF antigen, and bFGF may have a suppressive effect on iNOS expression in these rat arteritis models. On the other hand, TGF-beta1 was not considered to have a suppressive effect on iNOS expression in these models.

nitric oxide

tumor

arteritis

fenoldopam

theophylline

Arteritis

fenoldopam

theophylline

nitric oxide

tumor

fenoldopam

theophylline

theophylline

fenoldopam

arteritis


Low-molecular-weight heparin for the treatment of patients with mechanical heart valves.

BACKGROUND: The interruption of oral anticoagulant (OAC) administration is sometimes indicated in patients with mechanical heart valves, mainly before noncardiac surgery, non-surgical interventions, and pregnancy. Unfractionated heparin (UH) is currently the substitute for selected patients. Low-molecular-weight heparin (LMWH) offers theoretical advantages over UH, but is not currently considered in clinical guidelines as an alternative to UH in patients with prosthetic valves. HYPOTHESIS: The aim of the present study was to review the data accumulated so far on the use of LMWH in this patient population and to discuss its applicability in common practice. METHODS: For this paper, the current medical literature on LMWH in patients with mechanical heart valves was extensively reviewed. RESULTS: There were eight series and six case reports. None of the studies was randomized, and only one was prospective. Data to establish the thromboembolic risk were incomplete. After excluding case reports, the following groups were constructed: (a) short-term administration, after valve insertion (n = 212); (b) short-term, perioperative (noncardiac)/periprocedural (n = 114); (c) long-term, due to intolerance to OAC (n = 16); (d) long-term, in pregnancy (n = 10). The incidence rate of thromboembolism was 0.9% for all the studies and 0.5, 0, 20, and 0% in groups a, b, c, and d, respectively; for hemorrhage, the overall rate was 3.4% (3.8, 2.6, 10, and 0% for the respective groups). CONCLUSIONS: In patients with mechanical heart valves, short-term LMWH therapy compares favorably with UH. Data on mid- and long-term LMWH administration in these patients are sparse. Further randomized studies are needed to confirm the safety and precise indications for the use of LMWH in patients with mechanical heart valves.

Low-molecular-weight heparin

Unfractionated heparin

UH

Low-molecular-weight heparin

LMWH

UH

UH

LMWH

LMWH

thromboembolic

thromboembolism

hemorrhage

LMWH

UH

LMWH

LMWH


Topiramate-induced nephrolithiasis.

Topiramate is a recently developed antiepileptic medication that is becoming more widely prescribed because of its efficacy in treating refractory seizures. Urologists should be aware that this medication can cause metabolic acidosis in patients secondary to inhibition of carbonic anhydrase. In addition, a distal tubular acidification defect may result, thus impairing the normal compensatory drop in urine pH. These factors can lead to the development of calcium phosphate nephrolithiasis. We report the first two cases of topiramate-induced nephrolithiasis in the urologic literature.

Topiramate

nephrolithiasis

Topiramate

refractory seizures

metabolic acidosis

calcium phosphate

nephrolithiasis

topiramate

nephrolithiasis


Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients?

OBJECTIVE: Nephrotoxicity is the major adverse effect of amphotericin B (AmB), often limiting administration of full dosage. Selective distal tubular epithelial toxicity seems to be responsible for the profound potassium wasting that is a major clinical side effect of treatment with AmB. Potassium depletion also potentiates the tubular toxicity of AmB. This study was designed to assess the ability of spironolactone to reduce potassium requirements and to prevent hypokalemia in neutropenic patients on AmB treatment. METHODS: In this study 26 patients with various hematological disorders were randomized to receive either intravenous AmB alone or AmB and oral spironolactone 100 mg twice daily when developing a proven or suspected fungal infection. RESULTS: Patients receiving concomitant AmB and spironolactone had significantly higher plasma potassium levels than those receiving AmB alone (P = 0.0027). Those patients receiving AmB and spironolactone required significantly less potassium supplementation to maintain their plasma potassium within the normal range (P = 0.022). Moreover, urinary potassium losses were significantly less in patients receiving AmB and spironolactone than those receiving AmB alone (P = 0.040). CONCLUSION: This study showed that spironolactone can reduce potassium requirements and prevent hypokalemia by reducing urinary potassium loss in neutropenic patients on AmB treatment.

Spironolactone

amphotericin B

hypokalemia

cancer

Nephrotoxicity

amphotericin B

AmB

toxicity

potassium

AmB

Potassium

toxicity

AmB

spironolactone

potassium

hypokalemia

neutropenic

AmB

hematological disorders

AmB

AmB

spironolactone

fungal infection

AmB

spironolactone

potassium

AmB

AmB

spironolactone

potassium

potassium

potassium

AmB

spironolactone

AmB

spironolactone

potassium

hypokalemia

potassium

neutropenic

AmB


Dopamine D2 receptor signaling controls neuronal cell death induced by muscarinic and glutamatergic drugs.

Dopamine (DA), through D1/D2 receptor-mediated signaling, plays a major role in the control of epileptic seizures arising in the limbic system. Excitotoxicity leading to neuronal cell death in the affected areas is a major consequence of seizures at the cellular level. In this respect, little is known about the role of DA receptors in the occurrence of epilepsy-induced neuronal cell death. Here we analyze the occurrence of seizures and neurotoxicity in D2R -/- mice treated with the cholinergic agonist pilocarpine. We compared these results with those previously obtained with kainic acid (KA), a potent glutamate agonist. Importantly, D2R -/- mice develop seizures at doses of both drugs that are not epileptogenic for WT littermates and show greater neurotoxicity. However, pilocarpine-induced seizures result in a more widespread neuronal death in both WT and D2R -/- brains in comparison to KA. Thus, the absence of D2R lowers the threshold for seizures induced by both glutamate and acetylcholine. Moreover, the dopaminergic control of epilepsy-induced neurodegeneration seems to be mediated by distinct interactions of D2R signaling with these two neurotransmitters.

Dopamine

Dopamine

DA

epileptic seizures

Excitotoxicity

seizures

DA

epilepsy

seizures

neurotoxicity

pilocarpine

kainic acid

KA

glutamate

seizures

neurotoxicity

pilocarpine

seizures

KA

seizures

glutamate

acetylcholine

epilepsy

neurodegeneration


Treatment of risperidone-induced hyperprolactinemia with a dopamine agonist in children.

BACKGROUND: Risperidone, a potent antagonist of both serotonergic (5HT2A) and dopaminergic D2 receptors is associated with hyperprolactinemia in adults and children. Chronically elevated prolactin levels in children with prolactinomas may be associated with arrested growth and development resulting in either delayed puberty or short stature. These possibilities stress the importance of developing a safe and effective approach to drug-induced hyperprolactinemia in youth. We report the successful treatment of risperidone-induced hyperprolactinemia with cabergoline in youth. METHODS: We undertook a retrospective case review of four children with risperidone-induced hyperprolactinemia treated with cabergoline. RESULTS: Four males (age 6-11 years) with Diagnostic and Statistical Manual of Mental Disorders (fourth edition) bipolar disorder or psychoses, with risperidone-induced elevations in serum prolactin levels (57.5-129 ng/mL, normal 5-15 ng/mL), were treated with cabergoline (mean dose 2.13 +/- 0.09 mg/week). When serum prolactin levels normalized in all four subjects (mean 11.2 +/- 10.9 ng/mL), the cabergoline dose was reduced to 1 mg/week in three of four subjects. The mean duration of therapy with cabergoline was 523.5 +/- 129.7 days, and the mean duration of therapy with risperidone was 788.5 +/- 162.5 days. Cabergoline was well tolerated without adverse effects. CONCLUSIONS: Cabergoline may be useful for the treatment of risperidone-induced hyperprolactinemia in youth; however, further research is needed.

risperidone

hyperprolactinemia

dopamine

Risperidone

hyperprolactinemia

prolactinomas

delayed puberty

hyperprolactinemia

risperidone

hyperprolactinemia

cabergoline

risperidone

hyperprolactinemia

cabergoline

Mental Disorders

bipolar disorder

psychoses

risperidone

cabergoline

cabergoline

cabergoline

risperidone

Cabergoline

Cabergoline

risperidone

hyperprolactinemia


Cholestatic jaundice associated with the use of metformin.

We report a patient who developed cholestatic jaundice shortly after initiation of treatment with metformin hydrochloride. Ultrasound of the liver and abdominal CT were normal. An ERCP showed normal biliary anatomy. A percutaneous liver biopsy was obtained showing marked cholestasis, with portal edema, ductular proliferation, and acute inflammation. Metformin hydrochloride was discontinued, and the patient's jaundice resolved slowly over a period of several months. Given the onset of his jaundice 2 wk after the initiation of metformin, we believe that this case represents an example of metformin-associated hepatotoxicity, the first such case reported.

Cholestatic jaundice

metformin

cholestatic jaundice

metformin hydrochloride

cholestasis

edema

inflammation

Metformin hydrochloride

jaundice

jaundice

metformin

metformin

hepatotoxicity


Electro-oculography, electroretinography, visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction.

PURPOSE: Symptomatic visual field constriction thought to be associated with vigabatrin has been reported. The current study investigated the visual fields and visual electrophysiology of eight patients with known vigabatrin-attributed visual field loss, three of whom were reported previously. Six of the patients were no longer receiving vigabatrin. METHODS: The central and peripheral fields were examined with the Humphrey Visual Field Analyzer. Full visual electrophysiology, including flash electroretinography (ERG), pattern electroretinography, multifocal ERG using the VERIS system, electro-oculography, and flash and pattern visual evoked potentials, was undertaken. RESULTS: Seven patients showed marked visual field constriction with some sparing of the temporal visual field. The eighth exhibited concentric constriction. Most electrophysiological responses were usually just within normal limits; two patients had subnormal Arden electro-oculography indices; and one patient showed an abnormally delayed photopic b wave. However, five patients showed delayed 30-Hz flicker b waves, and seven patients showed delayed oscillatory potentials. Multifocal ERG showed abnormalities that sometimes correlated with the visual field appearance and confirmed that the deficit occurs at the retinal level. CONCLUSION: Marked visual field constriction appears to be associated with vigabatrin therapy. The field defects and some electrophysiological abnormalities persist when vigabatrin therapy is withdrawn.

vigabatrin

visual field constriction

visual field constriction

vigabatrin

vigabatrin

visual field loss

vigabatrin

visual field constriction

visual field constriction

vigabatrin

vigabatrin


Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial experience.

BACKGROUND: The aim of this study is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. METHODS: Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. RESULTS: In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233+/-34 to 210+/-56 micromol/liter (P<0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. CONCLUSIONS: RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

rapamycin

RAPA

cyclosporine

CsA

tacrolimus

Tac

toxicity

rapamycin

RAPA

CsA

Tac

nephrotoxicity

CsA

Tac

toxicity

facial dysmorphism

PTLD

hepatotoxicity

nephrotoxicity

creatinine

Facial dysmorphism

PTLD

pneumonia

Pneumocystis carinii pneumonia

infectious mononucleosis

PTLD

bronchiolitis obliterans

RAPA

pneumonia

PTLD

aphtous ulcers

RAPA

RAPA

CsA

RAPA

Pneumocystis carinii pneumonia


Worsening of levodopa-induced dyskinesias by motor and mental tasks.

Ten patients who had Parkinson's disease with disabling dyskinesia were included in this study to evaluate the role of mental (mental calculation) and motor (flexion/extension of right fingers, flexion/extension of left fingers, flexion/extension of the neck, speaking aloud) tasks on the worsening of peak-dose dyskinesia following administration of an effective single dose of apomorphine. Compared with the score at rest (1.3+/-0.3), a significant aggravation of the dyskinesia score was observed during speaking aloud (5.2+/-1.1, p<0.05), movements of right (4.5+/-1.0, p<0.05) and left (3.7+/-0.8, p<0.05) fingers, movements of the neck (5.1+/-1.0, p<0.05), and mental calculation (3.1+/-1.0, p<0.05). These results suggest that activation tasks such as "speaking aloud" could be used for objective assessment of dyskinesia severity.

levodopa

dyskinesias

Parkinson's disease

dyskinesia

dyskinesia

apomorphine

dyskinesia

dyskinesia


Structural and functional impairment of mitochondria in adriamycin-induced cardiomyopathy in mice: suppression of cytochrome c oxidase II gene expression.

The use of adriamycin (ADR) in cancer chemotherapy has been limited due to its cumulative cardiovascular toxicity. Earlier observations that ADR interacts with mitochondrial cytochrome c oxidase (COX) and suppresses its enzyme activity led us to investigate ADR's action on the cardiovascular functions and heart mitochondrial morphology in Balb-c mice i.p. treated with ADR for several weeks. At various times during treatment, the animals were assessed for cardiovascular functions by electrocardiography and for heart tissue damage by electron microscopy. In parallel, total RNA was extracted from samples of dissected heart and analyzed by Northern blot hybridization to determine the steady-state level of three RNA transcripts encoded by the COXII, COXIII, and COXIV genes. Similarly, samples obtained from the liver of the same animals were analyzed for comparative studies. Our results indicated that 1) treatment of mice with ADR caused cardiovascular arrhythmias characterized by bradycardia, extension of ventricular depolarization time (tQRS), and failure of QRS at high concentrations (10-14 mg/kg body weight cumulative dose); 2) the heart mitochondria underwent swelling, fusion, dissolution, and/or disruption of mitochondrial cristae after several weeks of treatment. Such abnormalities were not observed in the mitochondria of liver tissue; and 3) among the three genes of COX enzyme examined, only COXII gene expression was suppressed by ADR treatment, mainly after 8 weeks in both heart and liver. Knowing that heart mitochondria represent almost 40% of heart muscle by weight, we conclude that the deteriorating effects of ADR on cardiovascular function involve mitochondrial structural and functional impairment.

adriamycin

cardiomyopathy

adriamycin

ADR

cancer

cardiovascular toxicity

ADR

ADR

ADR

ADR

cardiovascular arrhythmias

bradycardia

swelling

ADR

ADR


Enhanced bradycardia induced by beta-adrenoceptor antagonists in rats pretreated with isoniazid.

High doses of isoniazid increase hypotension induced by vasodilators and change the accompanying reflex tachycardia to bradycardia, an interaction attributed to decreased synthesis of brain gamma-aminobutyric acid (GABA). In the present study, the possible enhancement by isoniazid of bradycardia induced by beta-adrenoceptor antagonists was determined in rats anaesthetised with chloralose-urethane. Isoniazid significantly increased bradycardia after propranolol, pindolol, labetalol and atenolol, as well as after clonidine, but not after hexamethonium or carbachol. Enhancement was not observed in rats pretreated with methylatropine or previously vagotomised. These results are compatible with interference by isoniazid with GABAergic inhibition of cardiac parasympathetic tone. Such interference could be exerted centrally, possibly at the nucleus ambiguus, or peripherally at the sinus node.

bradycardia

isoniazid

isoniazid

hypotension

tachycardia

bradycardia

gamma-aminobutyric acid

GABA

isoniazid

bradycardia

chloralose

urethane

Isoniazid

bradycardia

propranolol

pindolol

labetalol

atenolol

clonidine

hexamethonium

carbachol

methylatropine

isoniazid


Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy)

OBJECTIVE: To study the effect of folic acid-containing multivitamin supplementation in epileptic women before and during pregnancy in order to determine the rate of structural birth defects and epilepsy-related side effects. STUDY DESIGN: First a randomised trial, later periconception care including in total 12225 females. RESULTS: Of 60 epileptic women with periconceptional folic acid (0.8 mg)-containing multivitamin supplementation, no one developed epilepsy-related side effects during the periconception period. One epileptic woman delivered a newborn with cleft lip and palate. Another patient exhibited with a cluster of seizures after the periconception period using another multivitamin. This 22-year-old epileptic woman was treated continuously by carbamazepine and a folic acid (1 mg)-containing multivitamin from the 20th week of gestation. She developed status epilepticus and later symptoms of systemic lupus erythematodes. Her pregnancy ended with stillbirth. CONCLUSIONS: The epileptic pregnant patient's autoimmune disease (probably drug-induced lupus) could damage the blood-brain barrier, therefore the therapeutic dose (> or =1 mg) of folic acid triggered a cluster of seizures. Physiological dose (<1 mg) of folic acid both in healthy and 60 epileptic women, all without any autoimmune disease, did not increase the risk for epileptic seizures.

folic acid

SLE

folic acid

epilepsy

folic acid

epileptic

birth defects

epilepsy

epileptic

folic acid

epilepsy

epileptic

cleft lip and palate

cleft lip

cleft palate

seizures

epileptic

carbamazepine

folic acid

status epilepticus

systemic lupus erythematodes

stillbirth

epileptic

autoimmune disease

lupus

folic acid

seizures

folic acid

epileptic

autoimmune disease

epileptic seizures