Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension.

BACKGROUND: The use of appetite suppressants in Europe has been associated with the development of primary pulmonary hypertension (PPH). Recently, fenfluramine appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects. MATERIALS AND METHODS: We conducted a prospective surveillance study on patients diagnosed with pulmonary hypertension at 12 large referral centers in North America. Data collected on patients seen from September 1, 1996, to December 31, 1997, included the cause of the pulmonary hypertension and its severity. Patients with no identifiable cause of pulmonary hypertension were classed as PPH. A history of drug exposure also was taken with special attention on the use of antidepressants, anorexigens, and amphetamines. RESULTS: Five hundred seventy-nine patients were studied, 205 with PPH and 374 with pulmonary hypertension from other causes (secondary pulmonary hypertension [SPH]). The use of anorexigens was common in both groups. However, of the medications surveyed, only the fenfluramines had a significant preferential association with PPH as compared with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence interval, 1.7 to 32.4). The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users. An unexpectedly high (11.4%) number of patients with SPH had used anorexigens. CONCLUSION: The magnitude of the association with PPH, the increase of association with increasing duration of use, and the specificity for fenfluramines are consistent with previous studies indicating that fenfluramines are causally related to PPH. The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate pulmonary hypertension in patients with underlying conditions associated with SPH.

pulmonary hypertension

pulmonary hypertension

primary pulmonary hypertension

PPH

fenfluramine

pulmonary hypertension

pulmonary hypertension

pulmonary hypertension

PPH

amphetamines

PPH

pulmonary hypertension

pulmonary hypertension

fenfluramines

PPH

PPH

fenfluramines

fenfluramines

PPH

pulmonary hypertension


Clinical aspects of heparin-induced thrombocytopenia and thrombosis and other side effects of heparin therapy.

Heparin, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, heparin remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of heparin are meritorious, but side effects do exist. Bleeding is the primary untoward effect of heparin. Major bleeding is of primary concern in patients receiving heparin therapy. However, additional important untoward effects of heparin therapy include heparin-induced thrombocytopenia, heparin-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of heparin, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated heparin, at present the incidences of these side effects with newer low molecular weight heparins appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations.

heparin

thrombocytopenia

thrombosis

heparin

Heparin

thrombosis

heparin

thrombotic

heparin

Bleeding

heparin

bleeding

heparin

heparin

heparin

thrombocytopenia

heparin

osteoporosis

eosinophilia

skin reactions

allergic reactions

thrombocytopenia

alopecia

hyperkalemia

hypoaldosteronism

priapism

heparin

HITT

osteoporosis

heparin

heparins


A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy after liver transplantation.

PURPOSE: To report a case of bilateral optic neuropathy in a patient receiving tacrolimus (FK 506, Prograf; Fujisawa USA, Inc, Deerfield, Illinois) for immunosuppression after orthotropic liver transplantation. METHOD: Case report. In a 58-year-old man receiving tacrolimus after orthotropic liver transplantation, serial neuro-ophthalmologic examinations and laboratory studies were performed. RESULTS: The patient had episodic deterioration of vision in both eyes, with clinical features resembling ischemic optic neuropathies. Deterioration of vision occurred despite discontinuation of the tacrolimus. CONCLUSION: Tacrolimus and other immunosuppressive agents may be associated with optic nerve toxicity.

optic neuropathy

tacrolimus

optic neuropathy

tacrolimus

FK 506

tacrolimus

ischemic optic neuropathies

Deterioration of vision

tacrolimus

Tacrolimus

optic nerve toxicity


Hypercalcemia, arrhythmia, and mood stabilizers.

Recent findings in a bipolar patient receiving maintenance lithium therapy who developed hypercalcemia and severe bradyarrhythmia prompted the authors to conduct a retrospective study of bipolar patients with lithium-associated hypercalcemia. A printout of all cases of hypercalcemia that presented during a 1-year period was generated. After eliminating spurious hypercalcemias or those associated with intravenous fluids, the authors identified 18 non-lithium-treated patients with hypercalcemias related to malignancies and other medical conditions (group A) and 12 patients with lithium-associated hypercalcemia (group B). Patients in group B were not comparable to those in group A, as the latter were medically compromised and were receiving multiple pharmacotherapies. Thus, two control groups were generated: group C1, which included age- and sex-comparable lithium-treated bipolar normocalcemic patients, and group C2, which included bipolar normocalcemic patients treated with anticonvulsant mood stabilizers. The electrocardiographic (ECG) findings for patients in group B were compared with those of patients in groups C1 and C2. It was found that these groups did not differ in their overall frequency of ECG abnormalities; however, there were significant differences in the frequency of conduction defects. Patients with hypercalcemia resulting from medical diseases and bipolar patients with lithium-associated hypercalcemia had significantly higher frequencies of conduction defects. Patients in group A had significant mortality at 2-year follow-up (28%), in contrast to zero mortality in the other three groups. The clinical implications of these findings are discussed.

Hypercalcemia

arrhythmia

bipolar

lithium

hypercalcemia

bradyarrhythmia

bipolar

lithium

hypercalcemia

hypercalcemia

hypercalcemias

lithium

hypercalcemias

malignancies

lithium

hypercalcemia

lithium

bipolar

bipolar

hypercalcemia

bipolar

lithium

hypercalcemia


Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating amphotericin B.

NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the nephrotoxicity of amphotericin B.

nephrotoxicity

amphotericin B

amphotericin B

toxicity

toxicity

Fungizone

amphotericin B-sodium deoxycholate

D-AmB

amphotericin B

D-AmB

urea

creatinine

D-AmB

tubular necrosis

D-AmB

Amphotericin B

D-AmB

amphotericin B

nephrotoxicity

amphotericin B


Patterns of sulfadiazine acute nephrotoxicity.

Sulfadiazine acute nephrotoxicity is reviving specially because of its use in toxoplasmosis in HIV-positive patients. We report 4 cases, one of them in a previously healthy person. Under treatment with sulfadiazine they developed oliguria, abdominal pain, renal failure and showed multiple radiolucent renal calculi in echography. All patients recovered their previous normal renal function after adequate hydration and alcalinization. A nephrostomy tube had to be placed in one of the patients for ureteral lithiasis in a single functional kidney. None of them needed dialysis or a renal biopsy because of a typical benign course. Treatment with sulfadiazine requires exquisite control of renal function, an increase in water ingestion and possibly the alcalinization of the urine. We communicate a case in a previously healthy person, a fact not found in the recent literature. Probably many more cases are not detected. We think that a prospective study would be useful.

sulfadiazine

acute nephrotoxicity

Sulfadiazine

acute nephrotoxicity

toxoplasmosis

sulfadiazine

oliguria

abdominal pain

renal failure

renal calculi

ureteral lithiasis

sulfadiazine


Downbeat nystagmus associated with intravenous patient-controlled administration of morphine.

IMPLICATIONS: This case documents a patient who developed dizziness with downbeating nystagmus while receiving a relatively large dose of IV patient-controlled analgesia morphine. Although there have been case reports of epidural morphine with these symptoms and signs, this has not been previously documented with IV or patient-controlled analgesia morphine.

Downbeat nystagmus

morphine

dizziness

downbeating nystagmus

morphine

morphine

morphine


Hemodynamic and antiadrenergic effects of dronedarone and amiodarone in animals with a healed myocardial infarction.

The hemodynamic and antiadrenergic effects of dronedarone, a noniodinated compound structurally related to amiodarone, were compared with those of amiodarone after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed myocardial infarction. All dogs (n = 6) randomly received orally dronedarone (10 and 30 mg/kg), amiodarone (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to isoproterenol and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after dronedarone and to a lesser extent after amiodarone. Both dronedarone and amiodarone significantly reduced the exercise-induced tachycardia and, at the highest dose, decreased the isoproterenol-induced tachycardia. Thus, dronedarone and amiodarone displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, dronedarone might be particularly suitable for the treatment and prevention of various clinical arrhythmias, without compromising the left ventricular function.

dronedarone

amiodarone

myocardial infarction

dronedarone

amiodarone

amiodarone

myocardial infarction

dronedarone

amiodarone

isoproterenol

dronedarone

amiodarone

dronedarone

amiodarone

tachycardia

isoproterenol

tachycardia

dronedarone

amiodarone

dronedarone

arrhythmias


Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum.

BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and paclitaxel-refractory ovarian cancer.

doxorubicin

platinum

paclitaxel

ovarian and fallopian tube cancers

ovarian cancers

fallopian tube cancers

carcinoma of the peritoneum

doxorubicin

Doxil

platinum

ovarian cancer

toxicity

erythrodysesthesia

hand-foot syndrome

stomatitis

doxorubicin

platinum

paclitaxel

ovarian or fallopian tube cancers

ovarian cancers

fallopian tube cancers

peritoneal carcinoma

platinum

paclitaxel

doxorubicin

hand-foot syndrome

stomatitis

diarrhea

doxorubicin

doxorubicin

toxicity

stomatitis

hand-foot syndrome

platinum

paclitaxel

ovarian cancer


Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.

BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

olanzapine

bipolar mania

Olanzipine

olanzapine

bipolar mania

bipolar disorder

manic

olanzapine

Mania

Extrapyramidal Symptom

EPS

Olanzapine

Olanzapine

EPSs

olanzapine

weight gain

somnolence

Olanzapine

bipolar mania


The effect of pupil dilation with tropicamide on vision and driving simulator performance.

PURPOSE: To assess the effect of pupil dilation on vision and driving ability. METHODS: A series of tests on various parameters of visual function and driving simulator performance were performed on 12 healthy drivers, before and after pupil dilation using guttae tropicamide 1%. A driving simulator (Transport Research Laboratory) was used to measure reaction time (RT), speed maintenance and steering accuracy. Tests of basic visual function included high- and low-contrast visual acuity (HCVA and LCVA), Pelli-Robson contrast threshold (CT) and Goldmann perimetry (FIELDS). Useful Field of View (UFOV--a test of visual attention) was also undertaken. The mean differences in the pre- and post-dilatation measurements were tested for statistical significance at the 95% level using one-tail paired t-tests. RESULTS: Pupillary dilation resulted in a statistically significant deterioration in CT and HCVA only. Five of 12 drivers also exhibited deterioration in LCVA, CT and RT. Little evidence emerged for deterioration in FIELDS and UFOV. Also, 7 of 12 drivers appeared to adjust their driving behaviour by reducing their speed on the driving simulator, leading to improved steering accuracy. CONCLUSIONS: Pupillary dilation may lead to a decrease in vision and daylight driving performance in young people. A larger study, including a broader spectrum of subjects, is warranted before guidelines can be recommended.

pupil dilation

tropicamide

pupil dilation

pupil dilation

tropicamide

Pupillary dilation

Pupillary dilation


A case of isotretinoin embryopathy with bilateral anotia and Taussig-Bing malformation.

We report a newborn infant with multiple congenital anomalies (anotia and Taussig-Bing malformation) due to exposure to isotretinoin within the first trimester. In this paper we aim to draw to the fact that caution is needed when prescribing vitamin A-containing drugs to women of childbearing years.

isotretinoin embryopathy

anotia

Taussig-Bing malformation

anotia

Taussig-Bing malformation

isotretinoin

vitamin A


Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study.

The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous methoxamine or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. Methoxamine evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects.

methoxamine

stress incontinence

urinary stress incontinence

methoxamine

stress incontinence

Methoxamine

headache

stress incontinence


Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival.

BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF. METHODS: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted.

heart failure

Lisinopril

heart failure

CHF

lisinopril

CHF

Lisinopril

ACE inhibitor

lisinopril

CHF

hypotension

renal dysfunction

ACE inhibitor

hypotension

renal dysfunction

hyperkalemia

ACE inhibitor

creatinine

diabetes

ACE inhibitor

CHF


Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse.

OBJECTIVES: Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually. In combination, these substances are substantially more toxic than either drug alone. Their combined cardiac toxicity may be due to independent effects of each drug; however, they may also be due to cocaethylene (CE), a cocaine metabolite formed only in the presence of ethanol. The purpose of this study was to delineate the role of CE in the combined cardiotoxicity of cocaine and ethanol in a model simulating their abuse. METHODS: Twenty-three dogs were randomized to receive either 1) three intravenous (IV) boluses of cocaine 7.5 mg/kg with ethanol (1 g/kg) as an IV infusion (C+E, n = 8), 2) three cocaine boluses only (C, n = 6), 3) ethanol infusion only (E, n = 5), or 4) placebo boluses and infusion (n = 4). Hemodynamic measurements, electrocardiograms, and serum drug concentrations were obtained at baseline, and then at fixed time intervals after each drug was administered. RESULTS: Two of eight dogs in the C+E group experienced cardiovascular collapse. The most dramatic hemodynamic changes occurred after each cocaine bolus in the C+E and C only groups; however, persistent hemodynamic changes occurred in the C+E group. Peak CE levels were associated with a 45% (SD +/- 22%, 95% CI = 22% to 69%) decrease in cardiac output (p < 0.05), a 56% (SD +/- 23%, 95% CI = 32% to 80%) decrease in dP/dt(max) (p <.006), and a 23% (SD +/- 15%, 95% CI = 7% to 49%) decrease in SVO(2) (p < 0.025). Ventricular arrhythmias were primarily observed in the C+E group, in which four of eight dogs experienced ventricular tachycardia. CONCLUSIONS: Cocaine and ethanol in combination were more toxic than either substance alone. Co-administration resulted in prolonged cardiac toxicity and was dysrhythmogenic. Peak serum cocaethylene concentrations were associated with prolonged myocardial depression.

Cocaine

ethanol

cocaethylene

cardiotoxity

cocaine and ethanol abuse

cocaine abuse

ethanol abuse

abuse of cocaine and ethanol

abuse of cocaine

abuse of
ethanol

cardiac toxicity

cocaethylene

CE

cocaine

ethanol

CE

cardiotoxicity

cocaine

ethanol

cocaine

ethanol

cocaine

ethanol

cardiovascular collapse

cocaine

CE

decrease in cardiac output

Ventricular arrhythmias

ventricular tachycardia

Cocaine

ethanol

cardiac toxicity

cocaethylene

myocardial depression


Worsening of Parkinsonism after the use of veralipride for treatment of menopause: case report.

We describe a female patient with stable Parkinson's disease who has shown a marked worsening of her motor functions following therapy of menopause related symptoms with veralipride, as well as the improvement of her symptoms back to baseline after discontinuation of the drug. We emphasize the anti-dopaminergic effect of veralipride.

Parkinsonism

veralipride

Parkinson's disease

veralipride

veralipride


Viracept and irregular heartbeat warning.

A group of doctors in Boston warn that the protease inhibitor Viracept may cause an irregular heart beat, known as bradycardia, in people with HIV. Bradycardia occurred in a 45-year-old male patient who was Viracept in combination with other anti-HIV drugs. The symptoms ceased after switching to another drug combination.

Viracept

irregular heartbeat

Viracept

irregular heart beat

bradycardia

Bradycardia

Viracept


Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with propylthiouracil and the relationship between MPO-ANCA and clinical manifestations.

OBJECTIVE: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with propylthiouracil (PTU). The appearance of MPO-ANCA in these cases was suspected of being related to PTU because the titres of MPO-ANCA decreased when PTU was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during PTU therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. PATIENTS: We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting PTU therapy. Twenty-nine of them were later excluded because of adverse effects of PTU or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). MEASUREMENTS: MPO-ANCA was measured at intervals of 2-6 months. RESULTS: Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of PTU therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued PTU therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher fever, oral ulcers and polyarthralgia, but the symptoms resolved 2 weeks after stopping PTU therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing PTU. CONCLUSIONS: PTU therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis.

Graves' disease

propylthiouracil

vasculitis

Graves' disease

propylthiouracil

PTU

PTU

PTU

vasculitis

PTU

Graves' disease

Graves' disease

hyperthyroidism

Graves' disease

vasculitis

PTU

PTU

Graves' disease

PTU

PTU

vasculitic disorders

fever

oral ulcers

polyarthralgia

PTU

PTU

PTU

vasculitis


Prevalence of heart disease in asymptomatic chronic cocaine users.

To determine the prevalence of heart disease in outpatient young asymptomatic chronic cocaine users, 35 cocaine users and 32 age-matched controls underwent resting and exercise electrocardiography (ECG) and Doppler echocardiography. Findings consistent with coronary artery disease were detected in 12 (34%) patients and 3 (9%) controls (p = 0.01). Decreased left ventricular systolic function was demonstrated in 5 (14%) patients, but in none of the controls (p = 0.055). Finally, resting and peak exercise abnormal left ventricular filling was detected in 38 and 35% of patients as compared to 19 and 9% of controls, respectively (p = 0.11 and 0.02, respectively). We conclude that coronary artery or myocardial disease is common (38%) in young asymptomatic chronic cocaine users. Therefore, screening ECG and echocardiography may be warranted in these patients.

heart disease

cocaine

heart disease

cocaine

cocaine

coronary artery disease

abnormal left ventricular filling

coronary artery or myocardial disease

coronary artery
disease

myocardial disease

cocaine


Cardioprotective effects of Picrorrhiza kurroa against isoproterenol-induced myocardial stress in rats.

The cardioprotective effect of the ethanol extract of Picrorrhiza kurroa rhizomes and roots (PK) on isoproterenol-induced myocardial infarction in rats with respect to lipid metabolism in serum and heart tissue has been investigated. Oral pre-treatment with PK (80 mg kg(-1) day(-1) for 15 days) significantly prevented the isoproterenol-induced myocardial infarction and maintained the rats at near normal status.

isoproterenol

ethanol

isoproterenol

myocardial infarction

isoproterenol

myocardial infarction


Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall.

BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-sotalol, azimilide (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-sotalol and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 micromol/L) increased APD more than dl-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation.

ventricular tachycardia

long-QT syndrome

torsade de pointes

TdP

QT prolongation

sotalol

azimilide

TdP

Sotalol

QT prolongation

Azimilide

sotalol

azimilide

sotalol

azimilide

QT prolongation

sotalol

TdP

azimilide

sotalol

TdP

QT prolongation


Prenatal cocaine exposure and cranial sonographic findings in preterm infants.

PURPOSE: Prenatal cocaine exposure has been linked with subependymal hemorrhage and the formation of cysts that are detectable on cranial sonography in neonates born at term. We sought to determine if prenatal cocaine exposure increases the incidence of subependymal cysts in preterm infants. METHODS: We retrospectively reviewed the medical records and cranial sonograms obtained during a 1-year period on 122 premature (< 36 weeks of gestation) infants. Infants were categorized into 1 of 2 groups: those exposed to cocaine and those not exposed to cocaine. Infants were assigned to the cocaine-exposed group if there was a maternal history of cocaine abuse during pregnancy or if maternal or neonatal urine toxicology results were positive at the time of delivery. RESULTS: Five of the 122 infants were excluded from the study because of insufficient medical and drug histories. The incidence of subependymal cysts in the 117 remaining infants was 14% (16 of 117). The incidence of subependymal cysts in infants exposed to cocaine prenatally was 44% (8 of 18) compared with 8% (8 of 99) in the unexposed group (p < 0.01). CONCLUSIONS: We found an increased incidence of subependymal cyst formation in preterm infants who were exposed to cocaine prenatally. This result is consistent with results of similar studies in term infants.

cocaine

preterm infants

cocaine

hemorrhage

cysts

cocaine

subependymal cysts

subependymal cysts

cysts

preterm infants

cocaine

cocaine

cocaine

cocaine abuse

subependymal cysts

subependymal cysts

cysts

subependymal cysts

subependymal cysts

cysts

cocaine

subependymal cyst

subependymal cyst

cyst

preterm infants

cocaine


Thalidomide neuropathy in patients treated for metastatic prostate cancer.

We prospectively evaluated thalidomide-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic androgen-independent prostate cancer in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection.

Thalidomide

neuropathy

prostate cancer

thalidomide

neuropathy

androgen

prostate cancer

thalidomide

Thalidomide

thalidomide

neuropathy

Neuropathy

thalidomide

peripheral neuropathy


Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss.

The participation of reactive oxygen species in aminoglycoside-induced ototoxicity has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate ototoxicity in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from ototoxicity. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced ototoxicity. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention.

copper

zinc

superoxide

kanamycin

hearing loss

oxygen

aminoglycoside

ototoxicity

aminoglycoside

iron

superoxide

ototoxicity

Cu

Zn

superoxide

ototoxicity

kanamycin

kanamycin

kanamycin

superoxide

aminoglycoside

ototoxicity


Prednisone induces anxiety and glial cerebral changes in rats.

OBJECTIVE: To assess whether prednisone (PDN) produces anxiety and/or cerebral glial changes in rats. METHODS: Male Wistar rats were studied and 3 groups were formed (8 rats per group). The moderate-dose group received 5 mg/kg/day PDN released from a subcutaneous implant. In the high-dose group, implants containing PDN equivalent to 60 mg/kg/day were applied. In the control group implants contained no PDN. Anxiety was assessed using an open field and elevated plus-maze devices. The number of cells and cytoplasmic transformation of astrocytes and microglia cells were assessed by immunohistochemical analyses. RESULTS: Anxiety was documented in both groups of PDN treated rats compared with controls. The magnitude of transformation of the microglia assessed by the number of intersections was significantly higher in the PDN groups than in controls in the prefrontal cortex (moderate-dose, 24.1; high-dose, 23.6; controls 18.7; p < 0.01) and striatum (moderate-dose 25.6; high-dose 26.3; controls 18.9; p < 0.01), but not in hippocampus. The number of stained microglia cells was significantly higher in the PDN treated groups in the prefrontal cortex than in controls (moderate-dose, 29.1; high-dose, 28.4; control, 17.7 cells per field; p < 0.01). Stained microglia cells were significantly more numerous striatum and hippocampus in the high-dose group compared to controls. CONCLUSION: Subacute exposure to PDN induced anxiety and reactivity of microglia. The relevance of these features for patients using PDN remains to be elucidated.

Prednisone

anxiety

prednisone

PDN

anxiety

PDN

PDN

PDN

Anxiety

Anxiety

PDN

PDN

PDN

PDN

anxiety

PDN


Phase II study of carboplatin and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix.

BACKGROUND: The activity of the combination of carboplatin and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma.

carboplatin

doxorubicin

squamous cell carcinoma of the cervix

squamous cell carcinoma

carcinoma of the cervix

carboplatin

doxorubicin

cervical carcinoma

carboplatin

doxorubicin

Doxil

squamous cell cervical carcinoma

squamous cell
carcinoma

cervical carcinoma

toxicity

toxicity

myelosuppression

neutropenia

anemia

thrombocytopenia

neutropenic fever

neutropenic

fever

doxorubicin

toxicity

nausea

emesis

fatigue

mucositis

stomatitis

constipation

weight loss

hand-foot syndrome

skin reactions

carboplatin

doxorubicin

cervical carcinoma


Antimicrobial-induced mania (antibiomania): a review of spontaneous reports.

The authors reviewed reported cases of antibiotic-induced manic episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced mania. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced mania were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported manic episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of mania. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing mania while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced mania, the relative risk factors of developing an antimicrobial-induced manic episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "antibiomania."

mania

antibiomania

manic

mania

mania

clarithromycin

isoniazid

erythromycin

amoxicillin

clarithromycin

ciprofloxacin

ofloxacin

Cotrimoxazole

metronidazole

erythromycin

manic

clarithromycin

ciprofloxacin

mania

mania

mania

manic

antibiomania


Levodopa-induced ocular dyskinesias in Parkinson's disease.

Levodopa-induced ocular dyskinesias are very uncommon. Usually they occur simultaneously with limb peak-dose choreatic dyskinesias. We report on a patient with leftward and upward deviations of gaze during the peak effect of levodopa, and hypothesize that a severe dopaminergic denervation in the caudate nucleus is needed for the appearance of these levodopa-induce ocular dyskinesias.

Levodopa

ocular dyskinesias

Parkinson's disease

Levodopa

ocular dyskinesias

choreatic dyskinesias

levodopa

levodopa

ocular dyskinesias


A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial.

Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea.

glyceryl trinitrate

diclofenac

dysmenorrhea

dysmenorrhea

prostaglandins

nitric oxide

NO

glyceryl trinitrate

GTN

NO

dysmenorrhea

diclofenac

DCF

dysmenorrhea

DCF

GTN

DCF

GTN

pain

GTN

DCF

DCF

pelvic pain

GTN

GTN

GTN

Low back pain

Headache

GTN

DCF

GTN

headache

GTN

DCF

dysmenorrhea


Temocapril, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis.

The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/temocapril group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats.

Temocapril

angiotensin

glomerular injury

puromycin aminonucleoside

nephrosis

temocapril

angiotensin

proteinuria

hypertrophy

glomerulosclerosis

puromycin aminonucleoside

PAN

nephrotic

Nephrosis

PAN

PAN

PAN

temocapril

temocapril

Temocapril

PAN

PAN

temocapril

PAN

Temocapril

proteinuria

glomerulosclerosis

PAN

PAN

PAN

temocapril

temocapril

PAN

neprotic


Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants.

We report three cases of severe hypoxaemia after ibuprofen administration during a randomised controlled trial of prophylactic treatment of patent ductus arteriosus with ibuprofen in premature infants born at less than 28 weeks of gestation. Echocardiography showed severely decreased pulmonary blood flow. Hypoxaemia resolved quickly on inhaled nitric oxide therapy. We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if hypoxaemia occurs after prophylactic administration of ibuprofen.

Pulmonary hypertension

ibuprofen

hypoxaemia

ibuprofen

patent ductus arteriosus

ibuprofen

Hypoxaemia

nitric oxide

hypoxaemia

ibuprofen


Hyponatremia and syndrome of inappropriate anti-diuretic hormone reported with the use of Vincristine: an over-representation of Asians?

PURPOSE: This retrospective study used a pharmaceutical company's global safety database to determine the reporting rate of hyponatremia and/or syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) among vincristine-treated patients and to explore the possibility of at-risk population subgroups. METHOD: We searched the Eli Lilly and Company's computerized adverse event database for all reported cases of hyponatremia and/or SIADH as of 1 November 1999 that had been reported during the use of vincristine. RESULTS: A total of 76 cases of hyponatremia and/or SIADH associated with vincristine use were identified. The overall reporting rate was estimated to be 1.3/100,000 treated patients. The average age of patients was 35.6 +/- 28.3 years, and 62% were males. Approximately 75% of the patients were receiving treatment for leukemia or lymphoma. Among the 39 reports that included information on race, the racial distribution was: 1 Black, 3 Caucasian, and 35 Asian. CONCLUSION: Our data suggest that Asian patients may be at increased risk of hyponatremia and/or SIADH associated with vincristine use. Although the overall reported rate of SIADH associated with vincristine is very low, physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event.

Hyponatremia

Vincristine

hyponatremia

SIADH

vincristine

hyponatremia

SIADH

vincristine

hyponatremia

SIADH

vincristine

leukemia

lymphoma

hyponatremia

SIADH

vincristine

SIADH

vincristine


Delayed toxicity of cyclophosphamide on the bladder of DBA/2 and C57BL/6 female mouse.

The present study describes the delayed development of a severe bladder pathology in a susceptible strain of mice (DBA/2) but not in a resistant strain (C57BL/6) when both were treated with a single 300 mg/kg dose of cyclophosphamide (CY). Inbred DBA/2 and C57BL/6 female mice were injected with CY, and the effect of the drug on the bladder was assessed during 100 days by light microscopy using different staining procedures, and after 30 days by conventional electron microscopy. Early CY toxicity caused a typical haemorrhagic cystitis in both strains that was completely repaired in about 7-10 days. After 30 days of CY injection ulcerous and non-ulcerous forms of chronic cystitis appeared in 86% of DBA/2 mice but only in 4% of C57BL/6 mice. Delayed cystitis was characterized by infiltration and transepithelial passage into the lumen of inflammatory cells and by frequent exfoliation of the urothelium. Mast cells appeared in the connective and muscular layers of the bladder at a much higher number in DBA/2 mice than in C57BL/6 mice or untreated controls. Electron microscopy disclosed the absence of the typical discoidal vesicles normally present in the cytoplasm of surface cells. Instead, numerous abnormal vesicles containing one or several dark granules were observed in the cytoplasm of cells from all the epithelial layers. Delayed cystitis still persisted in DBA/2 mice 100 days after treatment. These results indicate that delayed toxicity of CY in female DBA/2 mice causes a bladder pathology that is not observed in C57BL/6 mice. This pathology resembles interstitial cystitis in humans and could perhaps be used as an animal model for studies on the disease.

toxicity

cyclophosphamide

cyclophosphamide

CY

CY

CY

toxicity

haemorrhagic

cystitis

CY

cystitis

cystitis

cystitis

toxicity

CY

interstitial cystitis


High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study.

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.

folinic acid

mitomycin C

gastric cancer

folinic acid

FA

gastric cancer

AGC

toxicity

FA

mitomycin C

MMC

toxicity

MMC

FA

MMC

AGC

FA

MMC

AGC

AGC

toxicities

leukopenia

thrombocytopenia

vomitus

diarrhea

stomatitis

hand-foot syndrome

hemolytic-uremic syndrome

HUS

FA

MMC

AGC

cisplatin

HUS


Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir.

BACKGROUND: Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir. METHODS: Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir. RESULTS: The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months. CONCLUSIONS: Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L.

leukocyturia

impaired renal function

indinavir

indinavir

indinavir

nephrotoxicity

indinavir

creatinine

creatinine

indinavir

indinavir

leukocyturia

leukocyturia

creatinine

hematuria

creatinine

leukocyturia

creatinine

leukocyturia

leukocyturia

leukocyturia

indinavir

indinavir

nephrotoxicity

creatinine

creatinine

leukocyturia

indinavir

leukocyturia

leukocyturia

creatinine

impairment of the renal function

nephrolithiasis

Indinavir

nephrotoxicity

leukocyturia

indinavir


Utility of troponin I in patients with cocaine-associated chest pain.

Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of creatine kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with cocaine-associated chest pain and suspected MI.

cocaine

chest pain

myocardial necrosis

myocardial infarction

MI

cocaine

chest pain

cocaine

chest pain

MI

MI

cocaine

creatine

MI

cardiac death

coronary disease

MI

MI

cardiac death

MI

MI

necrosis

cocaine

chest pain

MI


Acute interstitial nephritis due to nicergoline (Sermion).

We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN.

interstitial nephritis

nicergoline

Sermion

interstitial nephritis

AIN

nicergoline

Sermion

fever

acute renal failure

nicergoline

bendazac lysine

retinal vein occlusion

fever

skin rash

arthralgia

fever

eosinophilia

renal failure

AIN

nicergoline

nicergoline

methylprednisolone

nicergoline

AIN


Neuroleptic malignant syndrome complicated by massive intestinal bleeding in a patient with chronic renal failure.

A patient with chronic renal failure (CRF) developed neuroleptic malignant syndrome (NMS) after administration of risperidone and levomepromazine. In addition to the typical symptoms of NMS, massive intestinal bleeding was observed during the episode. This report suggests that NMS in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication.

Neuroleptic malignant syndrome

bleeding

chronic renal failure

chronic renal failure

CRF

neuroleptic malignant syndrome

NMS

risperidone

levomepromazine

NMS

bleeding

NMS

CRF

bleeding


Blood brain barrier in right- and left-pawed female rats assessed by a new staining method.

The asymmetrical breakdown of the blood-brain barrier (BBB) was studied in female rats. Paw preference was assessed by a food reaching test. Adrenaline-induced hypertension was used to destroy the BBB, which was evaluated using triphenyltetrazolium (TTC) staining of the brain slices just after giving adrenaline for 30 s. In normal rats, the whole brain sections exhibited complete staining with TTC. After adrenaline infusion for 30 s, there were large unstained areas in the left brain in right-pawed animals, and vice versa in left-pawed animals. Similar results were obtained in seizure-induced breakdown of BBB. These results were explained by an asymmetric cerebral blood flow depending upon the paw preference in rats. It was suggested that this new method and the results are consistent with contralateral motor control that may be important in determining the dominant cerebral hemisphere in animals.

Adrenaline

hypertension

triphenyltetrazolium

TTC

adrenaline

TTC

adrenaline

seizure


Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy.

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.

Carvedilol

doxorubicin

cardiomyopathy

cardiomyopathy

doxorubicin

mitochondrial dysfunction

carvedilol

doxorubicin

toxicity

doxorubicin

carvedilol

doxorubicin

calcium

doxorubicin

Doxorubicin

carvedilol

doxorubicin

Carvedilol

Ca

doxorubicin

Carvedilol

carvedilol

mitochondrial dysfunction

cardiomyopathy

doxorubicin

cancer


Cocaine-induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine-induced hyperactivity.

The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced hyperactivity was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced hyperactivity, but at the higher doses than those which were active in cocaine-induced hyperactivity. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced hyperactivity is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced hyperactivity.

Cocaine

hyperactivity

adenosine

amphetamine

hyperactivity

adenosine

cocaine

amphetamine

hyperactivity

adenosine

decreased the locomotor activity

adenosine

adenosine

CGS 21680

CPA

NECA

cocaine

CPA

cocaine

CGS 21680

NECA

cocaine

adenosine

cocaine

adenosine

DMPX

cocaine

Caffeine

CPT

adenosine

amphetamine

hyperactivity

cocaine

hyperactivity

adenosine

DMPX

adenosine

caffeine

amphetamine

adenosine

cocaine

amphetamine

cocaine

hyperactivity

adenosine

amphetamine

hyperactivity


Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction.

OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation.

Amiodarone

bradyarrhythmia

atrial fibrillation

myocardial infarction

amiodarone

atrial fibrillation

AF

bradyarrhythmia

bradyarrhythmia

amiodarone

ventricular arrhythmias

AF

myocardial infarction

MI

bradyarrhythmia

amiodarone

sotalol

calcium

digoxin

amiodarone

Digoxin

amiodarone

AF

MI

bradyarrhythmia

amiodarone


Indomethacin-induced morphologic changes in the rat urinary bladder epithelium.

OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by indomethacin. Nonsteroidal anti-inflammatory drug-induced cystitis is a poorly recognized and under-reported condition. In addition to tiaprofenic acid, indomethacin has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of indomethacin 20 mg/kg, and a therapeutic dose group (n = 10) in which oral indomethacin was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both indomethacin groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of lanthanum nitrate through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: Indomethacin resulted in histopathologic findings typical of interstitial cystitis, such as leaky bladder epithelium and mucosal mastocytosis. The true incidence of nonsteroidal anti-inflammatory drug-induced cystitis in humans must be clarified by prospective clinical trials.

Indomethacin

indomethacin

cystitis

tiaprofenic acid

indomethacin

indomethacin

indomethacin

indomethacin

lanthanum nitrate

Indomethacin

interstitial cystitis

mastocytosis

cystitis


An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer.

The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy.

thalidomide

androgen

prostate cancer

thalidomide

haematological malignancies

Thalidomide

thalidomide

androgen

prostate cancer

urea

constipation

drowsiness

dizziness

rash

peripheral sensory neuropathy

thalidomide

peripheral neuropathy

thalidomide

peripheral neuropathy


Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases.

BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients.

Central nervous system toxicity

levobupivacaine

Central nervous system
toxicity

cardiac toxicity

Levobupivacaine

bupivacaine

bupivacaine

grand mal seizures

levobupivacaine

levobupivacaine

epinephrine

grand mal seizures

epinephrine

seizures

sodium thiopental

succinylcholine

cardiovascular toxicity

levobupivacaine

epinephrine

levobupivacaine

cardiac toxicity

bupivacaine

levobupivacaine

convulsions

central nervous system toxicity

cardiac toxicity


Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders.

Myotonia congenita (MC) is caused by a defect in the skeletal muscle chloride channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations.

myotonia congenita

myotonic disorders

Myotonia congenita

MC

chloride

sustained membrane depolarisation

muscle spasm

suxamethonium

muscle spasms

myotonic condition

Myotonia

MC

ion channel disorders

malignant hyperthermia


Respiratory pattern in a rat model of epilepsy.

PURPOSE: Apnea is known to occur during seizures, but systematic studies of ictal respiratory changes in adults are few. Data regarding respiratory pattern defects during interictal periods also are scarce. Here we sought to generate information with regard to the interictal period in animals with pilocarpine-induced epilepsy. METHODS: Twelve rats (six chronically epileptic animals and six controls) were anesthetized, given tracheotomies, and subjected to hyperventilation or hypoventilation conditions. Breathing movements caused changes in thoracic volume and forced air to flow tidally through a pneumotachograph. This flow was measured by using a differential pressure transducer, passed through a polygraph, and from this to a computer with custom software that derived ventilation (VE), tidal volume (VT), inspiratory time (TI), expiratory time (TE), breathing frequency (f), and mean inspiratory flow (VT/TI) on a breath-by-breath basis. RESULTS: The hyperventilation maneuver caused a decrease in spontaneous ventilation in pilocarpine-treated and control rats. Although VE had a similar decrease in both groups, in the epileptic group, the decrease in VE was due to a significant (p < 0.05) increase in TE peak in relation to that of the control animals. The hypoventilation maneuver led to an increase in the arterial Paco2, followed by an increase in VE. In the epileptic group, the increase in VE was mediated by a significant (p < 0.05) decrease in TE peak compared with the control group. Systemic application of KCN, to evaluate the effects of peripheral chemoreception activation on ventilation, led to a similar increase in VE for both groups. CONCLUSIONS: The data indicate that pilocarpine-treated animals have an altered ability to react to (or compensate for) blood gas changes with changes in ventilation and suggest that it is centrally determined. We speculate on the possible relation of the current findings on treating different epilepsy-associated conditions.

epilepsy

Apnea

seizures

pilocarpine

epilepsy

epileptic

hyperventilation

hyperventilation

pilocarpine

epileptic

epileptic

pilocarpine

epilepsy


Increased serum soluble Fas in patients with acute liver failure due to paracetamol overdose.

BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of acute liver failure. The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects. Serum levels of tumor necrosis factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with acute liver failure (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with acute liver failure due to paracetamol overdose (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E hepatitis (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and aspartate aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas-mediated apoptosis in the liver and this together with increased tumor necrosis factor-alpha may be an important factor in liver cell loss.

acute liver failure

paracetamol

overdose

acute liver failure

acute liver failure

acute liver failure

tumor

necrosis

acute liver failure

acute liver failure

paracetamol

overdose

hepatitis

aspartate

acute liver failure

tumor

necrosis


Bilateral subthalamic nucleus stimulation for Parkinson's disease.

High frequency stimulation of the subthalamic nucleus (STN) is known to ameliorate the signs and symptoms of advanced Parkinson's disease. AIM: We studied the effect of high frequency STN stimulation in 23 patients. METHOD: Twenty-three patients suffering from severe Parkinson's disease (Stages III-V on Hoehn and Yahr scale) and, particularly bradykinesia, rigidity, and levodopa-induced dyskinesias underwent bilateral implantation of electrodes in the STN. Preoperative and postoperative assessments of these patients at 1, 3, 6 and 12 months follow-up, in "on" and "off" drug conditions, was carried out using Unified Parkinson's Disease Rating Scale, Hoehn and Yahr staging, England activities of daily living score and video recordings. RESULTS: After one year of electrical stimulation of the STN, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III) off medication improved by 62% and 61% respectively (p<0.0005). The subscores for the akinesia, rigidity, tremor and gait also improved. (p<0.0005). The average levodopa dose decreased from 813 mg to 359 mg. The cognitive functions remained unchanged. Two patients developed device-related complications and two patients experienced abnormal weight gain. CONCLUSION: Bilateral subthalamic nucleus stimulation is an effective treatment for advanced Parkinson's disease. It reduces the severity of "off" phase symptoms, improves the axial symptoms and reduces levodopa requirements. The reduction in the levodopa dose is useful in controlling drug-induced dyskinesias.

Parkinson's disease

Parkinson's disease

Parkinson's disease

bradykinesia

rigidity

levodopa

dyskinesias

Parkinson's Disease

Parkinson's Disease

akinesia

rigidity

tremor

levodopa

Parkinson's disease

levodopa

levodopa

drug-induced dyskinesias


Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma.

BACKGROUND: Focal subtenon carboplatin injections have recently been used as a presumably toxicity-free adjunct to systemic chemotherapy for intraocular retinoblastoma. OBJECTIVE: To report our clinical experience with abnormal ocular motility in patients treated with subtenon carboplatin chemotherapy. METHODS: We noted abnormal ocular motility in 10 consecutive patients with retinoblastoma who had received subtenon carboplatin. During ocular manipulation under general anesthesia, we assessed their eyes by forced duction testing, comparing ocular motility after tumor control with ocular motility at diagnosis. Eyes subsequently enucleated because of treatment failure (n = 4) were examined histologically. RESULTS: Limitation of ocular motility was detected in all 12 eyes of 10 patients treated for intraocular retinoblastoma with 1 to 6 injections of subtenon carboplatin as part of multimodality therapy. Histopathological examination revealed many lipophages in the periorbital fat surrounding the optic nerve in 1 eye, indicative of phagocytosis of previously existing fat cells and suggesting prior fat necrosis. The enucleations were technically difficult and hazardous for globe rupture because of extensive orbital soft tissue adhesions. CONCLUSIONS: Subtenon carboplatin chemotherapy is associated with significant fibrosis of orbital soft tissues, leading to mechanical restriction of eye movements and making subsequent enucleation difficult. Subtenon carboplatin is not free of toxicity, and its use is best restricted to specific indications.

carboplatin

retinoblastoma

carboplatin

toxicity

retinoblastoma

abnormal ocular motility

carboplatin

abnormal ocular motility

retinoblastoma

carboplatin

tumor

retinoblastoma

carboplatin

necrosis

rupture

carboplatin

fibrosis

carboplatin

toxicity


Ethambutol and optic neuropathy.

PURPOSE: To demonstrate the association between ethambutol and optic neuropathy. METHOD: Thirteen patients who developed optic neuropathy after being treated with ethambutol for tuberculosis of the lung or lymph node at Siriraj Hospital between 1997 and 2001 were retrospectively reviewed. The clinical characteristics and initial and final visual acuity were analyzed to determine visual outcome. RESULTS: All patients had optic neuropathy between 1 to 6 months (mean = 2.9 months) after starting ethambutol therapy at a dosage ranging from 13 to 20 mg/kg/day (mean = 17 mg/kg/day). Seven (54%) of the 13 patients experienced visual recovery after stopping the drug. Of 6 patients with irreversible visual impairment, 4 patients had diabetes mellitus, glaucoma and a history of heavy smoking. CONCLUSION: Early recognition of optic neuropathy should be considered in patients with ethambutol therapy. A low dose and prompt discontinuation of the drug is recommended particularly in individuals with diabetes mellitus, glaucoma or who are heavy smokers.

Ethambutol

optic neuropathy

ethambutol

optic neuropathy

optic neuropathy

ethambutol

tuberculosis of the lung or lymph node

tuberculosis of the lung

tuberculosis of
lymph node

optic neuropathy

ethambutol

visual impairment

diabetes mellitus

glaucoma

optic neuropathy

ethambutol

diabetes mellitus

glaucoma


Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate.

Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or aluminum chloride, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical glycopyrrolate. All patients had gustatory hyperhidrosis, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal hyperhidrosis. After applying topical glycopyrrolate, the subjective effect was excellent (no sweating after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced sweating) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly dry mouth and a sore throat in 2 patients (2% glycopyrrolate), a light headache in 1 patient (1.5% glycopyrrolate). The topical application of a glycopyrrolate pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects.

gustatory hyperhidrosis

glycopyrrolate

Gustatory hyperhidrosis

sweating

aluminum chloride

glycopyrrolate

gustatory hyperhidrosis

hyperhidrosis

glycopyrrolate

sweating

sweating

dry mouth

sore throat

glycopyrrolate

headache

glycopyrrolate

glycopyrrolate

gustatory hyperhidrosis


Pharmacological characteristics and side effects of a new galenic formulation of propofol without soyabean oil.

We compared the pharmacokinetics, pharmacodynamics and safety profile of a new galenic formulation of propofol (AM149 1%), which does not contain soyabean oil, with a standard formulation of propofol (Disoprivan 1%). In a randomised, double-blind, cross-over study, 30 healthy volunteers received a single intravenous bolus injection of 2.5 mg.kg-1 propofol. Plasma propofol levels were measured for 48 h following drug administration and evaluated according to a three-compartment model. The pharmacodynamic parameters assessed included induction and emergence times, respiratory and cardiovascular effects, and pain on injection. Patients were monitored for side effects over 48 h. Owing to a high incidence of thrombophlebitis, the study was terminated prematurely and only the data of the two parallel treatment groups (15 patients in each group) were analysed. Plasma concentrations did not differ significantly between the two formulations. Anaesthesia induction and emergence times, respiratory and cardiovascular variables showed no significant differences between the two treatment groups. Pain on injection (80 vs. 20%, p < 0.01) and thrombophlebitis (93.3 vs. 6.6%, p < 0.001) occurred more frequently with AM149 than with Disoprivan. Although both formulations had similar pharmacokinetic and pharmacodynamic profiles the new formulation is not suitable for clinical use due to the high incidence of thrombophlebitis produced.

propofol

propofol

propofol

Disoprivan

propofol

propofol

pain

thrombophlebitis

Pain

thrombophlebitis

Disoprivan

thrombophlebitis


Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials.

Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications.

Vinorelbine

vinorelbine

VNR

VNR

malignancies

VNR

cancer

VNR

VNR

VNR

VNR

vindesine

VDS

cardiotoxic

fluorouracil

anthracyclines

gemcitabine

GEM

cardiac diseases

Vinorelbine

VNR


MRI findings of hypoxic cortical laminar necrosis in a child with hemolytic anemia crisis.

We present magnetic resonance imaging findings of a 5-year-old girl who had a rapidly installing hemolytic anemia crisis induced by trimethoprim-sulfomethoxazole, resulting in cerebral anoxia leading to permanent damage. Magnetic Resonance imaging revealed cortical laminar necrosis in arterial border zones in both cerebral hemispheres, ischemic changes in subcortical white matter of left cerebral hemisphere, and in the left putamen. Although cortical laminar necrosis is a classic entity in adulthood related to conditions of energy depletions, there are few reports available in children. A wide review of the literature is also presented.

necrosis

hemolytic anemia

hemolytic anemia

trimethoprim-sulfomethoxazole

cerebral anoxia

necrosis

necrosis


The natural history of Vigabatrin associated visual field defects in patients electing to continue their medication.

PURPOSE: To determine the natural history of visual field defects in a group of patients known to have Vigabatrin-associated changes who elected to continue the medication because of good seizure control. METHODS: All patients taking Vigabatrin alone or in combination with other antiepileptic drugs for at least 5 years (range 5-12 years) were entered into a visual surveillance programme. Patients were followed up at 6-monthly intervals for not less than 18 months (range 18-43 months). In all, 16 patients with unequivocal defects continued the medication. Following already published methodology (Eye 2002; 16;567-571) monocular mean radial degrees (MRDs) to the I/4e isopter on Goldmann perimetry was calculated for the right eye at the time of discovery of a visual field defect and again after not less than 18 months follow-up. RESULTS: Mean right eye MRD at presentation was 36.98 degrees (range 22.25-51.0), compared to 38.40 degrees (range 22.5-49.75) after follow-up; P=0.338 unpaired t-test. Only one patient demonstrated a deterioration in visual field during the study period and discontinued treatment. CONCLUSION: Established visual field defects presumed to be due to Vigabatrin therapy did not usually progress in spite of continuing use of the medication. These data give support to the hypothesis that the pathogenesis of Vigabatrin-associated visual field defects may be an idiosyncratic adverse drug reaction rather than dose-dependent toxicity.

Vigabatrin

visual field defects

visual field defects

Vigabatrin

seizure

Vigabatrin

visual field defect

deterioration in visual field

visual field defects

Vigabatrin

Vigabatrin

visual field defects

toxicity


Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment.

BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in steroid-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors.

dermatitis

facial inflammatory dermatoses

tacrolimus

Tacrolimus

steroid

rosacea

perioral dermatitis

dermatitis

tacrolimus

inflammatory facial dermatoses

tacrolimus

rosacea

acne

eczema

periocular dermatitis

atopic dermatitis

papular rosacea

dermatitis

tacrolimus

tacrolimus