Last Dose Of Drug Research Articles

Pulmonary Disposition of Lomefloxacin in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. A Multiple-Dose Study

In this study we have measured the concentrations of lomefloxacin at steady state in serum and in the intrapulmonary region at specified intervals for 24 h following administration of the last dose of drug in patients suffering from acute exacerbation of chronic obstructive pulmonary disease (COPD). Twenty subjects were enrolled. They received lomefloxacin 400 mg orally once-daily for 5 consecutive days. All patients were divided into five groups, with 4 subjects in each group, according to sampling times (2, 4, 8, 12, and 24 h after the last dose). At bron-choscopy, bronchial biopsies and bronchoalveolar lavage (BAL) were performed. At 12 h after the last dose, serum concentration of lomefloxacin was >1.0 μg/mL and at 24 h it was still detectable, but, at all times, the concentrations in bronchial secretion, bronchial mucosa, and epithelial lining fluid (ELF) were greater than the concentrations in serum [bronchial secretions (μg/mL) = 2.5 ± 1.2; 2.2 ± 1.0: 2.0 ±1.1; 1.8 ± 1.1; 0.6 ± 0.3. bronchial mucosa (μg/g) = 5.9 ± 2.1; 6.2 ± 1.8; 2.6 ± 2.2; 1.9 ± 1.5; 1.0 ± 0.9. ELF (μg/mL) = 6.9 ± 2.8; 5.9 ± 2.6; 3.1 ± 1.9; 2.2 ± 1.0; 0.8 ± 1.3. serum (μg/mL) = 3.2 ± 1.4; 2.8 ± 0.9: 2.1 ± 1.5; 1.2 ± 1.1; 0.4 ± 0.8]. We must stress that we observed a large inter-individual variability in concentrations. Our data show that lomefloxacin once-daily induces high and sustained concentrations in the various potential sites of pulmonary infection and clearly indicate that the pharmacokinetic behavior of this fluoroquinolone permits once-daily administration in patients with acute exacerbations of COPD.

EFFECT OF LITHIUM ON CYCLOSPORIN INDUCED NEPHROTOXICITY IN RATS

Psychoactive drugs provide essential intervention in the care of transplant recipients, yet little is known of their interaction with immunosuppressants such as cyclosporin (CSA). Lithium (Li) is an invaluable drug for the treatment of manic disorders in organ transplant patients. As both these drugs are known to produce renal toxicity, the concomitant use of CSA and Li may be potentially harmful. The present study was undertaken to investigate the effect of CSA and Li chloride individually and in combination on renal structure and function of rats. Male Sprague-Dawley rats were divided into the following eight groups of seven animals each: group 1, control (vehicle only); group 2, Li (2mEq/kg i.p.) alone; group 3, CSA 12.5 mg/kg (subcutaneous); group 4, CSA 25 mg/kg; group 5, CSA 50 mg/kg; group 6, CSA 12.5 mg/kg + Li; group 7, CSA 25 mg/kg + Li; and group 8, CSA 50 mg/kg + Li. The drugs were given once a day for seven days; Li being administered 30 min before CSA. Twenty four hours after the last dose of drugs the animals were sacrificed and blood samples were analyzed for blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Li levels. The left kidney was analyzed for malondialdehyde (MDA) and conjugated dienes (CD) levels and right kidney was used for histopathological studies. Our results showed that Li alone did not produce any significant renal toxicity, whereas CSA dose dependently caused structural and functional changes in kidneys. However, significantly higher structural and functional impairment was observed in the animals treated with Li plus CSA as compared to CSA alone treated animals. Several fold increase in blood Li level was also noticed in the rats concomitantly treated with CSA and Li. A significant increase in MDA and CD in the rats treated with CSA plus Li suggests the role of oxidative stress in drug induced nephrotoxicity. These findings clearly demonstrate that even non toxic doses of Li may significantly exacerbate CSA induced nephrotoxicity in rats. The enhanced nephrotoxicity following concomitant use of these drugs may be attributed to significant increase in the bioavailability of Li and enhanced oxidative stress. Further clinical studies are warranted to investigate the interaction of these nephrotoxic drugs in human subjects.

High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection.

The use of isoniazid (INH) for the treatment of INH-resistant Mycobacterium tuberculosis infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptible M. tuberculosis Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body weight) was more effective than standard-dose INH (25 mg/kg) for therapy of tuberculosis infections caused by INH-resistant mutants of M. tuberculosis Erdman. Six-week-old CD-1 mice were infected with approximately 10(7) viable mycobacteria. Early control groups of infected but untreated mice were euthanized by CO(2) inhalation 1 week later when treatment was initiated. INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week for 4 weeks. Late control groups of untreated mice and treated mice were sacrificed 2 days after the last dose of drug. Spleens and right lungs were removed aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates. In the next study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic mutant of M. tuberculosis Erdman (INH MIC, 2 microg/ml) and the parent strain. This mutant was found to have a mutation in the KatG protein (Phe to Leu at position 183). In the first study, there was no dose response with increasing doses of INH. In the second study, there was no significant difference between the reduction of viable cell counts for mice treated with INH at 100 mg/kg and that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant). These preliminary results suggest that INH may be useful in combination therapy of M. tuberculosis infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 microg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose.

Pituitary-Adrenal Response in Preterm Very Low Birth Weight Infants after Treatment with Antenatal Corticosteroids

Antenatal corticosteroids have been widely used for the prevention of respiratory distress syndrome in preterm neonates, yet little is known about their effects on the hypothalamic-pituitary-adrenal axis in these infants. We prospectively evaluated pituitary-adrenal function in 61 preterm (<32 gestational weeks), very low birth weight (<1500 g) infants on days 7 and 14 of life using the human CRH stimulation test. The baseline and poststimulation plasma ACTH and serum cortisol concentrations did not differ significantly between infants whose mothers received no antenatal corticosteroids, and those whose mothers received 1–2 doses or >2 doses (mean 7.2 doses) of prenatal dexamethasone (P = > 0.12). The number of doses of dexamethasone and the time intervals between the last dose of drug and delivery did not significantly affect the pituitary-adrenal responsiveness on days 7 and 14 of life. Among infants who did not require mechanical ventilation at the time of the human CRH test, significantly higher plasma ACTH (P < 0.014) and lower serum cortisol concentrations (P < 0.02) were found on day 14 than on day 7. In contrast, none of the poststimulation hormone concentrations were significantly different in ventilated infants between days 7 and 14. The relationship between the blood hormone concentrations in each time epoch (day 7 and day 14) and possible confounding factors including gestational and postconceptional age, birth weight, sex, Apgar scores, mode of delivery, single or higher order births, and mode of ventilation were determined. Plasma ACTH concentrations on day 7 were found to be significantly higher in ventilated than in nonventilated infants (P = 0.006). However, none of the aforementioned factors correlated significantly with plasma ACTH concentrations on day 14. Serum cortisol concentrations on day 7 were significantly higher in infants of greater gestational age (P = 0.039) and birth weight (P= 0.013), with lower Apgar scores at 1 and 5 min (P= 0.021 and P = 0.049, respectively), and in those delivered vaginally (P = 0.047). Similarly, serum cortisol concentrations on day 14 were found to be significantly higher in infants with lower Apgar scores at 1 and 5 min (P = 0.011 and P = 0.014, respectively) and in infants requiring mechanical ventilation (P = 0.014). Our results suggest that single or multiple courses of antenatal dexamethasone have no long-lasting suppressive effects on pituitary-adrenal function in preterm, very low birth weight infants. Maturation of pituitary function appears to be more advanced than adrenal function. The organ’s ability to respond appropriately to various stressful stimuli indicates that the pituitary-adrenal axis is highly responsive at these early gestational ages.

Pituitary-adrenal response in preterm very low birth weight infants after treatment with antenatal corticosteroids.

Antenatal corticosteroids have been widely used for the prevention of respiratory distress syndrome in preterm neonates, yet little is known about their effects on the hypothalamic-pituitary-adrenal axis in these infants. We prospectively evaluated pituitary-adrenal function in 61 preterm (< 32 gestational weeks), very low birth weight (< 1500 g) infants on days 7 and 14 of life using the human CRH stimulation test. The baseline and poststimulation plasma ACTH and serum cortisol concentrations did not differ significantly between infants whose mothers received no antenatal corticosteroids, and those whose mothers received 1-2 doses or > 2 doses (mean 7.2 doses) of prenatal dexamethasone (P = > 0.12). The number of doses of dexamethasone and the time intervals between the last dose of drug and delivery did not significantly affect the pituitary-adrenal responsiveness on days 7 and 14 of life. Among infants who did not require mechanical ventilation at the time of the human CRH test, significantly higher plasma ACTH (P < 0.014) and lower serum cortisol concentrations (P < 0.02) were found on day 14 than on day 7. In contrast, none of the poststimulation hormone concentrations were significantly different in ventilated infants between days 7 and 14. The relationship between the blood hormone concentrations in each time epoch (day 7 and day 14) and possible confounding factors including gestational and postconceptional age, birth weight, sex, Apgar scores, mode of delivery, single or higher order births, and mode of ventilation were determined. Plasma ACTH concentrations on day 7 were found to be significantly higher in ventilated than in nonventilated infants (P = 0.006). However, none of the aforementioned factors correlated significantly with plasma ACTH concentrations on day 14. Serum cortisol concentrations on day 7 were significantly higher in infants of greater gestational age (P = 0.039) and birth weight (P = 0.013), with lower Apgar scores at 1 and 5 min (P = 0.021 and P = 0.049, respectively), and in those delivered vaginally (P = 0.047). Similarly, serum cortisol concentrations on day 14 were found to be significantly higher in infants with lower Apgar scores at 1 and 5 min (P = 0.011 and P = 0.014, respectively) and in infants requiring mechanical ventilation (P = 0.014). Our results suggest that single or multiple courses of antenatal dexamethasone have no long-lasting suppressive effects on pituitary-adrenal function in preterm, very low birth weight infants. Maturation of pituitary function appears to be more advanced than adrenal function. The organ's ability to respond appropriately to various stressful stimuli indicates that the pituitary-adrenal axis is highly responsive at these early gestational ages.

Experimental studies long-term l-carnitine treatment prolongs the survival in rats With adriamycin-induced heart failure

Background: The most serious consequence of heart failure is the shortened life expectancy,which may be associated with myocardial energy starvation. Methods and Results: Eight-week-old male Sprague-Dawley rats received 6 intraperitonealinjections of adriamycin (group A: total dose; 15 mg/kg body weight) or vehicle (group C) over 2 weeks. Rats then received either 272 mg/kg daily of oral l-carnitine (A-LC and C-LC groups) or saline (A-S and C-S groups) for 6 weeks. The cumulative mortality rate in the ALC group was significantly lower than in the A-S group (13 vs 42%, P = .028). Myocardial levels of high-energy phosphate compounds (ATP and creatine phosphate) and fatty acid metabolites (free carnitine, short-chain and long-chain acylcarnitine, and long-chain acyl CoA) in the left ventricle were measured the day after the last dose of drug or vehicle was administered. ATP was decreased by 73%, creatine phosphate by 61 %, free carnitine by 52%, short-chain acylcarnitine by 48%, and long-chain acylcarnitine by 56% in the A-S group compared to the C-S group. Long-chain CoA was increased by 168% in the A-S group. Levels of myocardial high-energy phosphate compounds and fatty acid metabolites were near normal in adriamycin- and l-carnitine-treated rats. Conclusions: Preservation of the myocardial level of carnitine by l-carnitine treatment prolongedsurvival of rats with adriamycin-induced failure by improving the myocardial metabolism of fatty acids.

Effects of cromakalim or glibenclamide on arrhythmias and dispersion of refractoriness in chronically infarcted in anesthetized dogs.

The proarrhythmic effects of the ATP-sensitive potassium channel modulators cromakalim (n = 10; 0.01 to 0.3 mg/kg i.v.), glibenclamide (n = 10; 0.3 to 10 mg/kg i.v.) or volume equivalents of vehicle (n = 10) were evaluated in post-infarcted anaesthetised dogs. Dogs were anaesthetised, subjected to an anterior-apical myocardial infarction, and allowed to recover. At 7.4 +/- 0.7 days post infarction, animals were anaesthetised again, electrophysiologic measurements (effective refractory periods, QT-intervals and ventricular fibrillation thresholds) were taken, and animals were tested for arrhythmias using a programmed electrical stimulation protocol. Only animals that did not have programmed electrical stimulation-inducible arrhythmias were used. Ventricular fibrillation thresholds were determined twice, once before the first dose then after the last dose of drug. At the end of the experiment, animals were subjected to ligation of the left circumflex coronary artery and survival was measured over the next two hours. Cromakalim significantly increased heart rate and decreased blood pressure. Although cromakalim significantly reduced effective refractory periods, it neither increased electrical dispersion, as determined by the standard deviation or coefficient of variance of the effective refractory period, nor did it enhance inducibility (0 out of 10 in both vehicle and cromakalim treated animals), change ventricular fibrillation thresholds, or reduce sudden death survival relative to vehicle. Glibenclamide did not increase electrical dispersion, but slightly increased the incidence of programmed electrical stimulation-induced arrhythmias (3 out of 10), and lowered ventricular fibrillation thresholds values. However, these changes were not statistically significant. Glibenclamide did not significantly affect survival relative to vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue-selective inhibition of sterol synthesis in mice by pravastatin sodium after a single or repeated oral administrations.

Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exhibits liver-selectivity in inhibiting sterol synthesis, when administered as a single oral dose to mice or rats, whereas lovastatin and simvastatin do not. This may be due to the fact that pravastatin is distributed intracellularly, to a large extent, in the liver and extracellularly in nonhepatic tissues. In the present study, we examined whether the difference in liver-selectivity among these three HMG-CoA reductase inhibitors observed in single-dose studies was preserved after repeated oral administrations of drugs to mice. De novo sterol synthesis in different tissues of mice was examined in vivo three hours after the last dose of drug by measuring incorporation of intraperitoneally injected [14C]acetate into total sterols. Pravastatin administered orally for 11 consecutive days at 5 and 10 mg/kg exhibited a greater liver-selectivity than lovastatin and simvastatin: sterol synthesis was inhibited more than 60% in the liver by all three drugs, whereas that in nonhepatic tissues was inhibited less than 10% by pravastatin and more than 30% by lovastatin and simvastatinin in most of the nonhepatic tissues examined. Pravastatin administered orally for 11 consecutive days at 10 mg/kg caused more selective inhibition of sterol synthesis in liver ex vivo than two other inhibitors at the same dose. Pravastatin inhibited de novo sterol synthesis from [14C]acetate into sterol fraction in the liver slices in vitro, but minimally in those of the spleen and testis, whereas lovastatin and simvastatin inhibited in those of all three tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrapulmonary pharmacokinetics of clarithromycin and of erythromycin

The intrapulmonary pharmacokinetics of orally administered clarithromycin (500 mg every 12 h for five doses) or erythromycin (250 mg every 6 h for nine doses) were studied in 32 healthy adult volunteers. Four of the subjects, two in the clarithromycin group and two in the erythromycin group, were smokers. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed at 4, 8, 12, 24, and 48 h after administration of the last dose of clarithromycin and at 4, 8, and 12 h after administration of the last dose of erythromycin. Clarithromycin was measured by high-performance liquid chromatography, and erythromycin was measured by a microbiological assay. No systemic sedation was used. There were no major adverse events. The concentrations of antibiotics in epithelial lining fluid (ELF) were calculated by the urea dilution method. The volumes (mean +/- standard deviation) of ELF were 1.9 +/- 2.0 ml and 1.5 +/- 0.7 ml in the clarithromycin and erythromycin groups, respectively (P > 0.05). There was no effect of smoking on the amount of bronchoalveolar lavage fluid recovered, the volume of ELF, or the number of erythrocytes present in the lavage fluid (P > 0.05 for all comparisons). The total number of alveolar cells, however, was almost threefold greater in the smokers versus that in the nonsmokers (P < 0.05). Clarithromycin was concentrated in ELF (range, 72.1 +/- 73.0 micrograms/ml at 8 h to 11.9 +/- 3.6 micrograms/ml at 24 h) and alveolar cells (range, 505.8 +/- 293.1 micrograms/ml at 4 h to 17.0 +/- 34.0 micrograms/ml at 48 h). 14-(R)-Hydroxyclarithromycin was also present in these compartments, but at lower concentrations than the parent compound. The concentrations of erythromycin in ELF and alveolar cells were low at 4, 8, and 12 h following the last dose of drug (range, 0 to 0.8 +/- microgram/ml in ELF and 0 to 0.8 +/- 1.3 microgram/ml in alveolar cells). The clinical significance of any antibiotic concentrations in these compartments in unclear. The data suggest, and we conclude, that clarithromycin may be a useful drug in the treatment of pulmonary infections, particularly those caused by intracellular organisms.

Low-dose intratympanic gentamicin treatment of Menière's disease.

To control attacks of vertigo while preserving both hearing and labyrinthine function, low doses of gentamicin were instilled intratympanically in nine patients with intractable unilateral Meniere's disease. Each patient received six instillations of antibiotic of 4 mg each (total dose, 24 mg). Patients were then followed for 2-4 years. Long-term results of treatment are reported according to the American Academy of Otolaryngology-Head and Neck Surgery 1985 criteria. Of the nine cases, three experienced complete control of vertiginous attacks, while six received substantial control. Post-treatment hearing acuity was unaffected, although disability following treatment became worse in one patient, a 66-year-old man. Caloric responses after therapy were absent or severely reduced in three ears, moderately reduced in two ears and unchanged in four ears. In three patients, labyrinthine function was found damaged 4-8 days after administration of the last dose of drug. Overall, intratympanic instillations of low doses of gentamicin in patients with intractable Meniere's disease were found to control vertiginous attacks with less damage to the inner ear function than that reported in the literature.

Progressive murine cytomegalovirus disease after termination of ganciclovir therapy in mice immunosuppressed by cyclophosphamide treatment.

Treatment of mice with cyclophosphamide causes immunosuppression and an enhancement of murine cytomegalovirus infection. In chemotherapy experiments, animals received cyclophosphamide (100 mg/kg by intraperitoneal [ip] injection) every 3-4 days starting 1 day before viral challenge. Once-daily ip treatments with ganciclovir (12.5, 25, and 50 mg/kg) for 5 or 10 days starting 24 h after viral challenge delayed but did not prevent death. In each case the animals died 8-12 days after the last dose of drug was given. Murine cytomegalovirus titers in tissues were suppressed during ganciclovir treatments but rose with discontinuation of therapy. Concanavalin A (T cell blastogenic) responses and, to a lesser extent, lipopolysaccharide (B cell blastogenic) responses were increased in ganciclovir-treated mice compared with the placebo group. Because of the progressive nature of the infection after termination of drug treatment, this model mimics the situation encountered in AIDS patients. The cyclophosphamide model will be useful to study drug treatment regimens.

Time Course of Change in Bronchial Reactivity with an Inhaled Corticosteroid in Asthma

The time course of change in FEV1, bronchial reactivity, and daily measures of asthma control (peak expiratory flow, symptoms, and beta 2-agonist inhaler use) was determined during 6 wk of treatment with inhaled budesonide, 800 micrograms twice a day, and for 2 wk following cessation of treatment in 40 asthmatic subjects in a double-blind, placebo-controlled, parallel group study. Histamine reactivity, expressed as the provocative dose of histamine causing a 20% fall in FEV1 (PD20), was measured at intervals during the 8 wk of the study, with more frequent measurements after the first and last dose of drug to provide a detailed profile of change at the start and end of treatment. The first dose of budesonide caused a small increase in median values of FEV1 (0.2 L) and PD20 (1.0 doubling dose of histamine), which was maximum at 6 h. There was a further increase in FEV1 and PD20 over the 6 wk in the budesonide group relative to placebo, the maximum increases (0.53 L, 3.4 doubling doses of histamine) being recorded 6 h after the last dose on Day 42. Following cessation of treatment, FEV1 and PD20 declined and PD20 returned to placebo values at 1 wk. Median PEF increased by 40 and 30 L/min in the morning and evening, respectively, with budesonide treatment. Symptom scores and beta 2-agonist inhaler use were lower in the budesonide group than the placebo group during treatment but tended to be similar (symptom scores) or higher (beta 2-agonist) in the 2 wk following cessation of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC)

Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.

Antihypertensive Efficacy of the Combination of Ketanserin + Thiazide in Hypertensives Older Than 50 Years

The antihypertensive effect of the combination of ketanserin, a new antiserotonergic agent, and thiazide has been evaluated in 35 patients with arterial hypertension of mild to moderate degree in the greater than 50-year-old age group. Twenty patients were given ketanserin (20 mg) + hydrochlorothiazide (25 mg) (treatment A) while the others were given ketanserin (40 mg) + hydrochlorothiazide (12.5 mg) (treatment B) once daily, for a period of 6 weeks. Twenty-four-hour blood pressure, measured by an automatic recorder, was significantly reduced by both combinations. In particular, treatment A reduced blood pressure from 169 +/- 15/95 +/- 6 mm Hg before treatment to 146 +/- 11/83 +/- 8, 149 +/- 13/82 +/- 10, 143 +/- 12/81 +/- 9, and 151 +/- 14/84 +/- 7 mm Hg at 2, 6, 8, and 24 h, respectively, after the last dose of drug. With treatment B, blood pressure was reduced from 167 +/- 11/97 +/- 7 mm Hg before treatment to 152 +/- 12/89 +/- 8, 151 +/- 15/85 +/- 8, 150 +/- 16/86 +/- 8, and 158 +/- 13/91 +/- 7 mm Hg at 2, 6, 8, and 24 h, respectively. Heart rate was not affected by both treatments despite the fact that ketanserin has been proved to induce a marked vasodilation. Cardiac workload (systolic blood pressure X heart rate) was slightly reduced by the treatments. Treatment A only induced transient dizziness after the first dose of drug; treatment B, on the other hand, induced drowsiness and more marked dizziness, which in one case was also observed after repeated doses of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

ALBENDAZOLE AS A POTENTIAL TREATMENT FOR HUMAN HYDATIDOSIS

The pharmacokinetics of albendazole was evaluated in 11 patients with hydatid disease who underwent surgery 12 h after the last dose of drug. Albendazole and its main metabolite, albendazole-sulphoxide, were assayed in the serum from peripheral and portal blood, the liver, bile, lungs, and hydatid cyst walls and fluid. After a 10-14 mg/kg daily oral dose of albendazole, concentrations of 1844±904 ng/g wet tissue of albendazole-sulphoxide were found in the liver and 749±34 ng/g wet tissue in the lungs. The level in hydatid cyst fluid was 921±314 ng/ml. The drug was also excreted through the bile. The same daily oral dose produced very stable blood levels after 2 to 4 days of treatment (600-1000 ng/ml). In another part of the study 3 patients with liver cysts, 2 with peritoneal cysts, and 5 with bone cysts received 7 mg/kg twice a day prophylactically and/or therapeutically for 30 days. In all cases the treatment was repeated several times after intervals of 2 weeks. The 3 patients with liver cysts were cured (probably due to treatment); there was no recurrence in the 2 patients with peritoneal cysts and very slight improvement in the 5 cases with bone cysts. The drug was clinically and biologically extremely well tolerated.

Control of Breathing after Fentanyl and Innovar Anaesthesia

Ventilation (VI), end-tidal (Pco2), mixed venous (PVco2) and the ventilatory response to carbon dioxide were measured before surgery, and during the first 4h of recovery in 18 adult patients who underwent elective limb surgery under fentanyl or Innovar anaesthesia. End-tidal and mixed venous PCO2 were increased significantly in the first 150 min after the last dose of drug (P

CONTROL OF BREATHING AFTER FENTANYL AND INNOVAR ANAESTHESIA

Ventilation (VI), end-tidal (PCO2), mixed venous (PvCO2) and the ventilatory response to carbon dioxide were measured before surgery, and during the first 4 h of recovery in 18 adult patients who underwent elective limb surgery under fentanyl or Innovar anaesthesia. End-tidal and mixed venous PCO2 were increased significantly in the first 150 min after the last dose of drug (P less than 0.001, P less than 0.01), but had returned to control values by 4 h. Ventilation and ventilatory response to carbon dioxide were significantly depressed in all patients (P less than 0.001), but returned to near control values at 4 h. Fentanyl and Innovar anaesthesia displaced the carbon dioxide response to the right, but no correlation was found between either the magnitude of the displacement of the response curve or the alteration in slope and the control values. This suggests that patients with a low value of VI/PCO2 are not more susceptible to the ventilatory depressed action of narcotic anaesthetics. Recovery of ventilatory responsiveness towards normal during the 4 h after anaesthesia, occurred in a graded and progressive manner, there was no evidence of a biphasic pattern of recovery.

Disulfiram doesn't always prevent drinking

Alcoholic patients sometimes contend that they can continue to drink while taking disulfiram (Antabuse). It may be true. Evidence of the claim's veracity comes from a study presented at the recent New Orleans meeting of the American Society for Clinical Pharmacology and Therapeutics and subsequently published by J. E. Peachey, MD, head, behavioral pharmacotherapy clinic, clinical institute, Addiction Research Foundation, Toronto (<i>Lancet</i>1981;1:943-944). Peachey and co-workers reported that nonalcoholic paid volunteers who were given disulfiram, then small alcoholic drinks, were able to imbibe additional ethanol without untoward effects. In the double-blind study, 18 volunteers were randomly assigned to receive either disulfiram, 3.5 mg each evening, calcium carbimide (Temposil), 0.7 mg twice a day, or placebo over a 48-hour period. Calcium carbimide is a "sensitizing drug" that is similar to disulfiram but not available in the United States. Twelve hours after the last dose of drug or placebo, the volunteers were

Adaptational responses to prolonged beta-adrenoceptor blockade in adult rabbits.

1 A method for measuring propranolol concentrations in plasma has been modified to permit estimations to be made on small volumes. The method has been used to correlate blockade of heart rate increases in response to intravenous isoprenaline, in both young and adult rabbits, with plasma concentrations of propranolol after subcutaneous injections of 2 or 4 mg/kg. It has been found that the relation between beta-adrenoceptor blockade and plasma concentrations is the same in rabbits as that determined by previous workers in man. 2 Adult Dutch dwarf rabbits were treated for 9 weeks twice daily subcutaneously with 2 mg/kg propranolol, or 10 mg/kg practolol, or with saline. 3 The treatment caused no change in heart weight in relation to body weight or in the water content of the hearts, in contrast to effects previously observed in young rabbits. 4 As in the young rabbits, treatment did cause a prolongation of action potential duration, as measured with intracellular electrodes in hearts of animals killed 24 h after the last dose of drug. 5 In another series of experiments, with a similar regime of treatment for 6 weeks, a significant reduction of diastolic blood pressure was observed in the propranolol group. 6 During the course of treatment and at the end, there was no change in the heart-rate increases observed in response to intravenous isoprenaline administered not less than 15 h after the previous dose of beta-blockers. Thus no functional alteration in sensitivity ot beta-adrenoceptor stimulation was apparent.

Cardiotoxic and possible leukemogenic effects of adriamycin in nonhuman primates.

10 monkeys (macaques) received adriamycin by monthly intravenous injections at 12 mg/m2 (1 mg/kg). 8 of the 10 monkeys developed congestive heart failure at an average cumulative adriamycin dose (310 mg/m2) well below that considered the safe upper limit (550 mg/m2) in man. Histologically, the myocardial lesions resembled those found in human anthracycline-induced cardiomyopathy. 1 of the 10 monkeys developed acute myeloblastic leukemia after receiving 324 mg/m2 of adriamycin; the 10th monkey is alive and well 26 months after the last dose of drug. Our results suggest that adriamycin is a more potent cardiotoxin in monkeys than in man, and that leukemia may be a consequence of prolonged treatment with this drug.