International journal of clinical pharmacology, therapy, and toxicology最新文献

To investigate whether or not DL-sodium lactate inhibits the renal excretion of purine bases and oxypurinol, we administered physiological saline containing 0.2 mol DL-sodium lactate to 7 normal subjects intravenously. DL-sodium lactate infusion decreased the urinary excretion and the fractional clearance of uric acid, xanthine and oxypurinol, but the fractional clearance of hypoxanthine was not affected. These results suggested that the implications of DL-sodium lactate-induced hyperuricemia must be considered in patients with gout on its long term and high dose administration, and that the implications of DL-sodium lactate-induced prolongation of half-life of oxypurinol must be considered in hyperuricemic patients treated with allopurinol. However, since the high dose and long term administration of DL-sodium lactate is clinically rare, the effect of DL-sodium lactate infusion on the urinary excretion of uric acid, xanthine and oxypurinol may not be clinically important.

We studied 16 mild to moderate essential hypertensive patients (14 male, 2 female; mean age 45 years, range 34-55 years) in order to investigate the effects of an ACE inhibitor, cilazapril (5 mg o.d.) and a selective beta-blocker, atenolol (100 mg o.d.) on the hemodynamics of the brachial and carotid arteries after an isometric stress test with a handgrip. Both drugs caused a statistically significant decrease in blood pressure after three months' treatment, but only cilazapril reduced it after the first dose. Heart rate was reduced only by atenolol (61 +/- 3 vs 71 +/- 3 bpm; p < 0.01). Changes in forearm compliance and characteristic impedance showed a difference statistically significant both for acute test and after three months of treatment. The increase in blood pressure during handgrip did not differ appreciably between the two treatment groups. On the contrary, after handgrip only cilazapril caused a significant increase of the reactive hyperemia.

Given the mortality and morbidity associated with acute iron intoxication, effective iron chelation which is easily administered in an emergency situation would be ideal. The pharmacokinetics of L1 were examined in 5 healthy adult male volunteers to assess its potential for use in acute iron overload. Ferrous sulfate (600 mg), L1 (900 mg), and ferrous sulfate and L1 were administered on three separate days, each one week apart. On each test day, blood samples were collected at regular intervals for the measurement of plasma L1 and total iron. Pharmacokinetic values were calculated. The data were also compared to that obtained in 10 patients with beta-thalassemia and chronic iron overload. In the normal volunteers, a 20% decrease in the area under the concentration time curve of plasma iron and of plasma L1 was demonstrated when they were co-administered. There was no change in urinary iron excretion when L1 was given with iron (p = 0.414). The elimination half-life of L1 in the thalassemia patients (137.65 +/- 48.65 min) was significantly longer than that in the healthy volunteers (77.56 +/- 13.0) (p = 0.0047) due to larger apparent volume of distribution. In all of the iron-overloaded individuals L1 resulted in increased urinary iron excretion. None of the other pharmacokinetic variables compared were significantly different between these two groups. These studies indicate that at levels below saturation, transferrin does not allow L1 to remove absorbed iron in healthy volunteers, whereas in thalassemia patients, who are beyond saturation of their iron binding capacity, the drug binds iron and promotes its excretion.

Pharmacokinetic data obtained from healthy subjects after a single i.v. infusion over 30 min of either astromicin (AST) or isepamicin (ISP), the newly developed aminoglycoside antibiotics, were analyzed by a computer program, NONMEM, together with those in patients having impaired renal functions of various degrees, which were cited from the literature. A two-compartment open model was utilized for the analysis, assuming that the total body clearance of drug (ClB) is linearly correlated with endogeneous creatinine clearance (Clcr). By the analysis, it was found that the body weight explains some part of interindividual variability in ClB of ISP, although it did not hold true in the case of AST. For each drug, the means and variances of ClB and the distribution volume of central compartment, and only the means of two intercompartmental constants (K12 and K21), all of which were obtained by the NONMEM analysis, were implemented in a Bayesian prediction program for a microcomputer. This, thus, clarified a point as to when blood sample should be collected in order to get the best prediction of individual ClB with the use of the above Bayesian program and the measurement of drug concentration in the sampled blood as a feedback information. For this purpose, the drug concentrations in plasma obtained in the multiple-dose study of each drug, in which the drug was administered in healthy subjects as i.v. infusion over 1 h every 12 h for 4.5 days, were used.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution of lidocaine and digoxin in myocardial and aorta tissues of open chest anesthetized dogs was studied, following the administration of 30 ml phosphate buffer solution of the drugs in the pericardial cavity where it was kept for increasing time intervals. Transfer of lidocaine (15 or 30 mg) from the solution to myocardium was almost complete within 60 min, while only 50% of digoxin (2 or 50 micrograms) was removed, and this occurred during the first 30 min. Accordingly, the absorption rate of lidocaine by heart tissues increased with time up to 60 min while that of digoxin decreased with time. Absorption of digoxin by the atria and absorption of both drugs by intrapericardial aorta were higher than that of other heart tissues, between 20 and 60 min. At 30 and 60 min, lidocaine was evenly distributed across the LV wall while digoxin 50 micrograms was mainly concentrated subepicardially. On the contrary, i.v. administration of digoxin resulted in even distribution in the LV wall without preferential concentration in the atria. The uptake of both drugs by aorta was several times lower compared to heart tissues after i.v. administration. Drug concentrations in LV wall almost at therapeutic level, were derived from solution of low concentration of the drug in the pericardial cavity. It is concluded that intrapericardial administration of the drugs may be used when increased concentration of them is desired in specific areas of the heart and the aorta.

We studied the effects of cimetidine, ranitidine and famotidine on the kinetics of naproxen. The mean t1/2 beta of naproxen in 6 subjects was 25.7 +/- 5.4 h (range 16 to 36). Naproxen acyl glucuronide accounts for 50.9 +/- 6.9% of the dose, its isomerized isoglucuronide for 6.8 +/- 2.6%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 4.1% and its isoglucuronide for 5.5 +/- 1.5% (n = 6). Naproxen (1.3 +/- 1.1%) and O-desmethylnaproxen (0.6 +/- 0.4%) are excreted in negligible amounts. Cimetidine, ranitidine and famotidine all reduced significantly the t1/2 beta of naproxen by 50% from 25 h to 13 h and the t1/2 alpha from 4.0 h to 1.1 h. No effect of the H2 antagonists was observed on the absorption of naproxen. They also reduced the Vss of naproxen by 50%. The amount of naproxen acyl glucuronide, naproxen isoglucuronide and O-desmethylnaproxen acyl glucuronide excreted in the urine, remained unchanged, 60%, 7%, and 14% respectively.

Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.

While on therapy for acute myeloid leukemia, a 15-year-old girl developed extensive punctate keratitis of both eyes following high-dose cytarabine therapy (HD-Ara-C). Pharmacokinetic monitoring showed an increase of the Ara-C plasma levels up to twice the steady-state level within 10 minutes after discontinuation of the Ara-C infusion. Calculations of Ara-C plasma half-life, plasma clearance and volume of distribution were within the expected range. Owing to the short half-life of Ara-C in blood due to rapid deamination, varying infusion velocities will result in markedly varying plasma levels. Higher peak plasma levels lead to proportionally higher diffusion into compartments like tears, aqueous humor and cerebrospinal fluid. In compartments which lack noteworthy deaminase activity, dose intensity will be much more enhanced than in plasma. Peak plasma levels, therefore, may be associated with multifold local toxicity without concurrent increase of hematological toxicity. Especially when the drug is given in small volumes of infusion, these considerations should be taken into account. Precise control of infusion parameters and application of artificial tears for dilution of the Ara-C concentration on the corneal surface should be part of keratitis prophylaxis.

A parallel, double-blind, placebo controlled and randomized study in a single center was done with ketoprofen 2.5% gel to treat acute soft tissue injuries. Patients applied the gel twice a day for seven days, corresponding to 250 mg of ketoprofen per day. Assessments were made on the third and seventh day by VAS, subjective evaluation and pain threshold algometry. The study group consisted of 29 patients and the control group 27 patients. Pain at rest was significantly relieved in the ketoprofen group, whereas in the placebo group the difference was not significant. In terms of side-effects, no difference between the groups was noticed. In both groups, local dermal irritation was found. Our results suggested that ketoprofen 2.5% gel was safe and superior to placebo in the treatment of soft tissue injuries.

Butorphanol and nalbuphine, narcotic agonist-antagonists were shown to cause no increase in biliary pressure in contrast to morphine in dogs or men. A non-invasive, ultrasonographic technique confirmed that morphine caused constriction of the common bile duct while placebo caused no effect. To prove the lack of constrictive effect of butorphanol and nalbuphine on the common bile duct, the changes in its diameter were measured following placebo or the two agonist-antagonists by ultrasonography. In a double-blind, randomized study, 17 patients undergoing open cholecystectomy were evaluated. No morphine or opioids were allowed for 12 hours prior to the study. After premedication with midazolam and glycopyrrolate, anesthesia was induced by midazolam, 50 micrograms.kg-1 and thiopental, 3.0-5.0 mg.kg-1. Tracheal intubation was facilitated by succinylcholine 1.0 mg.kg-1 and muscle relaxation was maintained with vecuronium. Anesthesia was maintained with isoflurane or enflurane and nitrous oxide in oxygen. After imaging the common bile duct by ultrasonography, placebo, nalbuphine 0.3 mg.kg-1 or butorphanol 40 micrograms.kg-1 were injected intravenously. The diameter of the common bile duct was measured before and at 4 and 8 minutes after drug administration. One-way analysis of variance and paired t-test were utilized for statistical analysis. P < 0.05 was considered significant. No significant changes in the common bile duct diameter was observed after placebo administration, nor was any change observed after either nalbuphine or butorphanol as compared to the baseline. The comparison of three groups of patients showed no statistically significant difference.(ABSTRACT TRUNCATED AT 250 WORDS)