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

The efficacy of a nicotine transdermal therapeutic system (TTS) (available size 10, 20 and 30 cm2; nicotine delivery rate = 0.7 mg/cm2/24 h) as an aid for smoking cessation, was evaluated in a randomized, single-blind, placebo-controlled, monocenter study using 160 heavy-smokers (> 20 cigarettes/day), male and female, who were divided into two matched parallel groups. The nicotine replacement treatment lasted for 3 months and was carried out according to the manufacturers recommendations. Abstinence was defined as smoking no cigarette during the last week of each month and COHb-levels < or = 1.2%. Efficacy was assessed using abstinence rates, withdrawal symptoms and cigarette consumption. Although at the commencement of the study all subjects expressed a high motivation to stop smoking, about a third were lost to follow-up at 4 weeks. This was attributed mainly to the lack of counselling and group dynamics. The greatest effect on smoking cessation and cigarette consumption was attributable to a non-specific aspect of treatment, i.e. the motivation to stop smoking on application of the first patch. On an intention-to-treat basis (all subjects), abstinence rates were 24% and 18% after 1 month, 24% and 14% after 2 months and 14% and 6% after 3 months for the nicotine-TTS and placebo-TTS, respectively. Nicotine-TTS was at least twice as effective as placebo in maintaining nicotine abstinence. The superiority of the nicotine-TTS was supported by the trend to a higher craving-for-cigarettes score and significantly higher blood COHb and cigarette consumption in the non-abstainers treated with placebo.

A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern understanding of actions and interactions of drugs which act at distinct molecular sites. It rests on a comparison of observed combined effects with calculated effects of independent action of A plus B--greater than independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of the antisecretory action of pirenzepine and H2-receptor antagonists (cimetidine, ranitidine). Briefly, peptone-stimulated acid output was measured in 15 min periods over 3 h after the injection of drugs in three trials, one with five duodenal ulcer patients, two of them with 8 healthy volunteers each. The doses of pirenzepine and H2-blockers were fixed in each trial. The results were either expressed by the total acid output (single-dose analysis) or by the acid secretion over 15 min as time course. The results with the drug combination show greater reduction in acid secretion in all three trials with respect to independent effects. The time-course studies more clearly showed greater reduction in acid output than the analysis of total acid output, not the least with respect to p-values of differences between observed combined effects and calculated independent effects. They were obtained by the chi-square (chi 2) goodness-of-fit test, recently applied for the evaluation of dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)

The program TopFit was developed and validated within the European pharmaceutical industry. It provides both pharmacokinetic data analysis support for international regulatory submissions of new drugs, and sophisticated techniques for model-based kinetic/dynamic evaluation during drug development. TopFit features are: (1) non-compartmental methods; (2) standard compartment models assembled from input and disposition modules; (3) a potentially unlimited number of linear user-defined models that accommodate metabolites, effects, and absorption profiles; (4) a library of 24 non-linear models. No user programming is required. A well-defined file structure allows ready exchange of data with other programs such as SAS. TopFit version 2.0 is now commercially available, with comprehensive documentation, in the form of an MS-DOS application for the PC.

The cocaine epidemic is growing at an alarming rate in the United States. Medical and social implications of cocaine abuse are many and include such aspects as intoxication, personal, financial and moral ruin. Complications associated with cocaine use more commonly involve the cardiovascular, central nervous system and the reproductive systems. One of the major concerns regarding cocaine abuse goes far beyond its ill effects on the user. High incidence of congenital malformations and the learning and behavioral disorders in the infants results in a growing number of "misfit" or "undesirable" citizens in the country. Hence, the healthcare providers, the politicians and the legal system must intensely direct their efforts at eradicating this menace.

Current methods for the treatment of glucose intolerance first discovered in pregnancy are reviewed and a systematic data-based approach is introduced. Gestational diabetes mellitus (GDM) is a leading cause of adverse perinatal outcome in 5% of all pregnancies in the United States. Early detection and initiation of treatment meant to restore euglycemia will prevent many of the major complications associated with hyperglycemia. Staged Diabetes Management (SDM) is introduced in this paper as an innovative approach for the detection and treatment of GDM and glucose intolerance in pregnancy. Relying on self-monitored blood glucose data, SDM guides the primary care physician through increasingly more complex regimens until euglycemia is reached. Computer-based technologies assist the clinical decision-making by producing Ambulatory Glucose Profiles (AGP), which are graphic representations of glycemic control. SDM combined with AGP technology are meant to significantly reduce the threefold greater risk of adverse outcome in pregnancy experienced by women with GDM.

Although the increase in the common bile duct pressure in response to morphine has been repeatedly reported in experimental animals and humans, this is the first double-blind non-invasive, ultrasonographic study designed to demonstrate constriction of the common bile duct caused by i.v. administration of morphine in surgical patients. In a double-blind, placebo-controlled, randomized study, 12 patients undergoing open cholecystectomy were enrolled. No 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 enflurane and nitrous oxide in oxygen. After imaging the common bile duct by ultrasonography, placebo or morphine, 0.2 mg/kg-1 was injected intravenously. The diameter of the common bile duct was measured before and 4 and 8 minutes after the drug. Student t-test was utilized for statistical analysis. P < 0.05 was considered significant. No significant change in common bile duct diameter was observed after placebo administration. Morphine caused a significant reduction in the diameter of the common bile duct. Before morphine, the mean +/- SD diameter was 9.5 +/- 3.3 mm; after morphine at 4 and 8 minutes, 7.2 +/- 2.1 and 5.8 +/- 2.1 mm, respectively. It is concluded that ultrasonography in a double-blind placebo-controlled design has proven to be a valid method for the evaluation of the effect of drugs on the common bile duct.(ABSTRACT TRUNCATED AT 250 WORDS)

The history of cocaine use goes back a long time. Initially, cocaine was used as a medicine by physicians and as a pleasure agent in over-the-counter preparations. The significance and intensity of cocaine use and abuse became well known soon thereafter and resulted in extensive regulations to curb its use. Cocaine is a powerful anesthetic agent with powerful vasoconstrictive properties. It can be absorbed from all mucous membrane sites and results in severe cardiovascular complications. The effects of cocaine on various organ systems are presented here.

In order to assess the liver protective activity and the antioxidant properties of a new silybin complex (IdB1016), we carried out a short-term pilot study on 20 patients with chronic active hepatitis (CAH), randomly assigned to 240 mg of silybin b.i.d. (10 patients, 4 m/6 f, mean age: 50 years) or placebo (10 patients, 2 m/8 f, mean age: 55 years). Blood samples were collected before and after 7 days of treatment for liver function tests (LFTs), malonaldehyde (MDA) as an index of lipid peroxidation, and copper (Cu) and zinc (Zn), two trace elements involved in protecting cells against free radical-mediated lipid peroxidation. In the treated group, there was a statistically significant reduction of mean (+/- SEM) serum concentrations of aspartate aminotransferase (AST) from 88.0 (+/- 13.3) to 65.9 (+/- 7.5) u/l, (p < 0.01), of alanine aminotransferase (ALT) from 115.9 (+/- 12.9) to 82.5 (+/- 10.6) u/l (p < 0.01), of gamma-glutamyltranspeptidase (gamma-GT) from 51.4 (+/- 9.3) to 41.3 (+/- 4.2) u/l (p < 0.02) and of total bilirubin (TB) from 0.76 (+/- 0.08) to 0.53 (+/- 0.04) mg/dl (p < 0.05). Alkaline phosphatase (AP) fell slightly from 143.4 (+/- 6.4) to 137.5 (+/- 7.8) u/l. There were no significant changes in MDA, Cu or Zn serum concentrations. These results show that IdB1016 may improve LFTs related to hepatocellular necrosis and/or increases membrane permeability in patients affected by CAH.

The rationality of specialist drug prescription in 154 patients older than 64 in 3 Zagreb homes for the aged was analyzed over an 11-month period. Categories analyzed were: number of prescribed drugs, justification of prescription, adequacy of the dose, route, form and therapy duration of the prescribed drugs, adequacy of the type of the prescribed drugs in the advanced age and the presence of contraindications of drugs used. The criterion of the rational drug use was the WHO's modified definition of rational drug therapy: "Application of an appropriate drug by a correct route in an adequate dose over a sufficiently long period of time". This basic criterion was further elaborated in relation to the analyzed categories. There were 2.66 (+/- 1.65) prescribed drugs per visit in which drugs were prescribed. In all analyzed categories, distinctive aberrations from the principles of rational drug prescription were found. One hundred and sixty-four (41.4%) of all drugs were unjustifiably prescribed and 103 (26.4%) were not dosed correctly. The duration of the therapy was inadequate for 60 (15.4%), route for 41 (10.5%), form for 32 (8.2%) of drugs prescribed. Seventy-five (19.3%) were not adequate because of patients' age and 15 (3.9%) were prescribed in spite of existing contraindications.

Current methods for the screening and diagnosis of glucose intolerance first discovered in pregnancy are reviewed and innovative approaches to the detection of metabolic disturbances in pregnancy are presented. Glucose intolerance first detected in pregnancy, termed gestational diabetes mellitus (GDM), is amongst the most significant risks of adverse fetal and maternal outcome. Normal pregnancy is characterized by both insulin resistance and pancreatic B cell compensation. In those pregnancies complicated by glucose intolerance reflected in hyperglycemia, insulin resistance appears to be heightened, both blood flow and transcapillary transport of insulin are compromised and insulin receptor and post receptor defects are exacerbated. The resulting hyperinsulinemia and hyperglycemia have, in turn, been associated with accumulated maternal fat deposition and fetal macrosomia. This cascade of events constitutes GDM or impaired glucose tolerance. The discovery of GDM is made through a process of screening and diagnosis, employing standardized oral glucose challenge tests. These tests were designed to identify those women at risk for subsequent development of non-insulin dependent diabetes mellitus. The current efficacy of glucose challenge tests has been questioned in light of increasing concern over their usefulness in detecting those women at risk for maternal and fetal complications of pregnancy. Alternative methods, including both the modification of the standardized tests, as well as the introduction of newer methodologies, such as capillary blood glucose monitoring, have been proposed. The implementation of newer approaches may result in improved detection of those women whose infants are at high risk for both metabolic and morphologic complications of persistent hyperglycemia in pregnancy.