The effect of anxiety and personality on the pharmacokinetics of oral midazolam.

UNLABELLED: We investigated the relationship between the pharmacokinetic variables of oral midazolam and patients' state/trait anxiety and personality. Twenty-six patients received the standard 15-mg oral dose for anxiolysis on the evening before otorhinolaryngological surgery. Blood samples were taken over a 9-h period after the administration, and the samples were analyzed for concentrations of midazolam and its two main metabolites by using a gas chromatography-mass spectrometry procedure. The pharmacokinetic variables maximum concentration, time to reach the maximum concentration, the elimination half-life, and the area under the curve were calculated from these data. When the patients were divided into groups with respect to their anxiety and personality scores, no significant differences in the pharmacokinetic variables of midazolam could be found. Only small, insignificant changes in the maximum concentrations were found with respect to nervousness and emotionality. We conclude that personality traits and anxiety levels had no effect on the pharmacokinetic variables of midazolam. IMPLICATIONS: We conclude that personality traits and anxiety levels had no effect on the pharmacokinetic variables of midazolam. Therefore, it is not necessary to obtain anxiety or personality scores to find the proper midazolam dose for the individual patient.

Rapid and simple method for detection of fenofibric acid in human serum by high-performance liquid chromatography.

A sensitive HPLC method for the determination of fenofibric acid (FA), the active form of fenofibrate in serum is described. FA from human serum samples was isolated by an easy one-step extraction procedure with a mixture of n-hexane and ethylacetate (90:10, v/v). The recovery was 84.8% of the total Fa in serum. The compound was separated isocratically on a reversed phase with acetonitrile and 0.02 M phosphoric acid (55:45, v/v) at a flow-rate of 1.0 ml/min. Absorbance at 287 nm was recorded for quantification. Validation presents a detection limit of 0.03 microgram/ml and a quantification limit of 0.1 microgram/ml (relative standard deviation at 0.1 microgram/ml = 7.1%). For an extensive validation of this method we determined the serum levels of FA in one young male volunteer and examined the pharmacokinetics of standard, mikronized and slow release formulation of fenofibrate after oral intake. This method is a rapid and reliable tool for quantitative determination of fenofibric acid in pharmacokinetic investigations.

Development of a pulmonary phenytoin-associated hypersensitivity reaction despite concomitant dexamethasone and prednisolone administration.

OBJECTIVE: This is the report about a very early onset of phenytoin hypersensitivity reaction showing respiratory insufficiency, fever, hepatic and skin reactions in a 68-year-old male patient who was concomitantly treated with high dose dexamethasone/prednisolone because of brain edema. CASE REPORT: The patient developed a hypersensitivity reaction one week after starting a phenytoin treatment, 250 mg daily intravenously, because of a focal epileptic seizure after a transsphenoidal resection of a pituitary tumor. The drug hypersensitivity was diagnosed first clinically and was confirmed by an in vitro rechallenge using the lymphocyte transformation test three months later. Phenytoin itself did not stimulate the lymphocytes' proliferation. The test was performed successfully using human reference sera. CONCLUSIONS: The results suggest that protein-bound reactive drug metabolites which are assumed to occur in the sera may be responsible for the reaction. Corticosteroids did not prevent the reaction and even seem to mask laboratory and clinical findings. Dexamethasone might accelerate the accumulation of potential allergotoxic epoxide metabolites. Both phenytoin and dexamethasone should be withdrawn urgently in the case of suspected hypersensitivity syndrome.

Reliability of symptom reports by healthy volunteers treated with placebo over several time periods.

In four test periods (medication-free control, three placebo periods with the suggestion randomised placebo or sedative or stimulant) 78 healthy medical students had to check off on a side-effect questionnaire those symptoms that they had experienced over the previous 72 h (adverse nondrug reactions). In the control period only 14 volunteers (18%) were without symptoms. In the course of 4 weeks this number doubled, and the number of symptoms complained decreased correspondingly, e.g. tiredness, headaches, muscle and joint pains etc. This development is relevant inasmuch as in phase-I studies the well-being of the volunteers is often monitored over protracted periods of time and perhaps decreasing interest or a decreasing motivation must be reckoned with. One or two rounds of tests present special situations, in any case, which cannot be reproduced. As the frequency of the symptoms complained of is modified by the personality structure, balanced groups must be formed for controlled studies. In Phase I trials it may sometimes be useful to characterize the volunteers psychologically.

The regional drug-therapy consultation service centre - a conception that has been serving patients and physicians alike for 30 years in Magdeburg (Germany).

OBJECTIVES: Thirty years ago, a drug therapy consultation service centre was established simultaneously with the Institute of Clinical Pharmacology based at the university hospital in Magdeburg. The combination of therapeutic drug monitoring and a drug information service including individual patient-oriented drug dosage and bedside consultation permits an effective support of the treatment of drug related therapeutic problems. Currently, the service offers drug monitoring for 161 drugs and additional 46 metabolites. METHODS AND DISCUSSION: In a representative 2-year period (1997-1998), drug monitoring was performed for 6293 patients, and 569 drug-related inquiries were answered. The main categories of required drug information were: pharmacokinetics/metabolism/analytical problems (38%), adverse drug reactions/drug safety (24%), therapeutic drug use/drug indication (21%) and pharmaceuticals (9%). Further activities of the institute refer to teaching of undergraduates, continuing education of local physicians in recent aspects of drug therapy, providing therapeutic bulletins and conducting supporting clinical studies.

[The pulmonary arteries and veins of miniature swine, together with a common view of their supportive and stabilizing functions in the lung]. / Die Arteriae und Venae pulmonales des Miniaturschweins, zugleich eine grundsätzliche Betrachtung ihrer Stütz- und Haltefunktion für die Lunge.

With respect to distribution and flow, the Vasa pulmonalia resemble those of the normal grown domestic pig to a great extent. The present article investigates whether, like the human lung (Hayek, 1970), the arrangement of the blood vessels has a function over and above that of directing blood; that is to say, a mechanical function. The arteries through which the blood streams act as flexible supporting structures, and the veins as elastic holding structures, for the quadrupede animal also.

Sulthiame-associated mild compensated metabolic acidosis.

Sulthiame is effectively used in the treatment of benign and symptomatic focal epilepsy in children. Hyperventilation as a symptom is a well known adverse effect of the drug. Alterations of the acid-base equilibrium have been described for the drug, however, very infrequently only in adults without a detailed evaluation of the disorders status. The case presented here demonstrates a mild compensated metabolic acidosis in a child which, for the first time, is described using the methods of complete blood gas and electrolytes analysis.

Adverse nondrug reactions: an update.

OBJECTIVE: Healthy volunteers are involved in stage I of clinical investigations. It appears to be necessary to characterize such subjects more closely. Representing an essential aspect are symptoms giving rise to complaints that are typical side effects of drugs but that often also occur as adverse nondrug reactions. Correlations are supposed to exist between personality, motivation, and emotion of subjects and the incidence of their complaints. METHODS: One hundred thirty medical students answered the "Questionnaire for Side Effects of Drugs" (Reidenberg and Löwenthal, 1968), and they were studied with regard to their personality (Freiburg Personality Inventory), motivation (Motivation Q-Sort) and emotion (State-Trait-Anxiety Inventory). RESULTS: The most frequent complaints noted in young healthy volunteers who did not take any drugs were fatigue (65%), headache (25%), and nasal congestions (30%). Only 11% of the medical students were free of symptoms, 50% stated that they had one or two symptoms, and 3% had more than six symptoms. Statistically significant, even though weak, correlations existed between the number of symptoms and the personality traits of nervousness and neuroticism, motivation, and trait-anxiety. However, cluster analysis was adopted to form two groups: One subgroup (not nervous, emotionally stable, success-motivated, and not very anxious) that stated less adverse nondrug reactions, and another contrasting subgroup that complained about symptoms more frequently. CONCLUSION: It appears that the distribution of the incidence of complaints in a nonselected group of healthy volunteers is not of a random character. The relevance of this finding to stage I clinical trials is evident.

Study on the bioequivalence of an oral nifedipine formulation and a sustained release reference preparation after single dose and repeated doses.

Pharmacokinetic parameters of an oral formulation of nifedipine (CAS 21829-25-4, Corinfar, test preparation T a dragee with 10 mg nifedipine) were compared with a reference preparation (R, a sustained release tablet with 20 mg nifedipine) in 16 healthy volunteers in a open two-way crossover study under the influence of ingestion of food. A GC/MS method was used to analyse the serum samples. The estimation of bioequivalence was based on a nonparametric statistical procedure of analysis of variance. Both, the test preparation T and the reference preparation R are bioequivalent at steady state. The main pharmacokinetic parameters (mean +/- standard deviation) used for the bioequivalence decision at steady state were AUC0- tau ss (T: 351.4 +/- 161.0 ng.ml-1.h; R: 345.5 +/- 146.8 ng.ml-1.h), Cmaxss (T: 67.3 +/- 29.5 ng.ml-1; 66.9 +/- 33.0 ng.ml-1) and HVDss (T: 3.8 +/- 1.3 h; R: 4.2 +/- 1.8 h). The bioequivalence of rate and extent of absorption was proved for both preparations at steady state by assessing mean serum level curves as well as by statistics (90% confidence intervals) using the main pharmacokinetic parameters AUC0 - tau ss (range: 0.84-1.02 point estimator: 0.92), Cmaxss (0.95-1.33; 1.15) HVDss (0.72-0.98; 0.82). The large interindividual variability of pharmacokinetics is typical of the drug and does not depend on the formulation used. No case of severe disturbance of circulatory function or other adverse events with the duty to treat occurred during the study. No volunteer dropped out.

Influence of endogenous and exogenous effectors on the pharmacokinetics of theophylline. Focus on biotransformation.

Theophylline has been widely used as a bronchodilatory drug for the treatment of neonatal apnoea in premature newborns and patients with obstructive airways disease. The development of analytical equipment and procedures to determine the systemic concentration of theophylline renders it possible to improve the effectiveness of theophylline therapy and reduce the incidence of toxic and adverse effects. Since the beginning of the 1970s, endogenous and exogenous factors (e.g. age, blood pH, concomitant diseases and drug therapy, meal preparation procedure, nutritional habits, pregnancy, gender, smoking and, to a lesser extent, biorhythms), influencing nearly all parameters of theophylline pharmacokinetics have been described. Drug absorption depends on galenic formulation, drug delivery, nutritional habits and the chemical derivatives used. The mean plasma protein binding rates depend on the method of plasma protein determination: acidic blood pH values and advanced age may result in reduced plasma proteins. The volume of distribution depends primarily on age; it is 2-fold greater in newborns than in adults. Furthermore, changes in blood pH values, the plasma protein content and the administration of concomitant drugs may vary this parameter. Biotransformation is the most clinically important pharmacokinetic parameter. Hepatic metabolism accounts for 90% of the metabolism of theophylline. Essentially, 2 microsomal isoenzymes of the cytochrome P450 system appear to be responsible for the N-methylation and 8-hydroxylation of the drug. Age and concomitant disease are the major endogenous effectors influencing biotransformation of theophylline, whereas biorhythms, gender and pregnancy are of lesser importance. Exogenous factors, such as concomitantly administered drugs, smoking and nutritional factors, affect biotransformation by inducing or inhibiting the metabolising enzymes. Because of intra- and interindividual variability in the pharmacokinetics of theophylline, which may be increased by the presence of endogenous and/or exogenous effectors, it is necessary to supervise theophylline therapy by therapeutic drug monitoring if target concentrations are to be achieved.

Quantification of aerobic energy turnover in epididymal bull spermatozoa.

Turnover rates of oxidative energy metabolism were measured as oxygen consumption in untreated and caffeine-stimulated epididymal bull spermatozoa respiring with lactate. Incubation of spermatozoa with 1 mM caffeine led to an increase in respiration of approx. 60%. The rate of uncoupled respiration and the vanadate-insensitive part of oxygen consumption were not affected by caffeine. The small effect of ouabain on respiration (-10%) indicated a minor contribution of Na+/K+-ATPase to the ATP consumption. The major part of ATP turnover was caused by motility shown by the strong linear correlation between respiration and motility in untreated and caffeine-treated spermatozoa. In comparison with ejaculated spermatozoa investigated in a previous study, epididymal cells exhibited the same rates of uncoupled and ouabain-sensitive respiration. The efficiency of transforming mitochondrially-produced ATP into cell motion was the same in epididymal and ejaculated spermatozoa. The ATP-producing capacity of sperm mitochondria was utilized in untreated epididymal, in caffeine-stimulated epididymal and in ejaculated spermatozoa, by 20-25%, 40-45% and 45-50%, respectively. The results showed that the capacity of mitochondrial. ATP formation remains unchanged after ejaculation and is utilized to a higher extent by stimulated motility. Treatment with caffeine affected epididymal spermatozoa in a similar manner.

[Respiration and motility of epididymal sperm from slaughtered bulls]. / Atmung und Motilität epididymaler Spermien von Schlachtbullen.

The simple method of retrograde flushing of spermatozoa from the epididymal cauda of slaughter bulls yielded an average of 2 x 10(9) spermatozoa from one cauda. The plasma membrane was intact in something between 80 and 85 percent of all epididymal spermatozoa. Respiratory rates and motility were clearly below values typical of ejaculated spermatozoa, though sizeable differences were found to exist for both parameters between individual preparations. The endogenous substrates available proved to be sufficient for such low metabolic activity, whereas higher energy turnover required the presence of exogenous substrates, such as lactate, pyruvate or fructose. Respiratory capacity, determined by uncoupling of oxidative phosphorylation in the presence of lactate, was comparable to that of ejaculated bull spermatozoa. The above findings are likely to suggest that the lower respiratory rates of epididymal spermatozoa were attributable to the fact that their consumption for motility of adenosine triphosphoric acid (ATP) was lower than that of ejaculated spermatozoa.