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.

Population pharmacokinetics of 2% topical dorzolamide in the aqueous humor of humans.

PURPOSE: To evaluate the concentration and kinetics of dorzolamide in the aqueous humor after its topical application. METHODS: Samples of aqueous humor were collected at the beginning of routine cataract surgery at defined intervals after topical application of a 2% solution of dorzolamide. After deep-frozen storage of the samples, drug extraction was achieved with a mixture of solvents. Quantification was carried out by high-performance liquid chromatography on a reversed-phase column. RESULTS: Peak concentrations of dorzolamide in aqueous humor were reached approximately 2 hours after application with 1000 ng/ml. Average values were approximately 1000 to 700 ng/ml after 4 to 6 hours and approximately 200 ng/ml after 12 hours. Mean half-life of absorption was 1.2 hours and for elimination 3.0 hours. CONCLUSIONS: Pharmacokinetics of dorzolamide in the aqueous humor of humans are in comparable dimensions as previously reported in experimental trials in pigmented rabbits. There is a clear linear absorption and elimination kinetic, which is demonstrated using the Bateman function. A better knowledge of the distribution and kinetics of dorzolamide will help to explain its reported effects on intraocular hemodynamics, distinct from its intraocular pressure lowering effect.

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.

The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia.

Haloperidol is the most commonly used antipsychotic drug in the therapy of acute schizophrenia. Clinicians have been using therapeutic drug monitoring in an attempt to improve clinical application of this drug. The scale of interest in this area is emphasised by the large number of studies (about 50) concerning the serum concentration-therapeutic effect relationship (SCTER) of haloperidol, including 35 studies on patients with acute schizophrenia. However, conflicting results concerning the existence and position of a therapeutic window have emerged. This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data are used for decision-making. For this purpose, a reproducible system for the evaluation of studies in this special area, a so-called total study score (TSS), was developed on an empirical basis. Thus, insufficient study design was found to be a reason for negative results. On the other hand, in spite of a great variability, the majority of studies with good design provided evidence for a significant SCTER: a bisigmoidal dependence of clinical effect on haloperidol serum concentration. The therapeutic effects of haloperidol increase at low concentrations, and the concentration has a maximum effect at about 10 micrograms/L and again decreasing at higher concentrations. The data of 552 patients also fit to this model in a single scatter plot (pseudo-r2 = 0.076, p < 0.001). The position of the therapeutic window was determined at about 5.6 to 16.9 micrograms/L. Patients treated with serum concentrations within this optimal range had a significantly better response compared with outside this range (p < 0.001, Student t-test). Therefore, a quantitative synthesis of all available data by means of effect-size analysis provides a mean effect-size (g) = 0.499 +/- 0.182 (standard deviation) for the comparison of haloperidol-treatment with serum concentrations within versus outside the therapeutic window. Thus, because of this moderate positive effect, serum concentration assay of haloperidol is recommended for patients with acute schizophrenia in a therapeutic drug monitoring programme. The modalities of haloperidol therapeutic drug monitoring in clinical practice are discussed, e.g. patient selection, method and time for serum concentration measurement, influence of premedication and comedication, interpretation of results and dose adjustment. Clinical investigations into this subject should focus on covariates which are responsible for the variability of the SCTER. Serum concentration assay is advised for investigations of nonresponse to exclude patients with pseudo-drug resistance.

Reduced haloperidol does not interfere with the antipsychotic activity of haloperidol in the treatment of acute schizophrenia.

The aim of this study was to investigate the effect of reduced haloperidol, the main metabolite of the antipsychotic drug haloperidol, on psychopathology improvement and extrapyramidal adverse effects in acute schizophrenia. The steady-state pharmacokinetics of reduced haloperidol was studied. Serum concentrations of reduced haloperidol (C(RH)) and haloperidol (C(H)) were measured in an open clinical trial over 6 weeks of treatment in 57 acutely schizophrenic patients. Psychopathology was measured by the Brief Psychiatric Rating Scale and several subscales. The assay of extrapyramidal adverse effects was conducted by means of the Extrapyramidal Symptom Rating Scale. A significant serum concentration-therapeutic effect relationship (SCTER) of haloperidol of the same data has been demonstrated. In our study, the influence of the metabolite reduced haloperidol on the antipsychotic activity of haloperidol was analysed by means of regression analysis of the residuals of the SCTER of haloperidol with C(RH). In addition, the steady-state pharmacokinetics of reduced haloperidol and direct relationships between C(RH) and the metabolite ratio C(RH)/C(H) with psychopathology improvement and extrapyramidal adverse effects were investigated. Reduced haloperidol was not found to interfere with the antipsychotic action of the parent drug. Patients with elevated C(RH) or elevated metabolite ratio C(RH)/C(H) did not show consistently lower clinical improvements compared with the fitting curve of the SCTER of haloperidol and therefore no significant relationship between C(RH) and the residuals of the SCTER of haloperidol was detected. Furthermore, no significant result was found in the analysis of the direct relationships of C(RH) and C(RH)/C(H) with clinical variables which, for example, indicate decreased outcome with increased C(RH). In contrast, because of the pharmacokinetic dependence of C(RH) and C(H), a trend for a bisigmoidal relationship with C(RH) emerged for some outcome variables which was traced as an epiphenomenon from the bisigmoidal SCTER of the parent drug (e.g. change of hostility after 3 weeks). No relationship of reduced haloperidol with extrapyramidal adverse effects could be detected. It is concluded that serum concentrations of reduced haloperidol are of minor value for the interpretation of data of therapeutic drug monitoring of haloperidol in patients with acute schizophrenia. Reduced haloperidol does not act as a 'false neuroleptic'.

Indicative therapeutic and toxic drug concentrations in plasma: a tabulation.

The table presented provides the therapeutic, toxic and lethal serum concentrations (to the extent demonstrable) of drugs. The use of plasma levels when administering drugs increases the likelihood of attaining a therapeutic response and serves to minimize the toxicity. The therapeutic range of agents should be used as a guideline and must be interpreted in conjunction with other monitoring parameters.

Psycho- and immunopharmacological factors relevant to selection of volunteers in clinical studies.

There are many well-known factors and variables which play a role in the evaluation of pharmacokinetic and pharmacodynamic results gained from healthy volunteers. The genetic constitution is influenced by age, sex, circadian and seasonal variations, dietary factors, immunological function, alcohol intake, smoking, etc. Vesell repeatedly pointed out these facts some time ago [Vesell 1982, Vesell and Passananti 1977]. Since Janke [1964], we have suspected that personality traits can also influence the drug response. The following overview is dedicated to this field designated as differential psychopharmacology which, from the point of view ofthe author, has been given too little attention by pharmacologists and clinical pharmacologists. It has been demonstrated that the effect of psychotropic drugs, including placebo, can be differentially influenced by personality traits, e.g. introversion/extroversion, high level neuroticism/low level neuroticism and success motivation/failure motivation. For example, relatively high doses of diazepam (0.3 mg/kg), when compared to placebo, only impaired the psychophysical performance of extroverted volunteers whereas introverted volunteers remained unaffected. Pharmacokinetic parameters, e.g. absorption, biotransformation, can also be affected by the level of neuroticism or by anxiety, as demonstrated for diazepam, caffeine, paracetamol and theophylline. The absorption kinetics of diazepam and caffeine clearly differ between volunteers with high neuroticism scores and those with low neuroticism scores. Emotionally unstable volunteers absorbed the substances more quickly and more completely than emotionally stable volunteers. There were surprising differences in various immunological indices between dominant and submissive subjects. In dominant volunteers the immune system was more activated than in submissive volunteers. In the future, it will become increasingly necessary to obtain results for such target groups and to avoid generalized data, which may conceal the actual events. Differential clinical psycho-neuro-immunopharmacology may be an approach which is helpful in the development of "volunteer models" for clinical research in Phase I.

Pharmacokinetic data of gamma-linolenic acid in healthy volunteers after the administration of evening primrose oil (Epogam).

Defects in the metabolism of gamma-linolenic acid are thought to play a major role in the pathogenesis of atopic eczema, but little is known about the pharmacokinetic behavior of this fatty acid and its metabolic products. We investigated the serum level-time courses of 8 fatty acids after the administration of Epogam, a preparation of evening primrose oil which contains gamma-linolenic acid as an active ingredient. From 6 volunteers, serum concentration time curves of gamma-linolenic acid and 7 other fatty acids were profiled 24 h with and without the administration of Epogam. Six capsules of Epogam were administered to each subject in the morning at 7:00 and further 6 capsules in the evening at 19:00. On the days of investigation the volunteers had a diet of low fat meals. The serum concentrations of the fatty acids were determined as their methyl esters by means of gas chromatography mass spectrometry. Gamma-linolenic acid shows an absorption-elimination pattern after the administration of Epogam and its AUC24h and Cmax are significantly increased over the baseline values. After the evening administration, t(max) is shorter (2.7 +/- 1.2 h) than after the morning administration (4.4 +/- 1.9 h). The other fatty acids show no significant increase in their concentrations, especially dihomo-gamma-linolenic acid and arachidonic acid, which are metabolic products of gamma-linolenic acid. Conclusively, an effect of the administration of gamma-linolenic acid on the serum concentrations of dihomo-gamma-linolenic acid and arachidonic acid and, therefore, on the biosynthesis of prostaglandin PGE1 and PGE2 could not clearly be established in healthy volunteers. Further investigations will show if there is a significant effect in patients suffering from atopic eczema.

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.

Absorption kinetics of paracetamol are not influenced by high anxiety levels in preoperative patients.

OBJECTIVE: If the absorption kinetics of orally administered drugs in preoperative patients are influenced by high anxiety levels as maintained by Simpson and Stakes [1987], then this aspect would have to be taken into consideration in the preparation for surgery and would make dose adjustments necessary in such patients. METHODS: We differentiated and quantified the anxiety level in 40 patients, 4 - 5 hours prior to an operation, using the State-Trait Anxiety Inventory (STAI). Subsequently, all patients were given 1000 mg of paracetamol and serum levels were analyzed by means of HPLC. RESULTS: Over the first 3 hours after application there were no significant differences in the parameters C(max) and t(max) between patients with high levels of anxiety and patients with low levels of anxiety. However, AUC (area under curve) values were slightly higher in patients with high levels of anxiety. CONCLUSIONS: No clinically relevant differences in absorption parameters were observed in patients with high and low levels of anxiety.

Therapeutic drug monitoring of clozapine and relapse--a retrospective study of routine clinical data.

OBJECTIVE: Therapeutic drug monitoring (TDM) of the atypical antipsychotic drug clozapine is recommended. Clinical studies have indicated a therapeutic window for clozapine serum levels in schizophrenic and schizo-affective patients during acute treatment, i.e. for patients who do not respond to treatment with typical antipsychotics. However, despite the frequent use of clozapine also in maintenance treatment, very few data are available showing the relationship between serum levels of clozapine and the prevention of relapse. Thus, the primary objective of the study was to investigate the relationship between serum levels ofclozapine and relapse during maintenance treatment. METHODS: A retrospective study of routine TDM-data was conducted. Samples obtained on an acute treatment ward from patients with < 4 days hospitalization (recent admissions) were regarded as samples associated with relapse. Samples which can be attributed to an intoxication were identified as described in the TDM-form. The serum level of clozapine, as well as age, gender, smoking habits, concurrent drugs, psychiatric diagnosis and dose of clozapine were evaluated. Data analysis was performed on individual samples and, alternatively, on multiple samples from a single patient which are summarized according to a typical clinical situation. RESULTS: 404 serum levels were measured in 86 patients. After exclusion of patients receiving acute treatment, 65 relevant clinical situations were identified in 50 patients: 12 relapses, 8 intoxications (a total of 20 situations with poor outcome) and 45 situations involving patients with good maintenance outcome. Samples involving relapse had serum levels of 198 +/- 211 ng/ml (10-624), intoxications had serum levels of 1,969 +/- 705 ng/ml (900-2,900) and those with good outcome had serum levels of 384 +/- 255 ng/ml (56-1,028) (mean +/- SD (range)). By means of sensitivity of receiver operating characteristic curves (ROC) a lower limit of the therapeutic window can be estimated at about 50-250 ng/ml and an upper limit at about 745-1,050 ng/ml. The frequencies of good and poor outcome were significantly different within and outside these ranges, e.g. chi2 = 11.8 and p < 0.001 for 250 to 745 ng/ml. Comparison of only good outcome and relapse provided a significant difference in the serum level of clozapine (Student's t-test p = 0.024). However, 67% of relapses were predicted in a model of logistic regression only if the variables serum level and concurrent treatment with other psychotropic drugs were included simultaneously as independent variables. Neither variable was able to predict relapse if used as a single variable in separate models. Finally, it was found that serum levels of clozapine were increased in women, in aged patients and in nonsmokers. CONCLUSIONS: It is tentatively concluded that serum levels of clozapine < 50 ng/ml are related to relapse irrespective of concurrent psychotropic drugs. In cases where there are no concurrent psychotropic drugs, serum levels of clozapine < 250 ng/ml are associated with relapse. The risk of relapse is low for serum levels of clozapine > 250 ng/ml irrespective of concurrent psychotropic drugs. The risk of intoxication is increased with serum levels > 750 ng/ml. The TDM of clozapine is recommended during maintenance treatment.

A capillary gas-liquid chromatographic method for the assay of the neuroleptic drug zotepine in human serum or plasma.

A capillary gas-liquid chromatographic method suitable for the assay of the atypical neuroleptic drug zotepine in human serum or plasma was developed. A liquid-liquid extraction with three subsequent extraction steps was applied for sample preparation. The minimum detectable concentration was 1.0 ng ml-1. The within-day relative standard deviation (RSD) (n = 6) was 5.3% at 5 ng ml-1, 3.6% at 10 ng ml-1 and 6.1% at 100 ng ml-1. The day-to-day RSD (n = 6) was 9.3% at 10 ng ml-1 and 5.1% at 100 ng ml-1. Steady-state serum levels of four schizophrenic patients were measured.

Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice.

The suitability of nanoparticles as a drug-carrier system for the antiepileptic valproic acid has been studied in mice. The aim of the study was to increase the brain-to-serum ratio of the drug to reduce dose-related side effects in the periphery. The influence of nanoparticles on the metabolism of valproic acid was also investigated. The serum kinetics and the brain tissue levels of valproic acid were not altered by administration with nanoparticles. However, the nanoparticles did inhibit the metabolic degradation of valproic acid via mitochondrial beta-oxidation but did not influence any other metabolic pathway. It can be concluded that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites. Using their ability to selectively block a pathway nanoparticles may serve as a tool to investigate the metabolic origin of metabolites and their contribution to therapeutic efficacy and side effects.

Aquaculture disease and health management.

Disease problems constitute the largest single cause of economic losses in aquaculture. In 1988, channel catfish producers lost over 100 million fish worth nearly $11 million. Estimates for 1989 predict even higher losses. The trout industry reported 1988 losses of over 20 million fish worth over $2.5 million. No data are available on losses sustained by producers of shellfish. Bacterial infections constitute the most important source of disease problems in all the various types of production. Gram-negative bacteria cause epizootics in nearly all cultured species. Fungal diseases constitute the second most important source of losses, especially in the culture of crustaceans and salmon. External protozoan parasites are responsible for the loss of large numbers of fry and fingerling fin fishes and are a cause of epizootics among young shellfish. The number of therapeutants approved by the Food and Drug Administration is limited. Research to support the registration of promising therapeutic agents is urgently needed.

Variation in response of channel catfish to Henneguya sp. infections (Protozoa: Myxosporidea).

Infections in channel catfish (Ictalurus punctatus, Rafinesque) induced by the sporozoan Henneguya (Protozoa: Myxosporidea) result in seven known and diverse disease manifestations. Most outstanding is an interlamellar branchial form responsible for significant losses among immature catfish, and a unique papillomatous form. The question of whether or not the species of Henneguya involved in these cases is H. exilis remains to be resolved.

[Special qualification of a photometric procedure for determination of salicylic acid in therapeutic drug monitoring]. / Besondere Eignung eines photometrischen Verfahrens zur Bestimmung von Salicylsäure im Therapeutischen Drug Monitoring.

A procedure for the determination of salicylic acid from human serum is presented. It is based on an acidic extraction, a basic reextraction and the detection of salicylic acid as its iron-III-complex by photometry. The procedure is quantitative over a wide range of linearity, easy to carry out and is especially suitable for therapeutic drug monitoring in the treatment of juvenile rheumatoid arthritis.

[Biologic availability of caffeine in subjects with regard to the variability of the elimination half life]. / Zur Bioverfügbarkeit von Coffein bei Probanden unter Berücksichtigung der Variabilität der Eliminationshalbwertszeiten.

400 mg of caffeine and sodium salicylate (= 220 mg of caffeine) were given orally and intravenously (at an interval of one week) to six test persons. The serum levels were determined; and certain pharmacokinetic parameters were measured, using an open one-compartment model. Finally, the absolute bioavailability was calculated. With one of the test persons this experiment was repeated ten times to evaluate the extent of the intra-individual variability of the half-life period and its repercussions on bioavailability.

Valproate metabolites in the rat brain--regional distribution in various brain areas.

To investigate the regional distribution of valproic acid (VPA) and 10 of its metabolites in the rat brain, the animals were treated with 300 mg/kg/day VPA i.p. on a 3 times daily dose regimen for 5 days, and the concentrations of the compounds in serum and 15 brain regions were measured. 2-(n-propyl)-(Z)-2-pentenoic acid [(Z)-2-en], a VPA metabolite expected to possess neurotoxic potency in humans, was determined in brain tissue for the first time. The brain/serum concentration ratio of (Z)-2-en was found to be about 14-fold higher than the ratio for its (E)-isomer, thereby demonstrating the influence of the double-bond configuration in the unsaturated metabolites on their ability to penetrate into the central nervous system. The concentrations of VPA and its metabolites in the brain regions were compared to c(hom), the calculated concentration for an assumed homogeneous distribution. The parent drug and its metabolites exhibited individual distribution patterns with varying degrees of inhomogeneity. Elevated metabolite concentrations were found especially in the motorium and the medulla oblongata. Decreased concentrations of VPA and several metabolites were found in the visual cortex.