[Diagnostics and treatment of suicidality; a matter of customization]. / Diagnostiek en behandeling van suïcidaliteit; een kwestie van maatwerk.

This article illustrates the importance of conducting a comprehensive analysis of suicidality through the case study of an adolescent patient dealing with both depressive disorder and obsessive-compulsive disorder. The aim of treating suicidality is to address the underlying psychiatric conditions and factors contributing to the disorder. This necessitates a thorough evaluation of the treatment environment, the establishment of continuous care, and ensuring safety. By utilizing a new model to distinguish various forms of suicidal behavior and examining suicidality as a distinct phenomenon, it becomes possible to create individualized diagnostic and treatment approaches, along with effective risk assessments. In the presented patient, intrusive thoughts significantly impacted her suicidality. The treatment approach for patient A involved employing eye movement dual task (EMDT), exposure therapy and strategies to enhance autonomy. This approach aims to reduce suicidality, facilitate recovery, and alleviate the fear of losing control.

Psychotropic drug use in a group of Dutch nursing home patients with dementia: many users, long-term use, but low doses.

The aim of this study was to describe the use of psychotropic drugs in a psychogeriatric nursing home, "Joachim en Anna", in Nijmegen, the Netherlands. To this end the medical records of 890 nursing home patients with dementia, admitted between 1980 and 1989, were analysed retrospectively. Each time pattern of psychotropic drug use was registered. Drugs were coded by means of the Anatomical Therapeutic Chemical classification system. The daily dose was expressed as the ratio of the mean prescribed daily dose and the defined daily dose. Side-effects and changes in prescription patterns throughout the years patients were admitted were analysed. A total of 3,090 time patterns of exposure to psychotropics were registered. Neuroleptics, benzodiazepines, and antidepressants accounted for 58, 32, and 9 percent of the time patterns, respectively. For almost every drug prescription the prescribed daily dose was lower than the defined daily dose. More than 75 percent of these nursing home patients had at least one prescription for a psychotropic drug during institutionalization. One or more side-effects were observed in 50 percent of the patients who used a neuroleptic. The total number of patients receiving psychotropics did not change throughout the study. Psychotropics were prescribed for long-term use, but in a low dose. Side-effects were frequently observed while the correct individual dose was being determined.

[Use of psychotropic drugs in a group of nursing home patients with dementia: many users, long-term use but low dosages]. / Psychofarmacagebruik bij een groep dementerende verpleeghuispatiënten: veel gebruikers, langdurig gebruik, maar lage doses.

Of 890 nursing home patients with dementia, admitted between 1980 en 1989 to Dutch nursing home 'Joachim en Anna' in Nijmegen, each episode of psychotropic drug use was retrospectively registered. Drugs were coded by means of the Anatomical Therapeutic Chemical (ATC)-classification system and the daily dose was expressed as the ratio of the prescribed daily dose and the internationally agreed defined daily dose. Side effects were analysed as were changes in prescription patterns throughout the years of patient admittance. A total of 3090 episodes were registered. Neuroleptics, benzodiazepines and antidepressants accounted for 58, 32 and 9% of the prescriptions. In almost every drug-prescription the prescribed daily dose was lower than the defined daily dose. More than 75% of the patients had at least one prescription for a psychotropic drug during institutionalization. Half of those patients who used a neuroleptic showed one or more side effects. Neither the total amount of patients with psychotropics nor the duration of usage changed throughout the years of patient admittance. It is concluded that a majority of these nursing home patients got at least one prescription of a psychotropic drug during institutionalization. Psychotropics were prescribed for long-term usage, but in low doses. Side effects were frequently observed in determining the right dose.

Sub-50 oral contraceptives affect folate kinetics.

The effects of long-term use of oral contraceptives containing less than 50 micrograms of estrogen (sub-50 OCs) on the kinetics of folic acid monoglutamate, vitamin B12 levels, and iron status have been studied in 29 OC users (Marvelon) and in 13 women without OC use serving as controls. At 210 min after oral folate loading the median serum folate concentration was significantly lower in OC users when compared to the control group. OC users showed significantly higher total iron binding capacity and significantly lower serum vitamin B12 concentrations. This data demonstrates that sub-50 OCs significantly affect folate kinetics and vitamin B12 levels. However, the folate and vitamin B12 status does not seem to be at risk.

Interaction of legume lectins with the cellular metabolism of differentiated Caco-2 cells.

The binding of the legume lectins Phaseolus vulgaris E4 and L4, Glycine max agglutinin, Vicia faba agglutinin, and Pisum sativum agglutinin to intact differentiated Caco-2 cells and to brush border membranes of differentiated Caco-2 cells was investigated, and their impact on the cellular metabolism and the microvilli of these cells was assessed. P. vulgaris isolectin E4 showed the most intense staining after binding of fluorescein isothiocyanate-labeled lectin to intact Caco-2 cells. P. sativum agglutinin showed the weakest staining intensity. The dissociation constant for P. vulgaris isolectin E4 and P. sativum agglutinin binding was 0.11 x 10(-5) and 1.69 x 10(-5) mol/L, respectively. The values of the dissociation constants for P. vulgaris isolectin L4, G. max agglutinin, and V. faba agglutinin were situated in between these extremes. Stimulation of thymidine, glucosamine, and fucose incorporation was observed after exposure to P. vulgaris isolectins and soybean agglutinin. V. faba agglutinin had an inhibitory effect, whereas P. sativum agglutinin showed little or no effect. Compared with control cells and P. vulgaris isolectin L4- and P. sativum agglutinin-incubated cells, the microvilli of P. vulgaris isolectin E4-, soybean agglutinin-, and V. faba agglutinin-incubated cells were shortened significantly. The data provide evidence that a correlation exists, not only between the dissociation constants of the lectins and the fluorescent staining intensity, but also between the dissociation constants of the lectins and the extent of the legume lectin-induced changes in the cellular metabolism.

The methyl-5 alpha-dihydrotestosterones mesterolone and drostanolone; gas chromatographic/mass spectrometric characterization of the urinary metabolites.

Before including the detection of the methyl-5 alpha-dihydrotestosterones mesterolone (1 alpha-methyl-17 beta-hydroxy-5 alpha-androstan-3-one) and drostanolone (2 alpha-methyl-17 beta-hydroxy-5 alpha-androstan-3-one) in doping control procedures, their urinary metabolites were characterized by gas chromatography/mass spectrometry. Several metabolites were found after enzymatic hydrolysis and conversion of the respective metabolites to their trimethylsilyl-enol-trimethylsilyl ether derivatives. The major metabolites of mesterolone and drostanolone were identified as 1 alpha-methyl-androsterone and 2 alpha-methyl-androsterone, respectively. The parent compounds and the intermediate 3 alpha,17 beta-dihydroxysteroid metabolites were detected as well. The reduction into the corresponding 3 beta-hydroxysteroids was a minor metabolic pathway. All metabolites were found to be conjugated to glucuronic acid.

Chaos and illusion.

Pharmacology is the study of the interaction of drugs with living organisms, especially humans. The body is a very complicated system, which suggests that the 'effect' induced by a drug is not a single entity but a change in several variables at the same time, all of which are interrelated in a nonlinear fashion. Research on nonlinear systems in other fields of science--commonly known as chaos theory--may therefore be of use in understanding pharmacology, as explained here by J. M. van Rossum and J. E. G. M. de Bie. They argue that in the study of drug effects, several variables should be measured simultaneously. Many pharmacologists prefer to construct an illusion of reality, studying just one of the essential variables and averaging data in a population of subjects, thus losing the opportunity to understand what a drug really does to a patient.

Doping control of testosterone and human chorionic gonadotrophin: a case study.

Doping control for testosterone and human Chorionic Gonadotrophin (hCG) requires special attention as a difference must be made between the endogenous and exogenous origin of both substances. The detection of exogenous testosterone is based on the ratio of testosterone- to epitestosterone-glucuronide (T/E) in urine. The problems with this ratio are discussed. For hCG analysis in urine the utilization of sandwich-type hCG specific assays instead of hCG/hCG beta competitive assays is recommended. A case study in which an athlete self-administered testosterone and hCG before a competition is described. The T/E ratio and hCG concentration in urine were followed during this period of self-administration. The results demonstrate the relevance of the T/E ratio and of the selected hCG assay. The ratio of testosterone to human Luteinizing Hormone (T/hLH) in serum also indicated the use of hormones. Although the athlete's urine was negative for exogenous testosterone directly after competition, he would have been found positive for hCG.

Rapid and sensitive gas-chromatographic determination of caffeine in blood plasma, saliva, and xanthine beverages.

A gas chromatographic procedure is reported for the determination of caffeine in plasma, saliva, and xanthine beverages. Using a 75 cm column packed with OV-17, nitrogen-sensitive detection, and 1 ml samples, a suitable limit of analysis (coefficient of variation (CV) = 10.2%) of 50 ng/ml was obtained in plasma. Within-day CVs at caffeine concentrations of 0.1-0.5-2.0-7.5-15.0 micrograms/ml in plasma were 7.7-5.6-4.8-3.8-3.4%, respectively. The limit of detection, defined as the injected quantity of caffeine giving rise to a signal to noise ratio of 2, is 40 pg, corresponding to a plasma concentration of 1 ng/ml. The procedure involves addition of the internal standard 7-pentyl theophylline and alkaline extraction of the sample with dichloromethane. The method described rivals any gaschromatographic assay published so far in rapidness and accuracy. Plasma and saliva caffeine concentrations were determined in a healthy male volunteer after swallowing 400 ml of coffee. The calculated pharmacokinetic parameters, assuming complete absorption of caffeine from the G.I. tract, agree well with previously published values.

R 50 595, a selective non-competitive antagonist of cisapride, BRL 24924 and 5-hydroxytryptamine on the guinea-pig ileum.

5-Hydroxytryptamine and substituted benzamides such as cisapride and BRL 24924 enhance the twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus preparation of the guinea-pig. The effects of these benzamides and 5-HT could possibly be mediated via similar receptor-effector systems. The aim of our study was therefore to determine whether R 50 595, an analogue of cisapride devoid of intrinsic activity, could specifically interfere with the effects of cisapride and BRL 24924 and if so, whether it would also affect the responses to serotonin. R 50 595 had no effect on the twitch responses of the electrically stimulated preparation up to a concentration of 3 X 10(-7) M. Cisapride and BRL 24924 both enhanced the contractile response to electrical stimulation by a maximum of 37 +/- 7% at 3 X 10(-7) M for cisapride and 36 +/- 6% for BRL 24924, also at 3 X 10(-7) M. R 50 595 (10(-7)(-3) X 10(-7) M) antagonized the effects of cisapride and BRL 24924 in a non-competitive way. 5-HT enhanced the contractile responses by a maximum of 24 +/- 3.2% at 3 X 10(-8) M. The effects of 5-HT were completely abolished at a concentration of 3 X 10(-7) M R 50 595. R 50 595 also antagonized the effects of 5-HT in a non-competitive way.(ABSTRACT TRUNCATED AT 250 WORDS)

Systems dynamics in clinical pharmacokinetics. An introduction.

Pharmacokinetics is in essence the study of the input/output relationships of the (human) body, which is considered as a system characterised by a density function of residence times. The input is the dosage rate, and the output is the concentration in the blood. The body transport function is first derived in a model-independent fashion, assuming linear kinetics. It is subsequently defined on the basis of a positive feedback loop of transport through the pulmonary and systemic circulation. Thus, the residence times distribution is based on transit times distributions and recirculation. The relevant dynamic systems parameters are cardiac output, extraction ratio, clearance, volume of distribution, mean transit time and mean residence time. In the case of drug absorption, mean absorption time and bioavailability are also important. In this review, the systems approach in pharmacokinetics is illustrated by clinical and computational experiments.

Pharmacokinetics from a dynamical systems point of view.

The pharmacological action of many drugs depends on several variables at the same time and therefore will be dominated by an attractor of a dimension greater than zero. The pharmacokinetic behavior is likely to be dominated by a zero dimensional point attractor so that it is highly predictable. Pharmacokinetics is discussed from a dynamical systems point of view, whereby the transport of drugs in the tissues and organs is considered a stochastic process characterized by density functions of transit times and blood flows. In the body, the tissues and organs are arranged in parallel, in series, and in a feedback-loop fashion. Consequently, the single-pass transport of drugs through the body is again a stochastic process characterized by the density function of total body transit times, the cardiac output, and the total body extraction. The drug molecules, however, may pass through the body several times before ultimately leaving the system by metabolism or excretion. As a result, the body may be regarded as a positive feedback system with the pulmonary circulation (and its tissues) as the forward transfer function and the systemic circulation (with all its tissues) as the feedback transfer function. Consequently, the total body transport function (closed loop) is again a stochastic process characterized by a density function of total body residence times. The relationship between the body transit time distribution and the body residence distribution is determined by the feedback-loop arrangement, the cardiac output, and the extraction ratio which can easily be written in the Laplace domain. The pharmacokinetic parameters logically follow from the systems approach. They are the cardiac output, the mean transit time, the extraction ratio, the clearance, the volume of distribution in steady state, the mean residence time, and the average number of recirculations. The dynamic systems approach in pharmacokinetics has been illustrated with some examples notably with caffeine.

Epidural morphine anesthesia for abdominal aortic surgery--pharmacokinetics.

Plasma and CSF pharmacokinetics of morphine given epidurally in combination with general anesthesia for abdominal aortic surgery were recorded. The initial plasma and CSF concentrations of morphine appeared at two minutes. The peak plasma concentrations of morphine were recorded at 8.0 +/- 2.6 minutes after epidural injection. Plasma mean residence time was 84 +/- 25.7 minutes, Vdss 121 +/- 30 L, and C1 1.5 +/- 0.32 L/min. Free morphine was not detected in plasma 360 minutes after epidural administration. The fraction of the epidural morphine that crossed the dura was 3.15% +/- 2.4 The peak CSF morphine concentrations were recorded at 56 +/- 31 minute. MRT (200 +/- 28 minute), Vdss (65 +/- 33.8 ml), and CL (0.32 +/- 0.15 ml/min) showed that variable fractions of morphine remained many hours in the CSF. Factors that could produce the interindividual variability of plasma and CSF concentrations and pharmacokinetics of epidural morphine were discussed. Abdominal aortic surgery appears to influence both plasma and CSF pharmacokinetics.

Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after intravenous administration.

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were investigated in rats following a single intravenous dose of 100 mg/kg and 150 mg/kg of amiodarone. The decline in serum and tissue concentrations of amiodarone and desethylamiodarone are described by biexponential functions. All aspects of the typical kinetic profile of the drug and its major metabolite, desethylamiodarone, are discussed. Amiodarone is preferentially distributed in decreasing order in thyroid gland, lung, kidney, liver, heart, adipose tissue, skeletal muscle and brain. The metabolite desethylamiodarone showed a distribution pattern which is similar to that observed for the parent drug. Our study indicates an extensive distribution of amiodarone, with the thyroid gland and lung as organs with specific binding sites or uptake mechanisms and adipose tissue as a depot with a large storage capacity. We also found a very extensive distribution of the metabolite desethylamiodarone with mainly lung and thyroid gland and to some lesser extent kidney, liver and heart as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. Our data demonstrate the advantages of intravenous loading dosages of amiodarone over oral doses, since considerably higher and longer lasting effective serum and tissue concentrations of amiodarone are reached while lower quantities of the less cardio-active metabolite are formed.

Pharmacokinetics of morphine in cerebrospinal fluid and plasma after epidural administration in man.

The morphine concentration in serum as well as in cerebrospinal fluid (CSF) after epidural administration of 0.1 mg/kg morphine to 10 patients undergoing aortic abdominal surgery, was determined. Model independent pharmacokinetic parameters in serum and CSF i.e. mean residence time (MRT), clearance (Cl) and apparent volume of distribution were calculated from the concentration time curves using a non-linear square regression fitting programme. Peak concentration of morphine in serum (86 ng/ml) and in CSF (2610 ng/ml) was reached after 10 min respectively 40 min of epidural injection.

Percutaneous absorption of 14C-labelled 2-chlorobenzaldehyde in rats. Metabolism and toxicokinetics.

2-Chlorobenzaldehyde might be produced when a moist skin is exposed to the riot control agent CS. CS-hydrolysis to 2-chlorobenzaldehyde and malononitrile occurs both in vitro and in vivo. No quantitative data have thus far been reported with respect to the percutaneous absorption and the cutaneous biotransformation of 2-chlorobenzaldehyde. Percutaneous absorption, biotransformation and elimination of 14-C-labelled 2-chlorobenzaldehyde was investigated in the rat. Following IV (25 microliters/kg) and IP (37.5 microliters/kg) 14C-2-chlorobenzaldehyde administration to rats, the plasma radioactivity declined rapidly over a 24 h period with similar plasma radioactivity-time profiles. Following cutaneous administration (75 microliters/kg) in a closed glass-cup on the skin a slow skin penetration occurred as indicated by plasma radioactivity levels. A slow increase in plasma radioactivity was followed by a slow decline of radioactivity in plasma over a 3-day period. Most of the radioactivity was found in the urine with low levels in faeces and exhaled air. The cutaneously administered radioactivity was also partly recovered from the glass-cup. For the qualitative and quantitative determination of metabolites in urine, a thin layer chromatography-radioautography method was used. The metabolic patterns of urinary excreted metabolites following cutaneous application and systemic administration of 14C-2-chlorobenzaldehyde to rats were very similar. No parent compound was recovered from the rat urine. 2-Chlorohippuric acid was the principal urinary metabolite. Quantitatively, the urinary excretion of 14C-2-chlorobenzyl alcohol following cutaneous application differed substantially from that after the systemic administration. There was no evidence of storage in the skin or skin toxicity of 2-chlorobenzaldehyde following cutaneous application.

Why do doping control labs need a tandem mass spectrometer?

The International Olympic Committee requires a confirmation by gas chromatography/mass spectrometry for all positive doping cases. Because of the severe consequences involved they should be more specific about the required information and determine the differences allowed. The use of tandem mass spectrometry in dope control should be required before the Olympic Games in Barcelona in 1992. This article shows the power of tandem mass spectrometry in the definite identification of a drug.

The problems of oral contraceptives in dope control of anabolic steroids.

PIP: Caution should be practiced with oral contraceptives in dope control of anabolic steroids. Research in the Netherlands has shown that there are problems in the area of dope control of anabolic steroids: 1) when the oral contraceptive norethisterone is introduced, it changes within the body to a small amount of 19-norandrosterone, the primary metabolite of the anabolic steroid 19-nortetosterone. As a result, this transformation makes it hard to detect the origin of 19-norandrosterone. The derivatives of the main metabolite of norethisterone and methenolone have similar retention times and mass fragments, making screening difficult. The main metabolite of norethisterone also interferes with methenolone, another anabolic steroid. However, the latter problem is a solvable one. The derivatisation process used to confirm the use of methenolone is described. More testing of urine samples after sporting events will be presented in a successive report. A gas chromatography-mass spectrometry process for detecting and confirming metabolites is recommended by the Medical Commission of the International Committee.^ieng

The pharmacokinetics of intradural morphine in major abdominal surgery.

The pharmacokinetics of intradural morphine used for major abdominal surgery were evaluated. Lumbar spinal fluid and plasma concentrations were measured at intervals after morphine 0.05 mg/kg had been injected intradurally in 21 patients scheduled for elective abdominal aortic surgery. The CSF morphine concentrations were fitted by a biexponential function. A non-compartmental model based on statistical moment theory was used for calculating the intradural morphine disposition. Mean residence time was 137 +/- 54.9 minutes, mean initial volume of distribution 15 +/- 5.49 ml, mean volume of distribution at steady-state 42 +/- 18.25 ml and mean clearance 0.34 +/- 0.18 ml/min (0.02 +/- 0.01 L/h). The moments of the morphine concentration-time curves and the pharmacokinetic parameters varied between the patients. They were not significantly different with regard to morphine dosage, or patient sex or age. Free morphine could not be detected in plasma. Morphine-3-glucuronide appeared in plasma at 5 minutes, increased to a maximum at 240 minutes and fell below the detection limit at about 16 hours after morphine administration. Possible clinical causes of interindividual variations in the CSF morphine concentrations and the pharmacokinetics of intradural morphine are discussed.

Simultaneous estimation of nicotine and cotinine levels in biological fluids using high-resolution capillary-column gas chromatography combined with solid phase extraction work-up.

A rapid and sensitive capillary gas-chromatographic method with nitrogen-sensitive detection is reported for the simultaneous analysis of nicotine and cotinine levels occurring in the plasma, saliva, and urine of regular tobacco smokers. The proposed assay has a linear output, has satisfactory accuracy over the range of concentrations of both amines encountered in active smokers, and has also been successful in the analysis of the urine samples of passive smokers. Its lower limit of sensitivity is 0.2 ng of nicotine and 0.5 ng of cotinine per ml of plasma or saliva or per 100 microliters of urine. The beneficial characteristics of the presented method were achieved by the combination of solid phase extraction of 0.1-1.0 ml of fluid specimens, capillary column gas chromatography with splitless injection and nitrogen sensitive detection, and the use of separate, structurally analogous compounds as internal standards for nicotine. The suitability of the assay is shown by plasma concentration-time curves of nicotine and cotinine in a steady smoker during a 24 hours period.