[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.

Cannabinoids with a propyl side chain in cannabis: occurrence and chromatographic behavior.

Neutral cannabinoids with a pentyl side chain-for example, cannabidiol, tetrahydrocannabinol, and cannabinol-are generally accompanied by homologs with a propyl side chain, of which at least one has psychotropic activity. Samples of hashish and marihuana from Asia especially sometimes have abundant amounts of propyl cannabinoids, the quantities being of the same order as that of the accompanying pentyl cannabinoids. Detection and identification of the propyl and pentyl cannabinoids in gas chromatography and thin-layer chromatography is discussed.

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.

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.

Cigarette smoking pharmacokinetics and its relationship to smoking behaviour.

The yield of a cigarette is determined by the tobacco blend, the length of the cigarette, the cigarette paper, the filter and air dilution. Cigarette yield has been defined by tradition and by law to be the yield of nicotine, tar and carbon monoxide obtained from a 35 ml puff volume of 2-second duration taken every minute during the burning time of the cigarette. Normally smokers draw a puff into their mouth and then inhale. Mouth delivery is largely determined by personal smoking behaviour. The puff volume, number of puffs taken per cigarette, and number of cigarettes smoked per day determine both the volume and the mass of daily mouth delivery. There are marked differences in smoking behaviour, and the delivery is substantially altered from the yield values obtained with the standardised test procedure. Body uptake of smoke ingredients is determined by smoke chemical parameters, smoker inhalation behaviour, lung morphology, and physiological parameters. The physiological parameters include tidal volume, vital capacity, rate of breathing, and rate of clearance for the lung. Given these behavioural and physiological differences in individual delivery and uptake it is not surprising that differences in measured parameters occur within smokers of cigarettes with a particular yield. Biological differences among individuals, such as metabolic and size differences, cause additional variations in these values. Therefore, the estimates of nicotine and tar delivery can vary widely in studies of individual uptake when the estimates are based upon sample population data. The variables in both smoking behaviour and in chemical and physiological factors which alter uptake make it essential to have a crossover design for any study. The large standard error for the plasma concentration of cotinine (a major metabolite of nicotine) within a sample population, and the log linear nature of the plasma cotinine concentration curve, requires a very large sample size for any study of cigarette delivery or uptake. When comparisons of brands are made, average values are misleading in that the skew to the high values obscures frequency differences among the lower values within the samples. It is important to remember that smoker compliance with study design is very essential.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

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)

Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity.

The effects of local injections of drugs into terminal areas of the mesolimbic dopamine system were investigated. Bilateral administration of dopamine, but not of noradrenaline and serotonin, into the nucleus accumbens of non-pretreated rats resulted in stimulation of locomotor activity. No clear or only minor effects were seen after injections of the dopamine metabolites 3-methoxytyramine, DOPAC and HVA and after injections of media with different pH and osmolality. d-Amphetamine proved more effective than dopamine in producing locomotor stimulation, whereas both stimulant and depressant effects were observed following injection of apomorphine into the nucleus accumbens. ET 495 and the noradrenaline agonists clonidine, phenylephrine and isoprenaline did not enhance locomotor activity, but theophylline was effective. Pretreatment with haloperidol, but not with clozapine, significantly reduced the effects of dopamine and theophylline. Locomotor stimulation was also found following bilateral administration of dopamine, d-amphetamine and apomorphine into the tuberculum olfactorium, whereas noradrenaline, serotonin and ET 495 produced no, or rather depressant effects. These results provide further evidence for an important role of the mesolimbic dopamine system with respect to locomotor activity.

Separation of inhibiting and stimulating effects of morphine on self-stimulation behaviour by intracerebral microinjections.

The effects on self-stimulation behaviour of 5 mug morphine HCl applied into the ventricular system and into different areas throughout the brain were studied. Injections into the ventricular system and in areas intermediate between the posterior hypothalamus and the periaqueductal grey matter had biphasic effects: an inhibition followed by an excitation. Injections into the posterior hypothalamus resulted in increased self-stimulation whereas injections into the periaqueductal grey matter and into the locus coeruleus were only inhibiting.

The nucleus accumbens of rats and dopaminergic mechanisms regulating locomotor behaviour.

Dopamine and (3,4-dihydroxyphenylamino)-2-imidazoline (DPI) were injected into the nucleus accumbens of rats locally pretreated with ergometrine. The results show that the ergometrine-induced locomotor activity is inhibited by both compounds suggesting that ergometrine inhibits certain types of dopamine receptors. The data are discussed in terms of distinct types of dopamine receptors.

Chemistor: a reusable telestimulation device for direct chemical stimulation of the nonhuman primate brain in freely moving animals.

A reusable telemetric multi-injector unit (chemistor) suitable for injections into the brain of primates has been developed and tested in chronic experiments with rhesus monkeys freely moving and interacting with other monkeys. The chemistor unit, which measures 15.0 by 15.0 by 7.5 mm and weight 5.8 g, consists of a microinjector, equipped with an internal mechanical power source, and an electronic circuit connected with a receiving coil; a total volume of 27.0 mul to be injected in quanta of 0.9 mul at freely chosen time intervals makes this unit suitable for 30 injections. The desirable protection against possible damage is provided by a circular, head-mounted container (dia. 43.0 mm and 10.3 mm high) which leaves place for two complete chemistors. The device is small, light in weight, reliable and resistant to physical damage.

Differential potentiometric method for determining dissociation constants of very slightly water-soluble drugs applied to the sulfonamide diuretic chlorthalidone.

A renewed application of potentiometric acid-base titrations is described, by which dissociation constants of practically water-insoluble drugs can be measured accurately. The method uses the difference in the amount of titrant between a suitable aqueous solvent and a solution of the drug in that solvent. Such potentiometric difference titrations were conducted on a 3.7 X 10(-4) M solution of chlorthalidone in 0.1 M aqueous KCl in the pH 3.5--10.6 range at 25 degrees. Nonlinear least-squares regression analysis was applied to the data. From four determinations, a value of 9.24 +/- 0.02 (mean +/- SEM) resulted for the apparent dissociation constant of the first chlorthalidone acid group. The thermodynamic dissociation constant was calculated at pKa1 = 9.35 (25 degrees) by using a correction for activity.

Subcutaneous injections of apomorphine, stimulus generalization and conditioning: serious pitfalls for the examiner using apomorphine as a tool.

This report shows that stimulus generalization occurs in rats conditioned by a single injection of apomorphine. The data suggest that apomorphine initially acts as an unconditioned stimulus (UCS) of an unconditioned response (UCR) that, in turn, produces stimuli which become conditioned stimuli (CS) of a conditioned response (CR) having a nature identical to that of the UCR. The study also shows that behaviour elicited by a subcutaneous injection of apomorphine depends on the part of the body selected for administration. The mentioned properties should be taken into account when apomorphine is used as a tool in studies on brain and behaviour.

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 and body distribution of amiodarone and desethylamiodarone in rats after oral administration.

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were studied in rats after single oral administration of 100 mg/kg and 200 mg/kg of amiodarone. The time-course of the concentrations of the drug and its main metabolite was determined by high performance liquid chromatography in serum and tissues up to 24 h. The mean absorption half-life of amiodarone was 1.83 h for both dosages and the mean elimination half-life was 15 h after the 100 mg/kg dosage and 105 h after the 200 mg/kg dosage. The mean bioavailability of oral amiodarone ranged from 17% to 60% with an average of 39%. Desethylamiodarone, the major metabolite of amiodarone, was present over the 24 h period of observation in relatively low levels of 30 to 60 ng/ml after the 100 mg/kg dose and 50 to 110 ng/ml after the 200 mg/kg dose respectively, which is circa 4% and 7% of the corresponding parent drug level. Amiodarone is preferentially distributed in decreasing order in lung, liver, thyroid gland, kidney, heart, adipose tissue, muscle tissue and brain. The metabolite desethylamiodarone exhibited a distribution pattern comparable to the parent drug. However, its maximum concentrations in serum and tissues were consistently lower than the corresponding amiodarone concentrations and varied from 18 to 55% (mean 27%), depending on the acute oral dose applied and on the kind of tissue. The amiodarone tissue/serum concentration ratios were high in lung tissue (60-100) and moderate to high in the other tissues except brain (3-60), and indicate an extensive distribution of the drug with the lung as an organ with specific binding sites or uptake mechanisms and adipose tissue as a reservoir with a large storage capacity. The metabolite tissue/serum concentration ratios were very high in lung tissue (500-800), high in renal, thyroid, liver and adipose tissue (80-200) and moderate in the other tissues except for brain (20-60); they indicate a very extensive distribution of desethylamiodarone with, primarily, lung and to some lesser extent kidney, liver and thyroid gland as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. A marked increase in the accumulation of amiodarone and desethylamiodarone was observed in adipose tissue after chronic oral administration, whereas the rise in kidney and brain was less pronounced and in the remaining tissues it was insignificant. Our data suggest that the rat is a good model for describing the single oral dose pharmacokinetics and body distribution of amiodarone and desethylamiodarone in man.

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.

[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.