[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.

High cumulative JC virus seroconversion rate during long-term use of natalizumab.

BACKGROUND AND PURPOSE: John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing-remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing. METHODS AND RESULTS: In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti-JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti-JCV antibody index in the non-converting patients during the follow-up. CONCLUSION: The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

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.

Multilayer compression bandaging in the acute phase of deep-vein thrombosis has no effect on the development of the post-thrombotic syndrome.

OBJECTIVE: The purpose of this randomized study was to evaluate the influence of immediate multilayer compression bandages before application of elastic stockings in the acute phase of deep-vein thrombosis (DVT) on development of the post-thrombotic syndrome (PTS). METHODS: Sixty-nine patients with acute symptomatic DVT were randomized to immediate bandaging (n = 34) or no bandaging (n = 35). After reduction of edema sized-to-fit elastic stockings were applied in all patients after 7-14 days. Follow-up visits and non-invasive examinations were planned after 7, 30 and 90 days and 1 year. Venous outflow resistance (VOR) was measured by strain gauge plethysmography. Thrombosis score (TS) and reflux were measured by duplex scanning. After one year patients were evaluated for clinical PTS using both the clinical scale of the CEAP classification and the Villalta score. RESULTS: Improvement of clinical symptoms and decrease of leg circumference was better on day 7 in the bandaging group, but after 1 and 3 months clinical symptoms had improved equally in both groups. In 7 patients in the no-bandaging group a bandage was applied after all because of persistent edema after 10 days. There were no differences in VOR, TS and reflux. Using the CEAP classification the incidence of PTS was 39% in patients with bandages and 42% in patients without bandages (RR 0.91, 95% CI 0.50-1.66). Using the Villalta score the incidence of PTS was resp. 29 and 33% (RR 0.87, 95% CI 0.41-1.8). There was no difference in severity of PTS. CONCLUSION: Immediate multilayer compression bandaging in the acute phase of DVT is effective in reducing edema and complaints in the first week, but has no effect on thrombus regression, valve incompetence and the development of clinical PTS after 1 year.

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.

Enhanced axonal metabolism during early natalizumab treatment in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging. MATERIALS AND METHODS: In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-ß or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter. RESULTS: At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-ß/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased. CONCLUSIONS: Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.

Psychomotor status.

Four case histories are reported, including a review of the available literature since 1956 (35 cases). Contrary to what might be inferred from the limited number of published cases, the actual prevalence of psychomotor status must be much higher, as probably many patients' conditions are mistakingly diagnosed as psychiatric. Neurologic and electroencephalographic examinations are indicated in all patients with an apparently acute psychotic behavior combined with an altered state of consciousness.

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.

Oxidation-reduction (redox) potentiometry in blood in geriatric conditions: a pilot study.

Oxidation-reduction (redox) potentials in blood were measured potentiometrically in 36 elderly people: 26 long-stay patients in a nursing home and 10 healthy elderly people (controls). The geriatric patients were obviously more affected by various chronic geriatric conditions, clearly used more medications, and had much higher quantitative invalidity scores (help index) compared to the control group. The average redox potential (Eh) in the geriatric patients was significantly (p less than 0.001) higher (300 mV +/- 24) than that in the control group (269 mV +/- 19). Repeated measurements showed some intraindividual variability of Eh. The pH in blood and a number of haematological and anthropometrical parameters did not differ significantly, except for the haemoglobin content, which was somewhat lower in the geriatric group (p less than 0.02). Eh did not correlate with the haemoglobin content. In addition, no effects of age or sex on the value of Eh were found. It was concluded that the general physical condition of the geriatric patients could be responsible for an increase of Eh, although drug effects and nutritional factors could not be excluded. Eh can be regarded as a measure for the balance of oxidant and reductant component in tissue fluids. Comparison between the Eh of younger and healthy elderly people indicates that this balance is apparently unaltered in healthy elderly persons, although elderly people may be more susceptible to disturbance by disease conditions, possibly as a result of a decreased homeostatic capacity of the redox balance. As many redox components play a role in the biochemistry of oxy-radicals, one may speculate on the possible value of Eh in relation to oxy-radical tissue damage.

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.

Dysfunctional presynaptic alpha 2-adrenoceptors expose facilitatory beta 2-adrenoceptors in the vasculature of spontaneously hypertensive rats.

Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha 2- and beta 2-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of presynaptic beta 2-adrenoceptors that enhance noradrenaline (NA) release in the portal vein of freely moving, unanesthetized SHR and normotensive Wistar rats (WR) using the beta 2-selective agonist fenoterol. The results show that the presynaptic beta 2-adrenoceptor population in SHR responds to significantly lower dosages of fenoterol than that in WR. The reason for this enhanced action, however, could not be attributed to the beta 2-adrenoceptor itself, nor to a diminished neuronal uptake of NA, but to a diminished responsiveness of the presynaptic alpha 2-adrenoceptor. Stimulation of presynaptic alpha 2-adrenoceptors with oxymetazoline (45 micrograms/min) decreased basal NA levels by 46% in WR and by 3% in SHR. Blockade of alpha 2-adrenoceptors, using 0.5 mg/kg yohimbine, induced a 4.86-fold rise in the basal NA level in WR but only a 1.89-fold rise in SHR. A subsequent dose of fenoterol, however, resulted in a further 2.5- and 2.6-fold rise in WR and SHR, respectively, indicating that there is a normal presynaptic beta 2-adrenoceptor population in the vasculature of SHR.

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.

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)

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.