Influence of treatment with inhalable heroin on pulmonary function.

This study aims to asses the influence of inhalable heroin on pulmonary function in chronic heroin-dependent patients treated with inhalable heroin. Among 32 patients (all cigarette smokers), a spirometric test was conducted at baseline and after an average period of 10 months of treatment with medically prescribed heroin. Patients showed a high frequency of pulmonary dysfunction at baseline [34%, with percentage of forced expiratory volume in 1 s (%FEV1)<80%]. However, after excluding those who started pulmonary treatment (n=2) or who used heroin intravenously only (n=2), no statistically significant differences in %FEV1 between baseline and follow-up were observed (n=28; mean %FEV1 86% at baseline vs. 91% at follow-up; p=0.09). This small and relatively brief study suggests that 10 months of co-prescribed inhalable heroine base does not seem to (further) deteriorate pulmonary function in chronic, cigarette smoking treatment refractory heroin addicts. Screening for and treatment of pulmonary dysfunction is recommended for methadone patients with and without co-prescribed heroin.

Increased opioid release in specific brain areas in animals exposed to prenatal morphine and emotional stress later in life.

Prenatal morphine treatment and emotional stress both have been shown to increase sensitivity to reward-related behaviors. It has been postulated that this increased sensitivity to rewarding stimuli may be the result of an enhanced release of endogenous opioids. In the present study, in vivo autoradiography was employed to investigate the endogenous opioid release in specific brain areas in rats. Pregnant animals were exposed to morphine or saline from day 8 of gestation till birth. Development of pups was monitored and play behavior was tested on postnatal day 21. Adult rats were exposed to repeated emotional stress or control treatment for five consecutive days and tested in a small open field 5 days later. [(3)H]-Diprenorphine was injected following this test to investigate endogenous opioid release. Prenatal morphine treatment increased play behavior and endogenous opioid release in a number of cortical and subcortical brain areas after being subjected to an open field challenge later in life. Emotional stress exposure increased locomotor activity in the open field irrespective of the type of prenatal treatment and increased endogenous opioid release in some specific brain areas. It is suggested that the increased release of endogenous opioids in the substantia nigra, the piriform cortex and the septum observed after both types of treatments is related to the increased sensitivity to reward.

Mast cell mediator tryptase levels after inhalation or intravenous administration of high doses pharmaceutically prepared heroin.

BACKGROUND: Opioids like morphine and heroin induce mast cell degranulation in vitro. The release of mast cell mediators like histamine and tryptase may lead to allergic symptoms. In this study it was investigated whether mast cell mediator release also occurs in vivo in addicted patients who participated in a heroin on medical prescription trial, and were under treatment with large doses of heroin in combination with methadone. METHOD: Plasma levels of tryptase, a specific marker for mast cell degranulation, were measured by immuno-assay at baseline and 60 min after heroin administration. Heroin was administered either by intravenous injection (11 subjects) or by inhalation (nine subjects). Single heroin doses varied from 200 to 450 mg. Besides tryptase, the plasma concentrations of heroin, its metabolite morphine and methadone were measured. RESULTS: After heroin injection, the mean tryptase plasma concentration increased dose dependently by on average 23.1% (95% CI 14.6-31.6%). After heroin inhalation, no tryptase release was observed. Heroin and morphine peak plasma concentrations were 3-5 times greater in heroin injectors than in inhalers. In heroin injectors, tryptase levels were related to morphine peak concentrations, but not to heroin concentrations. Tryptase plasma concentrations were not related to methadone levels. Mild allergic reactions were reported in five cases after intravenous heroin use, but not after inhalation. CONCLUSION: This study revealed that mast cell mediator tryptase concentrations increase after intravenous heroin injection in chronic opioid users, but not after heroin inhalation. This may be explained by the higher Cmax levels of metabolite morphine that were achieved after injection than after inhalation. Although statistical significance was reached, the degree of mast cell degranulation after intravenous injection of heroin was mild, and did not lead to clinically relevant side effects in this group of opioid-tolerant subjects.

Volatilisation of diacetylmorphine: in vitro simulation of 'chasing the dragon'.

In preparation for a trial on co-prescription of heroin to chronic treatment-resistant addicts, a pharmaceutical dosage form for smokable heroin was developed. During development of this product (a mixture of diacetylmorphine and caffeine), in vitro experiments were performed simulating 'chasing the dragon': the technique used by addicts for inhalation of heroin after volatilisation. Samples were heated on aluminium foil using a heating device and the vapours were collected and analysed using a HPLC-UV method. The recovery of diacetylmorphine and caffeine in vapours was studied after volatilisation of different powder mixtures at temperatures between 200 and 350 degrees C. Furthermore, the volatilisation set-up was combined with an Andersen sampler to determine the sizes of aerosol particles. Only small differences in recovery of diacetylmorphine and caffeine were found between temperatures and between powder mixtures: 46-62% of diacetylmorphine from the sample was recovered in vapour and 65-83% of caffeine. The only degradation product detected in vapour was 6-acetylmorphine (4.1-7.1%). In the temperature range studied, temperature mainly influenced the volatilisation rate. Mass median aerodynamic diameters of aerosols from diacetylmorphine-containing samples ranged from 1.8-4.1 microm; 45-60% of each sample was recovered as aerosol particles <5 microm. Volatilising pharmaceutical smokable heroin resulted in sufficient amounts of diacetylmorphine in vapour and in particles suitable for effective deposition in the lungs.

Contact allergy and respiratory/mucosal complaints from heroin (diacetylmorphine).

After the start of heroin (diacetylmorphine)-assisted treatment to a selected group of chronic treatment-resistant heroin-dependent patients in the Netherlands, we reported about work-related eczema and positive patch tests to heroin in some nurses and nasal and respiratory complaints. To investigate the prevalence of heroin contact allergy, we started a questionnaire-based study with follow-up by allergological examinations. Of 120 questionnaires sent, 101 (84%) was returned: 67 from nurses and 34 from other employees. Of 101 workers, 38 (38%) had reported work-related complaints: 33 of 67 (49%) nurses and 5 of 34 (15%) other employees. Patch tests to heroin were performed in 24 nurses and were positive in 8 (33%). All the 8 had eyelid or facial eczema and, in 6, accompanied by mucosal or respiratory complaints. The prevalence of heroin contact allergy in this study was 8% (8/101) among all employees and 12% (8/67) among nurses. Respiratory and mucosal complaints could not be ascribed to a contact allergy, and in these cases, serum was analysed for specific immunoglobulin E to heroin. A type 1 allergy to heroin could not be shown. These complaints are possibly due to the histamine-liberating effect of heroin, to atopic constitution, to a combination of these factors or - less likely - to other non-allergic factors.

Comparison of randomization techniques for clinical trials with data from the HOMERUS-trial.

BACKGROUND: Several methods of randomization are available to create comparable intervention groups in a study. In the HOMERUS-trial, we compared the minimization procedure with a stratified and a non-stratified method of randomization in order to test which one is most appropriate for use in clinical hypertension trials. A second objective of this article was to describe the baseline characteristics of the HOMERUS-trial. METHODS: The HOMERUS population consisted of 459 mild-to-moderate hypertensive subjects (54% males) with a mean age of 55 years. These patients were prospectively randomized with the minimization method to either the office pressure (OP) group, where antihypertensive treatment was based on office blood pressure (BP) values, or to the self-pressure (SP) group, where treatment was based on self-measured BP values. Minimization was compared with two other randomization methods, which were performed post-hoc: (i) non-stratified randomization with four permuted blocks, and (ii) stratified randomization with four permuted blocks and 16 strata. In addition, several factors that could influence outcome were investigated for their effect on BP by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: Minimization and stratified randomization did not lead to significant differences in 24-h ABPM values between the two treatment groups. Non-stratified randomization resulted in a significant difference in 24-h diastolic ABPM between the groups. Factors that caused significant differences in 24-h ABPM values were: region, centre of patient recruitment, age, gender, microalbuminuria, left ventricular hypertrophy and obesity. CONCLUSION: Minimization and stratified randomization are appropriate methods for use in clinical trials. Many outcome factors should be taken into account for their potential influence on BP levels. Recommendation. Due to the large number of potential outcome factors that can influence BP levels, minimization should be the preferred method for use in clinical hypertension trials, as it has the potential to randomize more outcome factors than stratified randomization.

Chronic cocaine injections attenuate behavioral response of kappa-opioid receptors to U-50,488H agonist.

Chronic injections of cocaine (20 mg/kg daily for 10 days) increase activity and decrease anxiety in male C57Bl/6j mice in comparison with animals chronically injected with normal saline. U-50,488H (kappa-opioid receptor agonist; 2.5 mg/kg) produced an anxiolytic effect in animals preinjected with normal saline and had no effect in animals chronically injected with cocaine. Presumably, chronic activation of dopaminergic systems caused by cocaine injections is paralleled by desensitization of kappa-opioid receptor system.

The Dutch heart health community intervention 'Hartslag Limburg': results of an effect study at organizational level.

BACKGROUND: 'Hartslag Limburg', a cardiovascular diseases (CVD) prevention programme, integrates a community strategy and a high-risk strategy to reduce CVD risk behaviours. This article presents the results of the effect evaluation study of the community intervention at the organizational level. Organizational changes were an intermediate goal of the Hartslag Limburg community intervention, as these are assumed to be a prerequisite for changes at the individual level. METHODS: A baseline-post-test control group design was used. The baseline measurement was conducted in 1998 and the post-test measurement in 2001. At baseline, 700 organizations were selected in the Maastricht region, and 577 in a control region. All organizations that were potentially significant agents in health-promoting activities were included. Data on organizational involvement in health-promoting activities were gathered by means of structured questionnaires, and sent to organization representatives by mail. RESULTS: The overall post-test percentage of organizations involved in at least one activity relating to physical activity was higher in the Maastricht region than in the control region. Furthermore, the number of activities per organization involved in activities relating to healthy eating, smoking behaviour or physical activity was higher in the Maastricht region than in the control region at post-test. CONCLUSIONS: This study provided valuable information about organizational involvement in health-promoting activities, as well as important information to consider in future research in this area. Due to the limitations of the study, the importance of measuring change at different social levels in community-based programmes, and the scarcity of effect studies of community interventions at the organizational level, further research on this subject is warranted.

Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice.

There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement.

Early amygdala damage disrupts performance on medial prefrontal cortex-related tasks but spares spatial learning and memory in the rat.

Recent studies have demonstrated that the postnatal development of connections between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) mature around postnatal days 13-15 (pd13-15), whereas these between the BLA and other structures such as the nucleus accumbens and the mediodorsal thalamus are completed by pd7. Accordingly, it is hypothesized that mPFC cytoarchitecture and hence its function may be specifically affected by neonatal (i.e. on pd7) but not later induced (i.e. on pd21) damage to the BLA. To test this hypothesis, rats received excitotoxic lesions to the BLA on either pd7 or pd21 and were subjected to two tests putatively sensitive to mPFC dysfunction, namely food hoarding and spontaneous alternation. In addition, rats were tested for spatial learning and memory, to determine any possible effects on hippocampal function. Consistent with the documented effects of mPFC lesions, pd7 damage to the BLA impaired spontaneous alternation and food hoarding performance, an effect that was not found in rats with BLA lesions induced on pd21. Spatial learning and memory, however, were not affected by the (neonatal) lesion procedure. Together, these results indicate that neonatal BLA damage affects species-specific sequential behavior and flexibility, which may be attributed to abnormal functioning of the mPFC.

Development and manufacture of diacetylmorphine/caffeine sachets for inhalation via 'chasing the dragon' by heroin addicts.

In 1998, two clinical trials were started in The Netherlands to evaluate the effect of coprescription of heroin and methadone on the mental and physical health and social functioning of chronic, treatment-resistant, heroin-dependent patients. Since 75-85% of the heroin addicts in The Netherlands use their heroin by "chasing the dragon," one of the two study arms concerned the coprescription of inhalable heroin. A pharmaceutical dosage form for inhalable heroin was developed for this trial, consisting of a 3:1 powder mixture of diacetylmorphine base and caffeine anhydrate. We describe the manufacturing process that was developed for filling sachets with this mixture in four dosages using a micro dose auger filler. In order to control product quality, in-process controls were developed to monitor the filling process and quality control tests were performed on the finished product. In-process control results have shown the filling process to be accurate and precise. The diacetylmorphine/caffeine sachets were shown to comply with the specifications for content and uniformity of mass. The finished product was found to be stable for 2 years when stored at 25 degrees C, 60% relative humidity and for 6 months when stored at 40 degrees C, 75% relative humidity.

Asymptomatic peripheral arterial occlusive disease predicted cardiovascular morbidity and mortality in a 7-year follow-up study.

OBJECTIVE: Asymptomatic peripheral arterial occlusive disease (PAOD) is a common atherosclerotic disorder among the elderly population. Scarce data are available on the risk of nonfatal and fatal cardiovascular diseases in these subjects. We investigated cardiovascular morbidity and mortality of asymptomatic PAOD subjects. STUDY DESIGN AND SETTING: A sample of 3649 subjects (40-78 years of age) was selected in collaboration with 18 general practice centers and followed up after the initial screening (mean follow-up time 7.2 years). Asymptomatic PAOD was determined by means of the ankle-brachial pressure index (ABPI). Main outcome measures were nonfatal cardiovascular events and mortality. RESULTS: Cox proportional hazard models showed that asymptomatic PAOD was significantly associated with cardiovascular morbidity (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3-2.1), total mortality (HR 1.4, 95% CI 1.1-1.8), and cardiovascular mortality (HR 1.5, 95% CI 1.1-2.1). CONCLUSION: Asymptomatic PAOD is a significant predictor of cardiovascular morbidity and mortality. In high-risk subjects, measurement of the ABPI provides valuable information on future cardiovascular events.

['Pharmacologic interventions in drug addiction': an advisory report from the Health Council of the Netherlands]. / 'Medicamenteuze interventies bij drugverslaving'; een advies van de Gezondheidsraad.

Addiction is a relapsing brain disease with a tendency towards chronicity. Biological, psychological and socio-cultural factors play a role in the onset and course of this disease. The Health Council of the Netherlands has issued a report on pharmacotherapeutic interventions. The treatment of addiction should be regarded as a medical intervention. A growing number of effective pharmacotherapies are becoming available for the treatment of heroin addiction, although not all of those are available in the Netherlands. Currently, no effective pharmacotherapies are available for the treatment of cocaine addiction. In polydrug addicts, pharmacotherapeutic interventions should be directed at the various separate addictions. In the majority of cases pharmacotherapy is part of an integrated treatment approach in which supportive psychosocial interventions are also important. The long-term continuation of treatment is usually indicated. The Health Council recommends that addiction physicians be put in charge of the multidisciplinary treatment. Medical schools should pay attention to the practical aspects of the treatment and management of addicts. The organisation and workforce of addiction treatment services should comply with the demands that are placed upon healthcare services. Public information campaigns about addiction and the treatment options for addicts can contribute to the destigmatisation of this patient category.

Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia.

Phencyclidine (PCP) has been described to exacerbate psychotic symptoms in patients suffering from schizophrenia. In rats, PCP, dose-dependently, induces hyperactivity, stereotyped behaviour and social isolation, postulated to represent the positive (hyperactivity, stereotypy) and negative (social isolation) symptoms of schizophrenia. Based on previous studies, ibotenic acid lesions in the amygdala on day 7 of life have been proposed as an animal model of psychiatric neurodevelopmental disorders like schizophrenia. The purpose of the present study was to determine whether the responsiveness to PCP on locomotor activity in animals lesioned in the amygdala on day 7 of life is different from the response to this drug in sham-operated animals. The effect of graded doses of PCP on behaviour was assessed in a small open field. Animals lesioned in the amygdala on day 7 of life appeared to be hyperresponsive to PCP compared to sham-operated animals. The hyperresponsiveness to PCP in rats lesioned in the amygdala on day 7 of life further contributes to the validation of this putative animal model of schizophrenia.

Changing world, changing doctors, changing education!

Future developments in the community will underline the need to provide a community-oriented health care system in which public health doctors collaborate with general practitioners, as the hospital-based health care system that currently exists in many countries will not be able to solve the problems of health care in the future. Increasing populations, increasing mobility all over the world, spread of new diseases (aids/hiv and ebola virus for example) will have great impact on our societies and the expectations of the societies and patients of their doctors. Most societies in which our young doctors will serve, expect their adults to live on healthily into their 80th. That means that the society of the future will be a double aging society (more older people who are older than before) with all concomitant burdens of degenerative chronic diseases. How should we handle the problems in 2025 when our capacities stay restricted to what we once learned in 2002? For this purpose the medical faculties have to change their curricula. The medical faculties will have to educate different kind of doctors, different from the doctors they have educated for many decades. These doctors must collaborate with other health care workers in primary health care teams. Collaboration in these teams requires mutual trust, win-win situations and agreement on the principles of health promotion programs. Only by collaboration between public health care and individual, personal health care it will be possible to achieve unity for health for all people. In the future both public health doctors and general practitioners need each other's complementary support and since they share the same area of interest, they need to work together.

ERK1/2 activation in rat ventral tegmental area by the mu-opioid agonist fentanyl: an in vitro study.

Opioid receptors in the ventral tegmental area, predominantly the mu-opioid receptors, have been suggested to modulate reinforcement sensitivity for both opioid and non-opioid drugs of abuse. The present study was conducted to study signal transduction proteins, which may mediate the functioning of mu-opioid receptors in the neurons of the ventral tegmental area. Therefore, brain slices of the ventral tegmental area were exposed in vitro to the specific mu-opioid agonist fentanyl and immunohistochemically stained for four different activated proteins using phospho-specific antibodies. Fentanyl dose-dependently activated extracellular signal-regulated protein in brain slices of the ventral tegmental area. This activation was reversible with naloxone. Furthermore, naloxone itself also activated extracellular signal-regulated protein kinase. Under the present conditions fentanyl did not affect extracellular signal-regulated protein kinase 1 and 2, Stat and cyclic AMP-response element-binding protein activity. The direct activation of extracellular signal-regulated protein kinase in ventral tegmental area slices by the mu-opioid agonist fentanyl may suggest a role of extracellular signal-regulated protein kinase in reward processes.

[Involvement of kappa-opioid receptors in mechanisms of aggressive and submissive types of behavior in male mice]. / Vovlechenie opioidnykh kappa-retseptorov v mekhanizmy formirovaniia agressivnogo i submissivnogo tipov povedeniia u samtsov myshei.

Effects of the kappa-opioid receptor agonist U-50.488H (0.0, 0.6, 1.25, 2.5 mg/kg. s.c., 30 min) on behavior of the winner with repeated experience of victories and the losers with repeated experience of social defeat in 20 daily agonistic confrontations as well as the control mice were investigated in the tests estimating exploratory activity (open-field) and communication (partition test). Different effects of drug on behaviors of animals with different social story were shown in both tests. In the losers, all doses of U-50.488H had anxiolytic effect, increasing the communication in the partition test. In the winners, the drug induced an increase of aggressive motivation. The control mice were less sensitive to the treatment. In the open-field test, U-50.488H increased the locomotor and exploratory activity in high anxious losers. Winners significantly differed in their reaction to drug treatment in most behavioral forms in comparison with the controls and losers. It was concluded that kappa-opioid receptors are specifically involved into mechanisms of formation of aggressive or submissive types of behaviors under positive or negative social experience.