Effects of chronic paroxetine treatment on dialysate serotonin in 5-HT1B receptor knockout mice.

The role of serotonin (5-HT)1B receptors in the mechanism of action of selective serotonin re-uptake inhibitors (SSRI) was studied by using intracerebral in vivo microdialysis in conscious, freely moving wild-type and 5-HT1B receptor knockout (KO 5-HT1B) mice in order to compare the effects of chronic administration of paroxetine via osmotic minipumps (1 mg per kg per day for 14 days) on extracellular 5-HT levels ([5-HT]ext) in the medial prefrontal cortex and ventral hippocampus. Basal [5-HT]ext values in the medial prefrontal cortex and ventral hippocampus, approximately 20 h after removing the minipump, were not altered by chronic paroxetine treatment in both genotypes. On day 15, in the ventral hippocampus, an acute paroxetine challenge (1 mg/kg i.p.) induced a larger increase in [5-HT]ext in saline-pretreated mutant than in wild-type mice. This difference between the two genotypes in the effect of the paroxetine challenge persisted following chronic paroxetine treatment. Conversely, in the medial prefrontal cortex, the paroxetine challenge increased [5-HT]ext similarly in saline-pretreated mice of both genotypes. Such a challenge produced a further increase in cortical [5-HT]ext compared with that in saline-pretreated groups of both genotypes, but no differences were found between genotypes following chronic treatment. To avoid the interaction with raphe 5-HT1A autoreceptors, 1 micro m paroxetine was perfused locally through the dialysis probe implanted in the ventral hippocampus; similar increases in hippocampal [5-HT]ext were found in acutely or chronically treated wild-type mice. Systemic administration of the mixed 5-HT1B/1D receptor antagonist GR 127935 (4 mg/kg) in chronically treated wild-type mice potentiated the effect of a paroxetine challenge dose on [5-HT]ext in the ventral hippocampus, whereas systemic administration of the selective 5-HT1A receptor antagonist WAY 100635 did not. By using the zero net flux method of quantitative microdialysis in the medial prefrontal cortex and ventral hippocampus of wild-type and KO 5-HT1B mice, we found that basal [5-HT]ext and the extraction fraction of 5-HT were similar in the medial prefrontal cortex and ventral hippocampus of both genotypes, suggesting that no compensatory response to the constitutive deletion of the 5-HT1B receptor involving changes in 5-HT uptake capacity occurred in vivo. As steady-state brain concentrations of paroxetine at day 14 were similar in both genotypes, it is unlikely that differences in the effects of a paroxetine challenge on hippocampal [5-HT]ext are due to alterations of the drug's pharmacokinetic properties in mutants. These data suggest that there are differences between the ventral hippocampus and medial prefrontal cortex in activation of terminal 5-HT1B autoreceptors and their role in regulating dialysate 5-HT levels. These presynaptic receptors retain their capacity to limit 5-HT release mainly in the ventral hippocampus following chronic paroxetine treatment in mice.

Tabaco y medicamentos: ¿amistades peligrosas? / Tobacco and medicaments: dangerous liaison?

El estilo de vida, los hábitos alimentarios, el consumo de bebidas alcohólicas y el tabaco pueden ocasionar ciertas modificaciones en la actividad y/o toxicidad de los medicamentos. Partiendo de un análisis de la literatura científica reciente, los autores han identificado una serie de puntos en lo que concierne a las interacciones entre tabaco y medicamentos, y los mecanismos y las consecuencias terapéuticas de estas interacciones. En cuanto al tabaco, las interacciones farmacodinámicas se deben a la nicotina, mientras que las interacciones farmacocinéticas a los principales compuestos presentes en el humo de los cigarrillos.-Tabaco e interacciones farmacocinéticas: el fenómeno principal, fuente de interacciones medicamentosas, es la inducción de los citocromos 1A1, 1A2, 2E1 por los hidrocarburos aromáticos policíclicos, con una variabilidad interindividual de origen genético.-Tabaco e interacciones farmacodinámicas: la mayor parte de las interacciones objetivadas en el plan biológico no implican una adaptación de la conducta terapéutica. Sin embargo, con ciertos medicamentos, es necesario adaptar la posología o los ritmos de las tomas. Ése es el caso de ciertos antálgicos, antiulcerosos, antiarrítmicos, antidiabéticos o psicótropos.La influencia del tabaco sobre las propiedades farmacológicas de los medicamentos es especialmente difícil de evaluar y todavía se ignoran un sinnúmero de interacciones potenciales. Sería de gran interés realizar más estudios durante el desarrollo de un nuevo medicamento (AU)

[Changes in pharmacists practices (1996 - 2000) related to harm reduction policy (condoms, injecting equipment, methylmorphine) and maintenance therapy delivery (buprenorphine, methadone)]. / Evolution de l'implication du pharmacien d'officine dans la prévention des dommages liés à l'usage de drogues et la dispensation des traitements de substitution.

AIMS: To measure pharmacists involvement in harm reduction programs and in delivery of maintenance therapies in order to estimate their contribution to the new public health policy. METHOD: A longitudinal study was conducted among 327 pharmacies located in the southern suburban area of Paris (28 communities) using a standardized questionnaire. RESULTS: The response rate was 95% in 1996 and 92% in 2000. The number of condoms offered to intravenous drug users (IDU) decreased dramatically from 99% to 24% while delivered units decreased from 857 to 566 per day for needles and from 1200 to 760 per month per pharmacy for methylmorphine tablets (14.93 mg/tablet). Pharmacists delivered injecting equipment to some of their patients under opiate treatment: methylmorphine 19%, buprenorphine 35%, methadone 14%. Their contribution to the local healthcare network on addiction decreased from 38% to 20%. Nevertheless, the pharmacists attitude towards the IDU and public health policy was found to be improving with problems being mentioned for 62% of the cases in 1996 and for 16% in 2000. CONCLUSION: Pharmacists are rapidly and intensively changing their practices and are discovering a new comprehensive relationship with IDU. Better pharmacist involvement is associated with a shift in local healthcare network concentration, reinforcing the general practitioner-pharmacist partnership.

Slow metabolism and long half life of methadone in a patient with lung cancer and cirrhosis.

In a patient on methadone maintenance treatment, admitted for lung cancer suspicion, a slight decrease in pain dose response to morphine have necessitated adjustments of methadone treatment founded on clinical check-up and methadone assay. Plasma methadone concentrations were 4 fold higher than mean plasma concentration for control population at the same dose. Half-life was above 70 hours and clearance and metabolic index were strongly decreased. In this patient, daily dose methadone occurred in progressive accumulation and neuro-physiological tolerance without clinical incidence, except decrease in morphine effectiveness compared to our knowledge. Cancer, cirrhosis and adjuvant therapy contributions (fluconazole, omeprazole) to this original methadone kinetic are discussed. Methadone and morphine dose clinical adjustments are described. However, the main objective of this case report is focused on plasma methadone assay contribution to therapeutic adjustment of the interval dose in a single patient with a complex clinical situation.

[Value of trimeprazine among hypnotics in a psychiatric facility]. / Place de l'alimémazine parmi les hypnotiques dans un établissement de soins psychiatriques.

Trimeprazine (TPZ) has been marketed in France since 1959, as tablets and solution containing respectively 5 mg and 40 mg/ml. TPZ is a phenothiazine derivative with known antihistaminic and sedative effects. The first approved indication for TPZ is in the treatment of allergy. However, its frequent sedative effects are undesirable in this indication. The second approved indication is in the treatment of insomnia (5-20 mg/day) and TPZ is an alternative to conventional hypnotics as diazepam, flunitrazepam, zolpidem, butobarbital... Due to the prescription frequency of this medicine in our hospital, we analyzed the naturalistic prescriptions mode and the clinical end point in patients hospitalized for mental illness. On the one hand, using the hospital prescription software, we analyzed: prescriptions frequency, dose regimen and drug associations with hypnotics, anxiolytics and sedative antipsychotics. On the other hand, we came into contact with physicians in order to know their opinion on TPZ and the whole point of that indication. The results showed a very high prescription frequency (139/400 patients; 35%), a marked increase in dose compared to those approved by the French Drug Administration (5-20 mg/day: 5%; 20-200 mg/day: 95%) and main drug association with hypnotics, tranquilizers or antipsychotics, respectively 38%, 65% and 91%. Clinical end points are: non addictive properties and an easily adequation of posology for the drinkable drop form in contrast with tablets. Thus, TPZ appears as a first-line hypnotic in spite of its adverse effects common to phenothiazine (atropinic and antidopaminergic effects) and is a usefull medicine for the treatment of insomnia in psychotic patients.

Substitution with buprenorphine in methadone- and morphine sulfate-dependent patients. Preliminary results.

In France, during the 1990s, there have been some rapid developments in the treatment of opioid addiction with the introduction of legal substitution agents. Originally, some patients were treated with morphine sulfate, but this was superseded by high dose buprenorphine (Subutex(R)) and methadone. This resulted in those patients originally treated with morphine being transferred to either of these two licensed products. A study investigating the effects of the transition from morphine to either buprenorphine or methadone was undertaken. Supplementary to this, a trial investigating transition between these new compounds was also conducted. The primary outcome measures for these trials were retention rate, which was assessed at 5, 9 and 12 months, and the precipitation of withdrawal symptoms. The studies showed that transferring patients between substitution agents can be accomplished without severe withdrawal symptoms, although specific management may be required for transfer from high doses of methadone to buprenorphine. High long-term retention rates were observed in the studies, with most drop-outs occurring directly after transfer. Results suggest that patients on long-term buprenorphine maintenance therapy may have good compliance in comparison with other agents.

Evolution of plasma homovanillic acid (HVA) in chronic schizophrenic patients treated with haloperidol.

In a 4-week study of 14 drug-free schizophrenic patients (according to DSM-III-R), free and conjugated fractions of plasma homovanillic acid (pHVA) were repeatedly measured. Free HVA levels decreased during the first 2 h of haloperidol intake (P < 0.03). Conjugated HVA levels slowly decreased during the following weeks (P < 0.05), while free HVA levels remained stable. After 4 weeks, free HVA levels remained unchanged 2 h after morning haloperidol intake, but conjugated HVA levels tended to increase. In haloperidol responders, at baseline the free/total HVA ratio was significantly higher than that in non-responders (P < 0.01). Tolerant patients, i.e. those whose post-treatment free HVA levels decreased below pre-treatment levels, were not found to respond better to haloperidol than non-tolerant patients. The balance between free and conjugated pHVA may be a better reflection of the action of haloperidol than free pHVA levels and it may be of prognostic value in terms of drug response.