Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Projecte de legalització d'una activitat dedicada a l'explotació ramadera i a la formatgeria artesanal

La integració en una mateixa activitat d'una explotació ramadera ecològica basada en el bestiar cabrú de llet i d'una formatgeria artesanal basada en varietats autòctones de formatge de cabra, permet ocupar un nínxol de mercat encara poc explotat actualment a Catalunya. D'igual manera, la dificultat que tenen actualment molts dels formatgers artesans del país per trobar llet de cabra en quantitats suficients i amb unes mínimes garanties higiènico-sanitàries dificulten l'avanç d'un sector amb molt bones perspectives de futur com és el de la formatgeria artesanal i justifica la necessitat de crear noves explotacions (o reconvertir-ne de ja existents) orientant-les de ple vers l'aprofitament lleter del bestiar cabrú, que és actualment molt reduït en l'àmbit Català. A més d'això, les actuals exigències en el camp del benestar animal així com en el camp de la qualitat i de la seguretat alimentaria, exigeixen a les explotacions ramaderes i a les indústries alimentàries el compliment d'una sèrie de requisits, tan de disseny dels locals i de les instal•lacions, com de control de les activitats i dels productes elaborats, que garanteixin en tot moment la seva correcte gestió i funcionament en aquestes matèries. L'objectiu d'aquest projecte, doncs, és la legalització d'una activitat, que anomenarem “Mas Peirot, S.L.”, dedicada a l'explotació ramadera ecològica de bestiar cabrú de llet i a la formatgeria artesanal de formatge de cabra. És important mencionar que tot i tractar-se d'un projecte de legalització d'una activitat,, també s'hi han contemplat aspectes i detalls relacionats amb l'execució de la mateixa, al tractar-se d'unes obres d'una certa complexitat i considerant que així es tracten amb més detall i rigorositat les actuacions projectades. En concret, en aquest projecte es planifiquen les operacions de rehabilitació de dues naus ramaderes actualment en desús, per tal que puguin destinar-se a l'explotació ramadera de bestiar cabrú i a la formatgeria artesanal, projectant-se així mateix totes les instal•lacions necessàries per tal que a les mencionades naus s'hi puguin desenvolupar les activitats citades. Com a conclusions més importants d'aquest projecte podem dir que amb un cens de 100 caps de bestiar cabrú és possible obtenir una producció mitjana de llet de 32.500 litres anuals, que es corresponen a un volum total de 3.823 quilograms de formatge a l'any (de les tipologies Formatge Garrotxa i Formatge de cabra amb oli, ambdues varietats tradicionals catalanes) obtenint un benefici de 21.389,47 Euros/any durant els primers 15 anys i un benefici de 33.386,39 Euros/any a partir del 16è any, cosa que permetrà recuperar la inversió inicial de 172.716,76 Euros que valen les naus i instal•lacions projectades, en un termini de 8 anys i permetrà, com s'ha dit, ocupar un nínxol de mercat encara poc explotat per la indústria agroalimentària a Catalunya.

Estudi tècnic-econòmic per a la instal·lació d'una granja d'ànecs per a producció de foie-gras situada en el terme municipal de Fontanals de Cerdanya

Inversors però, principalment professionals de l'àmbit agrari, per tal de buscar una diversificació de l'activitat agrícola i ramadera que desenvolupen a les seves finques, sobretot joves emprenedors, poden estar interessats en produccions alternatives com la producció d'ànecs per a foie-gras, per tal de complementar la seva renda agrària. Actualment cal augmentar la competitivitat de les finques agrícoles per tal que aquestes siguin econòmicament viables. L’objectiu de l'estudi és determinar la viabilitat econòmica d’una explotació ramadera d’ànecs per a la producció de foie-gras, en el terme municipal de Fontanals de Cerdanya, analitzant les diverses alternatives en quant a dimensionament i disseny de les instal·lacions, segons el cicle productiu de l’animal. L'alternativa escollida per realitzar l'estudi es la de semi-integració (cria, engreix i embocat), de règim semi-intensiu (durant l'etapa de l'engreix), amb animals mascles de la raça híbrida Mulard. Les instal·lacions tindran una capacitat de 6.500 animals, amb lots de 250 caps. Aquest dimensionament permet, durant la fase d'embocat, en la qual es requereix més dedicació, que la demanda de mà d'obra pugui ser satisfeta per un únic treballador. La principal conclusió que es pot extreure de l'estudi és que la inversió projectada és massa elevada i que aquesta econòmicament no és viable o rendible, ja que la despesa és massa elevada. Es mouen uns fluxos de caixa molt elevats i el marge comercial és molt reduït. Únicament si l'objectiu del promotor és obtenir una remuneració per la seva feina, sempre i quan és produeixi un augment del preu actual de la carn i una disminució del preu del pinso, es podria recomanar que es portés a terme la implantació de l'explotació, intentant, però, reduir la despesa d'execució de construccions i instal·lacions.

The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine.

The selective serotonin reuptake inhibitor fluoxetine is administered as a racemic mixture, and R- and S-fluoxetine are metabolized in the liver by N-demethylation to R- and S-norfluoxetine, respectively. R- and S-fluoxetine and S-norfluoxetine are equally potent selective serotonin reuptake inhibitors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic fluoxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D6 in vivo and in vitro and recent studies in vivo have shown that racemic fluoxetine is metabolized by CYP2D6. The primary aim of the present study was to investigate the stereoselective metabolism of fluoxetine and norfluoxetine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was administered to six poor and six extensive metabolizers of sparteine. Blood samples were collected during 6 weeks for poor metabolizers and 3 weeks for extensive metabolizers. Once a week a sparteine test was performed. The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereoselective gas chromatography-mass spectroscopy method. In the poor metabolizers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, respectively, the corresponding values in the extensive metabolizers were 36 l/h and 40 l/h, respectively. For both enantiomers, the phenotype difference was statistically significant. In poor metabolizers, the elimination half-lives were 6.9 days and 17.4 days for R- and S-norfluoxetine, respectively, and in the extensive metabolizers it was 5.5 days for both enantiomers, a significant phenotypical difference only for S-norfluoxetine. For fluoxetine the elimination half-lives were 9.5 and 6.1 days in poor metabolizers for the R- and S-enantiomer, respectively. The corresponding values in the extensive metabolizers were 2.6 and 1.1 days, respectively. Also for this parameter, the differences were statistically significant. This study shows that CYP2D6 catalyses the metabolism of R- and S-fluoxetine and most likely the further metabolism of S-norfluoxetine but not of R-norfluoxetine.

The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychotic patients

In this open, 30-day trial, the pharmacokinetics, safety and tolerability of a combination therapy of risperidone (4 or 6 mg/day)and fluoxetine (20mg/day from day 6) were evaluated in 11 psychotic inpatients. CYP2D6 genotyping revealed that 3 and 8 patients were poor metabolizers (PMs) and extensive metabolizers (EMs) of debrisoquine, respectively. The mean (+/- SD) AUC of risperidone increased from 83.1 +/- 46.8 ng.h/ml and 398.3 +/- 33.2 ng.h/ml (monotherapy) to 345.1 +/- 158.0 ng.h/ml (p < 0.05) and 514.0 +/- 144.2 ng.h/ml (p < 0.001) when coadministered with fluoxetine in EMs and PMs, respectively. The AUC of the active moiety (risperidone plus 9-hydroxy-risperidone) increased from 470.0 +/- 170.0 ng.h/ml to 663.0 +/- 243.3 ng.h/ml (p < 0.05)and from 576.3 +/- 19.6 ng.h/ml to 788.0 +/- 89.1 ng.h/ml (ns) in EMs and PMs, respectively. In EMs, the AUC of 9-hydroxy-risperidone remained similar (monotherapy vs. combination therapy: 386.8 +/- 153.0 ng.h/ml vs. 317.7 +/- 125.2 ng.h/ml, ns),whereas it increased in PMs (178.3 +/- 23.5 ng.h/ml vs. 274.0 +/- 55.1 ng.h/ml (p < 0.05)). Ten of the 11 patients showed a clinical improvement (reduction of 20% or more in total PANSS score and 70% on the mean MADRS score compared to baseline). The severity and incidence of extrapyramidal symptoms and adverse events did not significantly increase when fluoxetine was added.

Effects of carbamazepine coadministration on plasma concentrations of the enantiomers of mianserin and of its metabolites.

Concentrations of the enantiomers of unconjugated and of total (unconjugated plus conjugated) mianserin, desmethylmianserin and 8-hydroxymianserin were measured in 12 patients before and after the introduction of carbamazepine. The dose of mianserin was 60 mg/d, carbamazepine was coadministered at 400 mg/d for 4 weeks, and blood samples were taken at weekly intervals after the introduction of carbamazepine. Each week, carbamazepine significantly decreased plasma concentrations of unconjugated and total (S)-mianserin (the more potent enantiomer) and of unconjugated and total (R)-mianserin. On average, plasma concentrations of unconjugated and total (S)-mianserin and of unconjugated and total (R)-mianserin were 55%, 56%, 66%, and 55%, respectively, of the corresponding values before introduction of carbamazepine. These results strongly suggest the involvement of CYP3A4, the major CYP enzyme induced by carbamazepine, in the metabolism of both enantiomers of mianserin. A strong decrease in the concentrations of (S)-8-hydroxymianserin was also measured (on average, the concentrations were 69% of the corresponding values before carbamazepine introduction). Conversely, plasma concentrations of unconjugated and of total (S)-desmethylmianserin, (R)-desmethylmianserin, and (R)-8-hydroxymianserin were only slightly modified by carbamazepine. From a clinical point of view, as a therapeutic window for (S)-mianserin has been recently suggested, the dose of racemic mianserin for a patient whose (S)-mianserin concentrations have been stabilized within this therapeutic window would need to be approximately doubled if carbamazepine, at 400 mg/d, is introduced as a comedication.

When "enough" is not enough: new perspectives on optimal methadone maintenance dose.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

Internet, salud y pacientes bien informados: una buena práctica al alcance de todos

Actualmente los pacientes son cada vez más activos y autónomos, y están mejor informados por lo que se sienten comprometidos con su salud. Ello es debido a la importante presencia de las TIC, que favorecen el uso de Internet como fuente de información, y también a los cambios sociales y culturales que fomentan una nueva relación "profesional de la salud-paciente".Asimismo, la evolución de la sanidad centrada en el paciente conduce a una elección informada del usuario que quiere participar en las decisiones que afectan a su estado de salud.Desde octubre de 2011, en la consulta de enfermería familiar y comunitaria del EAP Mataró-6 de Mataró (Barcelona) se lleva a cabo la actividad de educación para la salud a personas con enfermedades crónicas centrada en la información sobre salud en Internet.

Organic News, March 23, 2010, Vol. 13

Newsletter produced by Iowa Department of Agriculture and Land Stewardship about Organic News in farming.

Organic News, October 28, 2010, Vol. 12

Newsletter produced by Iowa Department of Agriculture and Land Stewardship about Organic News in farming.

State of Iowa Employee Benefits Handbook, November 2010

Examples of the information available include: • Links to health and dental plans • Health plan comparisons • Health and Dependent Care Flexible Spending Account information • Deferred Compensation information • Life and Long Term Disability insurance information • Link to Employee Assistance Program (EAP) Web site • Link to Employee Discount Program • Link to Wellness Web site which includes information about - Smoking Cessation Program - Prescription Drug information - Wellness activities

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

State of Iowa Employee Benefits Handbook, December 2002

Examples of the information available include: • Links to health and dental plans • Health plan comparisons • Health and Dependent Care Flexible Spending Account information • Deferred Compensation information • Life and Long Term Disability insurance information • Link to Employee Assistance Program (EAP) Web site • Link to Employee Discount Program • Link to Wellness Web site which includes information about - Smoking Cessation Program - Prescription Drug information - Wellness activities

State of Iowa Employee Benefits Handbook, December 2002

Examples of the information available include: • Links to health and dental plans • Health plan comparisons • Health and Dependent Care Flexible Spending Account information • Deferred Compensation information • Life and Long Term Disability insurance information • Link to Employee Assistance Program (EAP) Web site • Link to Employee Discount Program • Link to Wellness Web site which includes information about - Smoking Cessation Program - Prescription Drug information - Wellness activities

Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.

OBJECTIVE: The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. RESULTS: Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.