Group schema-focused therapy enriched with psychomotor therapy versus treatment as usual for older adults with cluster B and/or C personality disorders: a randomized trial.

BACKGROUND: Several types of psychotherapy have been proven successful in the treatment of personality disorders in younger age groups, however studies among older patients are lacking. We developed a group schema-focused therapy (SFT) enriched with psychomotor therapy (PMT) for older adults with cluster B and/or C personality disorders. This paper describes the design of a randomized controlled trial (RCT). We will evaluate the (cost-)effectiveness of this therapy protocol in specialized mental health care. We hypothesize that our treatment program is cost-effective and superior to treatment as usual (TAU) in reducing psychological distress and improving quality of life in older adults treated to specialized mental healthcare. METHODS: A multicenter RCT with a one-year follow-up comparing group schema-focused therapy enriched with psychomotor therapy (group SFT + PMT) and TAU for adults aged 60 years and older who suffer from either a cluster B and/or C personality disorder. The primary outcome is general psychological distress measured with the 53-item Brief Symptom Inventory. Secondary outcomes are the Schema Mode Inventory (118-item version) and the Young Schema Questionnaire. Cost-effectiveness analysis will be performed from a societal perspective with the EuroQol five dimensions questionnaire and structured cost-interviews. DISCUSSION: This study will add to the knowledge of psychotherapy in later life. The study specifically contributes to the evidence on (cost-) effectiveness of group SFT enriched with PMT adapted to the needs of for older adults with cluster b and/or c personality. TRIAL REGISTRATION: Netherlands Trial Register NTR 6621 . Registered on 20 August 2017.

Gender differences in the treatment of patients with acute myocardial infarction. A multihospital, community-based perspective.

OBJECTIVE: As part of a community-wide study examining temporal trends in the incidence and survival rates of acute myocardial infarction, we examined differences between the sexes in overall utilization rates and changes over time, therein, of various therapies used in the management of acute myocardial infarction. DESIGN: Nonconcurrent prospective study. PATIENTS: Three thousand three hundred sixty-one men and 2119 women hospitalized with validated acute myocardial infarction in 16 hospitals in the Worcester, Mass, metropolitan area during 1975, 1978, 1981, 1984, 1986, 1988, and 1990. RESULTS: After controlling, by means of a logistic regression analysis, for a variety of patient-related factors that could affect physician prescribing patterns, women were significantly more likely to receive diuretics during hospitalization for acute myocardial infarction, whereas men were significantly more likely to receive antiplatelet agents, lidocaine, and other antiarrhythmic agents. No statistically significant differences were seen between men and women with regard to the use of anticoagulants, beta-blockers, calcium channel blockers, digoxin, nitrates, and thrombolytic agents. Marked increases over time (1975 through 1990) were seen in the use of anticoagulants, antiplatelet agents, beta-blockers, lidocaine, and nitrates in each of the sexes, while declines were seen in the use of digoxin and diuretics. Use of thrombolytic therapy increased between 1986 and 1990, whereas use of calcium channel blockers decreased over this period for both men and women. CONCLUSIONS: The results of this multihospital, population-based, observational study suggest that physician practice patterns in the pharmacologic treatment of men and women hospitalized with acute myocardial infarction are very similar.

Formation of meprobamate from carisoprodol is catalysed by CYP2C19.

Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.

Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes.

Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of debrisoquine and 4-hydroxydebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h. However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxydebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxydebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for debrisoquine to 4-hydroxydebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that the same situation also applies to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates.

Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine.

OBJECTIVE: To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamic (heart rate, accommodation, and salivation) of tolterodine and its 5-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine). METHODS: Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period. Doses were given as the tartrate salt. The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamic were measured. RESULTS: The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 +/- 2.1 l/hr) compared with extensive metabolizers (44 +/- 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001). The terminal half-life of the 5-hydroxymethyl metabolite (2.9 +/- 0.4 hours) was slightly longer than that of the parent compound (2.3 +/- 0.6 hours) among extensive metabolizers, but the 5-hydroxymethyl metabolite was undetectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in both panels. The decrease occurred when the concentration of unbound tolterodine and 5-hydroxymethyl metabolite among extensive metabolizers was comparable with that of tolterodine among poor metabolizers. CONCLUSIONS: Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite.

10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.

OBJECTIVE: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxy-nortriptyline line in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional C gamma P2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates. METHODS: Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN; debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CY2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. RESULTS: There was a clear relation between the C gamma P2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio both correlated significantly with the debrisoquin metabolic ratio (rS = -0.89, p = 0.0001; rS = 0.92, p = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline. CONCLUSION: The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes.

OBJECTIVES: To study the impact of the CYP2D6*10 allele on the disposition of nortriptyline in Chinese subjects. METHODS: A single dose of 25 mg nortriptyline was given orally to 15 healthy Chinese volunteers who were classified as extensive metabolizers after phenotyping with debrisoquin (INN, debrisoquine) and who were genotyped by allele-specific polymerase chain reaction. Five subjects were homozygous for CYP2D6*1, 5 subjects were homozygous for CYP2D6*10, and 5 subjects were heterozygous for these 2 alleles. Plasma concentrations of nortriptyline and its main metabolite 10-hydroxynortriptyline were measured by liquid chromatography-mass spectrometry, and the pharmacokinetics were studied during 168 hours after the dose. RESULTS: Subjects who were homozygous for CYP2D6*10 had significantly higher total areas under the plasma concentration-time curve (AUC), lower apparent oral clearances, and longer mean plasma half-life of nortriptyline than subjects in the CYP2D6*1/*1 and the heterozygous groups. For 10-hydroxynortriptyline, the AUC was lower and the plasma half-life was longer in subjects who were homozygous for CYP2D6*10 than in subjects in the other 2 groups. CONCLUSION: The CYP2D6*10 allele in Chinese subjects was associated with significantly higher plasma levels of nortriptyline compared with the CYP2D6*1 allele because of an impaired metabolism of nortriptyline to 10-hydroxynortriptyline, particularly in the subjects with the CYP2D6*10/*10 genotype. The results suggest that genotyping of CYP2D6 may be a useful tool in predicting the pharmacokinetics of nortriptyline.

Patient delay and receipt of thrombolytic therapy among patients with acute myocardial infarction from a community-wide perspective.

The duration of patient delay from the time of onset of symptoms of acute myocardial infarction (AMI) to hospital presentation, and the relation of delay time and various patient characteristics to receipt of thrombolytic therapy were examined as part of a community-based study of patients hospitalized with AMI in the Worcester, Massachusetts, metropolitan area. In all, 800 patients with validated AMI hospitalized at 16 hospitals in the Worcester metropolitan area in 1986 and 1988 constituted the study sample. Patients delayed on average 4 hours between noting symptoms suggestive of AMI and presenting to area-wide emergency departments with no significant change observed between 1986 and 1988. The shorter the time interval of delay, the greater the likelihood of receiving thrombolytic therapy; patients arriving at the emergency department within 1 hour of the onset of acute symptoms were approximately 2.5 and 6.5 times more likely to receive thrombolytic agents than were those presenting to the hospital between 4 and 6, and greater than 6 hours, respectively, after the onset of symptoms. Results of a multivariate analysis showed increasing length of delay, older age, history of hypertension or AMI and non-Q-wave AMI to be significantly associated with failure to receive thrombolytic therapy.

Live bacterial delivery systems for development of mucosal vaccines.

By expression of foreign antigens in attenuated strains derived from bacterial pathogens and in non-pathogenic commensal bacteria, recombinant vaccines are being developed that aim to stimulate mucosal immunity. Recent advances in the pathogenesis and molecular biology of these bacteria have allowed rational development of new and improved bacterial carriers and more effective gene expression systems. These advances have improved the performance and versatility of these delivery systems to induce mucosal immunity to recombinant antigens in animal models. Application of these (improved) technologies for development of human vaccines is still limited and awaits further exploration.

Pathogenicity of Peptostreptococcus micros morphotypes and Prevotella species in pure and mixed culture.

Recently, an atypical rough colony morphotype of Peptostreptococcus micros, a species which is found in ulcerating infections, including periodontitis, was isolated. The virulence of morphotypes alone and in combination with Prevotella intermedia and P. nigrescens was investigated both in vivo and in vitro. All strains tested induced abscesses containing fluid pus in a mouse skin model, and lesions caused by monocultures of the rough morphotype strains of P. micros were statistically significantly larger than those induced by the smooth morphotype strains. Inocula containing both morphotypes produced similar sized abscesses compared to mono-inocula containing the same bacterial load. Both Prevotella species induced small abscesses when inoculated alone, and when Pr. nigrescens was inoculated with one of the other strains, the abscesses were not significantly different from the abscesses induced by the mono-infections of this strain. Synergy, in terms of higher numbers of colony forming units (cfu) in the mixed inocula, was found for all combinations of the rough morphotypes of P. micros and both Prevotella spp. Pus from abscesses caused by combinations of Peptostreptococcus and Prevotella spp. transmitted the infection to other mice, but no abscesses were formed in mice inoculated with pus induced by mono-inocula. These results demonstrated synergic activity between both rough and smooth P. micros strains and oral Prevotella strains. The in-vitro co-culture experiments produced no evidence of growth stimulation. The effect of P. micros strains on the immune system was investigated by testing their ability to initiate luminol-dependent chemiluminescence of polymorphonuclear leucocytes in the presence and absence of human serum. In the latter, the rough morphotype strains initiated higher counts than the smooth morphotype strains. Further work is needed to elucidate the difference in virulence between the smooth and the rough morphotype cells of P. micros and the nature of the interaction with the Prevotella spp.

Does age incidence explain all season-of-birth effects in the literature?

Lewis (1989) has suggested that the effect of so-called age incidence on season-of-birth data may be a sufficient explanation of the anomalies found in many samples of schizophrenic patients. Various predictions made by Lewis do not agree, however, with data available from some of the sources he quoted. Age incidence can be a source of error when a small age difference has a considerable effect on the likelihood of being included in a sample. Depending on methods of ascertainment, this is unusual in empirical studies.

Is the familial/sporadic subdivision a method of genetics?

Subdividing a sample of patients on the basis of family history into familial and sporadic cases is a simple research method whose purpose is often misunderstood. What it can do is to reveal etiological heterogeneity by refuting a hypothesis of homogeneity. If familial cases prove to be different from sporadic cases in some respect, the question of a refutation arises. Homogeneity is usually assumed in genetic work on schizophrenia. This assumption is also widespread outside genetic circles, but it is not necessarily true. If it is false, research into the causes of schizophrenia must be redirected. The author claims that the use of familial/sporadic subdivisions is a clinical research method that does not require genetic expertise. Geneticists may frown upon it for its lack of sophistication, but the important thing is whether it works in actual attempts to refute the homogeneity view.

Comparative characterization of the leukocidic and hemolytic activity of Moraxella bovis.

The cytotoxic effect of Moraxella bovis 118F on bovine neutrophils was evaluated and characterized by use of a 51Cr release assay. Neutrophils harvested from healthy adult cattle were labeled with 51Cr. The leukocidic activity produced by M bovis 118F, a hemolytic strain of M bovis, was heat-labile. A live culture of strain 118F, at a ratio of 100 bacteria/neutrophil, released 97.7% of the 51Cr from labeled neutrophils. Neither a heat-killed preparation of M bovis 118F nor a live or heat-killed preparation of M bovis IBH63 (a nonhemolytic and nonpathogenic strain) induced significant (P greater than 0.05) release of 51Cr. Moraxella bovis 118F broth culture filtrates prepared for evaluation of leukocidic activity also were evaluated for hemolytic activity. These 2 toxic activities had several characteristics in common. Both were filterable, heat-labile, produced by a hemolytic strain, and were released during early logarithmic phase growth from broth cultures. Leukocidic and hemolytic activities were protected from degradation by phenylmethyl sulfonyl fluoride, a serine protease inhibitor. Leukocidic and hemolytic activities were dependent on calcium ions. Filtrate resulted in 54.1% 51Cr release from labeled neutrophils and contained 646.7 hemolytic U/ml, respectively, when saline (0.85% NaCl) + 10 mM CaCl2 solution was used as diluent. Neither saline solution nor saline + 10 mM MgCl2 solution supported leukocidic or hemolytic activity. Serum, obtained from several calves 10 to 38 days after M bovis inoculation, substantially neutralized leukocidic and hemolytic activities, compared with paired preinoculation serum samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the effects of AZD3480 on cardiac repolarization: a thorough QT/QTc study using moxifloxacin as a positive control.

In order to evaluate their potential effects on cardiac repolarization, all new drugs must undergo clinical electrocardiographic evaluation in a thorough QT/QTc (TQT) study. AZD3480, a central nervous system-selective, neuronal nicotinic receptor (NNR) agonist, is predominantly metabolized by cytochrome P450 2D6 (CYP2D6). Employing an innovative design, this TQT study assessed the effects of supratherapeutic doses of AZD3480, relative to those of placebo, on cardiac repolarization in healthy male volunteers genotyped as either poor metabolizers (PMs) or extensive metabolizers (EMs) of CYP2D6 substrates. Supratherapeutic doses of AZD3480-resulting in ~10- and ~50-fold higher exposures (PMs and EMs, respectively) than achieved with a 20-mg dose-had no pharmacologic effect on cardiac repolarization relative to placebo. Likewise, no safety/tolerability concerns were observed after either supratherapeutic or 20-mg dosing to either population. No clinically relevant treatment-related changes or trends were observed in laboratory parameters, vital signs, or electrocardiogram (ECG). This study demonstrated that AZD3480 does not prolong QT/QTc interval.