Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study.

BACKGROUND: Hospitalization is a costly and distressing event associated with relapse during schizophrenia treatment. No information is available on the predictors of psychiatric hospitalization during maintenance treatment with olanzapine long-acting injection (olanzapine-LAI) or how the risk of hospitalization differs between olanzapine-LAI and oral olanzapine. This study aimed to identify the predictors of psychiatric hospitalization during maintenance treatment with olanzapine-LAI and assessed four parameters: hospitalization prevalence, incidence rate, duration, and the time to first hospitalization. Olanzapine-LAI was also compared with a sub-therapeutic dose of olanzapine-LAI and with oral olanzapine. METHODS: This was a post hoc exploratory analysis of data from a randomized, double-blind study comparing the safety and efficacy of olanzapine-LAI (pooled active depot groups: 405 mg/4 weeks, 300 mg/2 weeks, and 150 mg/2 weeks) with oral olanzapine and sub-therapeutic olanzapine-LAI (45 mg/4 weeks) during 6 months' maintenance treatment of clinically stable schizophrenia outpatients (n=1064). The four psychiatric hospitalization parameters were analyzed for each treatment group. Within the olanzapine-LAI group, patients with and without hospitalization were compared on baseline characteristics. Logistic regression and Cox's proportional hazards models were used to identify the best predictors of hospitalization. Comparisons between the treatment groups employed descriptive statistics, the Kaplan-Meier estimator and Cox's proportional hazards models. RESULTS: Psychiatric hospitalization was best predicted by suicide threats in the 12 months before baseline and by prior hospitalization. Compared with sub-therapeutic olanzapine-LAI, olanzapine-LAI was associated with a significantly lower hospitalization rate (5.2% versus 11.1%, p < 0.01), a lower mean number of hospitalizations (0.1 versus 0.2, p = 0.01), a shorter mean duration of hospitalization (1.5 days versus 2.9 days, p < 0.01), and a similar median time to first hospitalization (35 versus 60 days, p = 0.48). Olanzapine-LAI did not differ significantly from oral olanzapine on the studied hospitalization parameters. CONCLUSIONS: In clinically stable schizophrenia outpatients receiving olanzapine-LAI maintenance treatment, psychiatric hospitalization was best predicted by a history of suicide threats and prior psychiatric hospitalization. Olanzapine-LAI was associated with a significantly lower incidence of psychiatric hospitalization and shorter duration of hospitalization compared with sub-therapeutic olanzapine-LAI. Olanzapine-LAI did not differ significantly from oral olanzapine on hospitalization parameters.

Generic drugs in Spain: price competition vs. moral hazard

This paper examines competition between generic and brand-name drugs in the regulated Spanish pharmaceutical market. A nested logit demand model is specified for the three most consumed therapeutic subgroups in Spain: statins (anticholesterol), selective serotonin reuptake inhibitors (antidepressants) and proton pump inhibitors (antiulcers). The model is estimated with instrumental variables from a panel of monthly prescription data from 1999 to 2005. The dataset distinguishes between three different levels of patients’ copayments within the prescriptions and the results show that the greater the level of insurance that the patient has (and therefore the lower the patient’s copayment), the lower the proportion of generic prescriptions made by physicians. It seems that the low level of copayment has delayed the penetration of generics into the Spanish market. Additionally, the estimation of the demand model suggests that the substitution rules and promotional efforts associated with the reference pricing system have increased generic market share, and that being among the first generic entrants has an additional positive effect.

Demand for pharmaceutical drugs: A choice modelling experiment

Despite the importance of supplier inducement and brand loyalty inthe drug purchasing process, little empirical evidence is to be foundwith regard to the influence that these factors exert on patients decisions. Under the new scenario of easier access to information,patients are becoming more demanding and even go as far asquestioning their physicians prescription. Furthermore, newregulation also encourages patients to adopt an active role in thedecision between brand-name and generic drugs. Using a statedpreference model based on a choice survey, I have found evidenceof how significant physicians prescription and pharmacists recommendation become throughout the drug purchase process and,to what extent, brand loyalty influences the final decision. Asfar as we are aware, this paper is the first to explicitlytake consumers preferences into account rather than focusingon the behavior of health professionals.

Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide.

Subtypes of adolescents with substance use disorders and psychiatric comorbidity using cluster and discriminant analysis of MMPI-A profiles

The main aim of this study was to replicate and extend previous results on subtypes of adolescents with substance use disorders (SUD), according to their Minnesota Multiphasic Personality Inventory for adolescents (MMPI-A) profiles. Sixty patients with SUD and psychiatric comorbidity (41.7% male, mean age = 15.9 years old) completed the MMPI-A, the Teen Addiction Severity Index (T-ASI), the Child Behaviour Checklist (CBCL), and were interviewed in order to determine DSMIV diagnoses and level of substance use. Mean MMPI-A personality profile showed moderate peaks in Psychopathic Deviate, Depression and Hysteria scales. Hierarchical cluster analysis revealed four profiles (acting-out, 35% of the sample; disorganized-conflictive, 15%; normative-impulsive, 15%; and deceptive-concealed, 35%). External correlates were found between cluster 1, CBCL externalizing symptoms at a clinical level and conduct disorders, and between cluster 2 and mixed CBCL internalized/externalized symptoms at a clinical level. Discriminant analysis showed that Depression, Psychopathic Deviate and Psychasthenia MMPI-A scales correctly classified 90% of the patients into the clusters obtained.

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA incancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA incancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.

Impact of geographical and cultural factors on clinical trials in acute mania: lessons from a ziprasidone and haloperidol placebo-controlled study

Clinical trials today are conducted in multiple countries to enhance patient recruitment and improve efficiency of trials. However, the demographic and cultural diversity may contribute to variations in study outcomes. Here we conducted post-hoc analyses for a placebo-controlled study with ziprasidone and haloperidol for the treatment of acute mania to address the demographic, dosing, and outcome disparities in India, Russia and the USA. We compared the baseline characteristics, outcomes and discontinuations in patients and explored the relationship between the outcome measures across these countries. We found substantial differences in baseline characteristics of subjects, administered dosage and disease severity in India compared to the USA and Russia. Conversely, US subjects had a higher placebo response compared to subjects in Russia and India. These results are probably due to demographic differences in patient populations and psychiatric clinical practice across countries. While we offer initial ideas to address the disparities identified in this analysis, it is clear that further research to improve our understanding of geographical differences is essential to ensure globally applicable results for clinical trials in psychiatry.

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance

Subtypes of adolescents with substance use disorders and psychiatric comorbidity using cluster and discriminant analysis of MMPI-A profiles

The main aim of this study was to replicate and extend previous results on subtypes of adolescents with substance use disorders (SUD), according to their Minnesota Multiphasic Personality Inventory for adolescents (MMPI-A) profiles. Sixty patients with SUD and psychiatric comorbidity (41.7% male, mean age = 15.9 years old) completed the MMPI-A, the Teen Addiction Severity Index (T-ASI), the Child Behaviour Checklist (CBCL), and were interviewed in order to determine DSMIV diagnoses and level of substance use. Mean MMPI-A personality profile showed moderate peaks in Psychopathic Deviate, Depression and Hysteria scales. Hierarchical cluster analysis revealed four profiles (acting-out, 35% of the sample; disorganized-conflictive, 15%; normative-impulsive, 15%; and deceptive-concealed, 35%). External correlates were found between cluster 1, CBCL externalizing symptoms at a clinical level and conduct disorders, and between cluster 2 and mixed CBCL internalized/externalized symptoms at a clinical level. Discriminant analysis showed that Depression, Psychopathic Deviate and Psychasthenia MMPI-A scales correctly classified 90% of the patients into the clusters obtained.

Treatment of cancer with oral drugs: a position statement by the Spanish Society of Medical Oncology

Cancer treatment involves the participation of multiple medical specialties and, as our knowledge of the disease increases, this fact becomes even more apparent. The degree of multidisciplinarity is determined by several factors, which include the severity and type of disease, the increasing diversity in the available pharmacological and non-pharmacological therapies, and the range of specialists involved in cancer therapy, such as medical oncologists, radiotherapists, gynecologists, gastroenterologists, urologists, surgeons, and pneumologists, among others. Across Europe, the situation of cancer care can be variable due to the diversity of health systems, differences in drug reimbursement, and the degree of establishment of Medical Oncology as a medical specialty in the European Union states.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

Non conventional biological treatment based on Trametes versicolor for the elimination of recalcitrant anticancer drugs in hospital wastewater

This work presents a study about the elimination of anticancer drugs, a group of pollutants considered recalcitrant during conventional activated sludge wastewater treatment, using a biological treatment based on the fungus Trametes versicolor. A 10-L fluidized bed bioreactor inoculated with this fungus was set up in order to evaluate the removal of 10 selected anticancer drugs in real hospital wastewater. Almost all the tested anticancer drugs were completely removed from the wastewater at the end of the batch experiment (8 d) with the exception of Ifosfamide and Tamoxifen. These two recalcitrant compounds, together with Cyclophosphamide, were selected for further studies to test their degradability by T. versicolor under optimal growth conditions. Cyclophosphamide and Ifosfamide were inalterable during batch experiments both at high and low concentration, whereas Tamoxifen exhibited a decrease in its concentration along the treatment. Two positional isomers of a hydroxylated form of Tamoxifen were identified during this experiment using a high resolution mass spectrometry based on ultra-high performance chromatography coupled to an Orbitrap detector (LTQ-Velos Orbitrap). Finally the identified transformation products of Tamoxifen were monitored in the bioreactor run with real hospital wastewater