Gender analysis of moxifloxacin clinical trials

Purpose: To determine the inclusion of women and the sex-stratification of results in moxifloxacin Clinical Trials (CTs), and to establish whether these CTs considered issues that specifically affect women, such as pregnancy and use of hormonal therapies. Previous publications about women’s inclusion in CTs have not specifically studied therapeutic drugs. Although this type of drug is taken by men and women at a similar rate, adverse effects occur more frequently in the latter. Methods: We reviewed 158 published moxifloxacin trials on humans, retrieved from MedLine and the Cochrane Library (1998–2010), to determine whether they complied with the gender recommendations published by U.S. Food and Drug Administration Guideline. Results: Of a total of 80,417 subjects included in the moxifloxacin CTs, only 33.7% were women in phase I, in contrast to phase II, where women accounted for 45%, phase III, where they represented 38.3% and phase IV, where 51.3% were women. About 40.9% (n = 52) of trials were stratified by sex and 15.3% (n = 13) and 9% (n = 7) provided data by sex on efficacy and adverse effects, respectively. We found little information about the influence of issues that specifically affect women. Only 3 of the 59 journals that published the moxifloxacin CTs stated that authors should stratify their results by sex. Conclusions: Women are under-represented in the published moxifloxacin trials, and this trend is more marked in phase I, as they comprise a higher proportion in the other phases. Data by sex on efficacy and adverse effects are scarce in moxifloxacin trials. These facts, together with the lack of data on women-specific issues, suggest that the therapeutic drug moxifloxacin is only a partially evidence-based medicine.

An ethnopharmacological and historical analysis of “Dictamnus”, a European traditional herbal medicine

Ethnopharmacological relevance and background: “Dictamnus” was a popular name for a group of medicinal herbaceous plant species of the Rutaceae and Lamiaceae, which since the 4th century have been used for gynaecological problems and other illnesses BCE and still appear in numerous ethnobotanical records. Aims: This research has as four overarching aims: Determining the historical evolution of medical preparations labelled “Dictamnus” and the different factors affecting this long-standing herbal tradition. Deciphering and differentiating those medicinal uses of “Dictamnus” which strictly correspond to Dictamnus (Rutaceae), from those of Origanum dictamnus and other Lamiaceae species. Quantitatively assessing the dependence from herbal books, and pharmaceutical tradition, of modern Dictamnus ethnobotanical records. Determining whether differences between Western and Eastern Europe exist with regards to the Dictamnus albus uses in ethnopharmacology and ethnomedicine. Methods: An exhaustive review of herbals, classical pharmacopoeias, ethnobotanical and ethnopharmacological literature was conducted. Systematic analysis of uses reported which were standardized according to International Classification of Diseases – 10 and multivariate analysis using factorial, hierarchical and neighbour joining methods was undertaken. Results and discussion: The popular concept “Dictamnus” includes Origanum dictamnus L., Ballota pseudodictamnus (L.) Benth. and B. acetabulosa (L.) Benth. (Lamiaceae), as well as Dictamnus albus L. and D. hispanicus Webb ex Willk. (Rutaceae), with 86 different types of uses. Between 1000 and 1700 CE numerous complex preparations with “Dictamnus” were used in the treatment of 35 different pathologies. On biogeographical grounds the widespread D. albus is a far more likely prototypical “Dictamnus” than the Cretan endemic Origanum dictamnus. However both form integral parts of the “Dictamnus” complex. Evidence exists for a sufficiently long and coherent tradition for D. albus and D. hispanicus, use to treat 47 different categories of diseases. Conclusions: This approach is a model for understanding the cultural history of plants and their role as resources for health care. “Dictamnus” shows how transmission of traditional knowledge about materia medica, over 26 centuries, represents remarkable levels of development and innovation. All this lead us to call attention to D. albus and D. hispanicus which are highly promising as potential herbal drug leads. The next steps of research should be to systematically analyse phytochemical, pharmacological and clinical evidence and to develop safety, pharmacology and toxicology profiles of the traditional preparations.

Adolescent Illicit Drug Use and Subsequent Academic and Psychosocial Adjustment : an Examination of Socially-Mediated Pathways

Background: Questions remain regarding the consequences of illicit drug use on adolescent adjustment and the nature of mechanisms that may explain these consequences. In this study, we examined whether early-onset illicit drug use predicts subsequent academic and psychosocial adjustment and whether associations are socially-mediated by decreased school engagement and increased peer deviancy. Method: 4885 adolescents were followed throughout secondary school. We used regressions to determine whether illicit drug use in grade 7 predicted academic achievement, school dropout, depressive symptoms, and conduct problems in grades 10–11, adjusting for potential confounders. We used path analysis to test whether significant associations were mediated by school engagement and peer deviancy in grade 8. Results: Illicit drug use predicted conduct problems and school dropout, but not academic achievement and depressive symptoms. The association between illicit drug use and conduct problems was fully mediated by increased peer deviancy. The association between illicit drug use and school dropout was partially mediated by increased peer deviancy, but remained mostly direct. No indirect association via decreased school engagement was found. Examination of reverse pathways revealed that conduct problems and academic achievement in grade 7 predicted drug use in grades 10–11. These associations were mediated by peer deviancy and school engagement (conduct problems only). Conclusion: Adolescent illicit drug use influences the risk of school dropout and conduct problems in part by contributing to deviant peer affiliation. Reciprocal social mediation characterizes the association between drug use and conduct problems. A reverse mechanism best explains the association with academic achievement.

A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts.

Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48-72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development.

Neospora caninum calcium-dependent protein kinase 1 is an effective drug target for neosporosis therapy.

Despite the enormous economic importance of Neospora caninum related veterinary diseases, the number of effective therapeutic agents is relatively small. Development of new therapeutic strategies to combat the economic impact of neosporosis remains an important scientific endeavor. This study demonstrates molecular, structural and phenotypic evidence that N. caninum calcium-dependent protein kinase 1 (NcCDPK1) is a promising molecular target for neosporosis drug development. Recombinant NcCDPK1 was expressed, purified and screened against a select group of bumped kinase inhibitors (BKIs) previously shown to have low IC50s against Toxoplasma gondii CDPK1 and T. gondii tachyzoites. NcCDPK1 was inhibited by low concentrations of BKIs. The three-dimensional structure of NcCDPK1 in complex with BKIs was studied crystallographically. The BKI-NcCDPK1 structures demonstrated the structural basis for potency and selectivity. Calcium-dependent conformational changes in solution as characterized by small-angle X-ray scattering are consistent with previous structures in low Calcium-state but different in the Calcium-bound active state than predicted by X-ray crystallography. BKIs effectively inhibited N. caninum tachyzoite proliferation in vitro. Electron microscopic analysis of N. caninum cells revealed ultra-structural changes in the presence of BKI compound 1294. BKI compound 1294 interfered with an early step in Neospora tachyzoite host cell invasion and egress. Prolonged incubation in the presence of 1294 interfered produced observable interference with viability and replication. Oral dosing of BKI compound 1294 at 50 mg/kg for 5 days in established murine neosporosis resulted in a 10-fold reduced cerebral parasite burden compared to untreated control. Further experiments are needed to determine the PK, optimal dosage, and duration for effective treatment in cattle and dogs, but these data demonstrate proof-of-concept for BKIs, and 1294 specifically, for therapy of bovine and canine neosporosis.

Dynamics of the Developing Chick Chorioallantoic Membrane Assessed by Stereology, Allometry, Immunohistochemistry and Molecular Analysis.

The chick chorioallantoic membrane (CAM) is a widely used model for the study of angiogenesis, tumour growth, as well as drug efficacy. In spite of this, little is known about the developmental alteration from its appearance to the time of hatching. In the current study the CAM has been studied by classical stereology and allometry. Expression levels of selected angiogenesis-related molecules were estimated by RT-PCR and cell dynamics assessed by proliferation and apoptosis assays. Absolute CAM volume increased from a low of 0.47 ± 0.11 cm3 at embryonic day 8 (E8) to a high of 2.05 ± 0.27 cm3 at E18, and then decreased to 1.6 ± 0.47 cm3 at E20. On allometric analysis, three growth phases were identifiable. Between E8-13 (phase I), the CAM grew fastest; moderately in phase II (E13-18) but was regressing in phase III (E18-20). The chorion, the mesenchyme and the allantoic layers grew fastest in phase I, but moderately in phase II. The mesenchyme grew slowly in phase III while the chorion and allantois were regressing. Chorionic cell volume increased fastest in phase I and was regressing in phase III. Chorionic capillaries grew steadily in phase I and II but regressed in phase III. Both the chorion and the allantois grew by intrinsic cell proliferation as well as recruitment of cells from the mesenchyme. Cell proliferation was prominent in the allantois and chorion early during development, declined after E17 and apoptosis started mainly in the chorion from E14. VEGFR2 expression peaked at E11 and declined steadily towards E20, VEGF peaked at E13 and E20 while HIF 1α had a peak at E11 and E20. Studies targeting CAM growth and angiogenesis need to take these growth phases into consideration.

Drug-induced torsades de pointes in an underserved urban population. Methadone: is there therapeutic equipoise?

BACKGROUND Although it has been well established that methadone use can result in prolonged QTc/torsades de pointes (TdP) and has been labeled as one of the main drugs that cause TdP, it is still prescribed indiscriminately, and several cases of methadone-associated TdP have been seen in our community. METHODS Our objective was to determine the associated factors for prolonged QTc and the development of torsades de pointes (TdP) in our underserved patient population. We found 12,550 ECGs with prolonged QTc between 2002 and 2013. Medical records were reviewed in order to identify precipitating factors for prolonged QTc and to detect incidence of TdP. RESULTS We identified 2735 patients with prolonged QTc who met the inclusion criteria. Of these, 89 (3%) experienced TdP. There was a greater prevalence of HIV infection in the TdP group (11.2 vs. 3.7%, p < 0.001). Furosemide, hydrochlorothiazide, selective serotonin reuptake inhibitors (SSRIs), amiodarone, ciprofloxacin, methadone, haloperidol, and azithromycin were the drugs most often associated with prolonged QTc (31, 8.2, 7.6, 7.1, 3.9, 3.4 and 3.3%, respectively). However, the agents most commonly associated with TdP were furosemide (39.3%), methadone (27%), SSRIs (19.1%), amiodarone (18%), and dofetilide (9%). The medications with statistical significance in the multivariate analysis for TdP development in descending order were as follows: ranolazine (odds ratios [OR] = 53.61, 95% confidence interval [CI] 5.4-524, p < 0.001), dofetilide (OR = 25, CI 6.47-103.16, p < 0.001), voriconazole (OR = 21.40, CI 3.24-124.25, p < 0.001), verapamil (OR = 10.98, CI 2.62-44.96, p < 0.001), sotalol (OR = 12.72, 1.95-82.81, p = 0.008), methadone (OR = 9.89, CI 4.05-24.15, p < 0.001), and SSRI (OR = 2.26, CI 1.10-5.96, p < 0.001). This multivariate analysis revealed that amiodarone and HIV infection were not implicated in TdP. CONCLUSION Methadone was by far the leading medication implicated in the development of TdP and an independent predictor in both univariate and multivariate analyses despite the fact that it was not the most common QT-prolonging medication in our population.

The pragmatics of computer-mediated communication between South African and Mexican drug traffickers

South Africa and Mexico are ripe with drug trafficking. The gangs and syndicates running the drug businesses in these two countries collaborate occasionally. Communication between these international drug business partners takes place on social media. Their main language of communication is English, mixed with some limited use of Spanish and Afrikaans. The key purpose of the interactions between the South African and Mexican parties is the organisation of their business activities. This study aims at examining how the drug traffickers position each other and themselves regarding their common business interest and how their relationship evolves throughout their interactions. Moreover, it is of interest to look at how these people make use of different social media and their affordances. For this a qualitative analysis of the interaction between two drug traffickers (one South African and one Mexican) on Facebook, Threema and PlayStation 4 was performed. Computer-mediated communication between these two main informants was studied at various stages of their relationship. Results show that at first the interaction between the South African and Mexican drug traffickers consists of interpersonal negotiations of power. The high risk of the drug business and gang/syndicate membership paired with intercultural frictions causes the two interlocutors to be extremely cautious and at the same time to mark their position. As their relationship develops and they gain trust in each other a shift to interpersonal negotiations of solidarity takes place. In these discursive practices diverse linguistic strategies are employed for creating relational effects and for positioning the other and the self. The discursive activities of the interactants are also identity practices. Thus, the two drug traffickers construct identities through these social practices, positioning and their interpersonal relationship.

Adolescent Illicit Drug Use and Subsequent Academic and Psychosocial Adjustment : an Examination of Socially-Mediated Pathways

Background: Questions remain regarding the consequences of illicit drug use on adolescent adjustment and the nature of mechanisms that may explain these consequences. In this study, we examined whether early-onset illicit drug use predicts subsequent academic and psychosocial adjustment and whether associations are socially-mediated by decreased school engagement and increased peer deviancy. Method: 4885 adolescents were followed throughout secondary school. We used regressions to determine whether illicit drug use in grade 7 predicted academic achievement, school dropout, depressive symptoms, and conduct problems in grades 10–11, adjusting for potential confounders. We used path analysis to test whether significant associations were mediated by school engagement and peer deviancy in grade 8. Results: Illicit drug use predicted conduct problems and school dropout, but not academic achievement and depressive symptoms. The association between illicit drug use and conduct problems was fully mediated by increased peer deviancy. The association between illicit drug use and school dropout was partially mediated by increased peer deviancy, but remained mostly direct. No indirect association via decreased school engagement was found. Examination of reverse pathways revealed that conduct problems and academic achievement in grade 7 predicted drug use in grades 10–11. These associations were mediated by peer deviancy and school engagement (conduct problems only). Conclusion: Adolescent illicit drug use influences the risk of school dropout and conduct problems in part by contributing to deviant peer affiliation. Reciprocal social mediation characterizes the association between drug use and conduct problems. A reverse mechanism best explains the association with academic achievement.

Cost-benefit, cost-effectiveness research of drug abuse prevention : implications for programming and policy /

Shipping list no.: 99-0004-P.

Analysis of some laser light show effects for classification purposes /

Mode of access: Internet.

National survey on drug abuse : main findings, 1979 /

Mode of access: Internet.

Coordinating clinical trials in psychopharmacology : planning, documentation, and analysis /

Mode of access: Internet.

Drug alliance program activities in neighborhood-based illicit drug abuse prevention /

"Submitted under contract number 90-043-1003."

Drug alliance program activities in neighborhood-based illicit drug abuse prevention :

"Submitted under contract number 90-043-1003."