Antitubercular drug discovery: the molecular modification as promise tool

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Prescription patterns for diabetes mellitus and therapeutic implications: a population-based analysis

Objective: To analyze drug prescriptions for insulin and oral antidiabetic drugs in type 1 and type 2 diabetes mellitus patients seen in the Brazilian Public Healthcare System (Unified Health System - SUS) in Ribeirao Preto, SP, Brazil. Subjects and methods: All the patients with diabetes seen in the SUS in the western district of Ribeirao Preto, SP, Brazil between March/2006 and February/2007 were included in the study. Results: A total of 3,982 patients were identified. Mean age of the patients was 60.6 years, and 61.0% were females. Sixty percent of the patients were treated with monotherapy. Doses of oral antidiabetic drugs were lower in monotherapy than in polytherapy. Ten patients received doses of glibenclamide or metformin above the recommended maximum doses, and in elderly patients there was no reduction in drug doses. Conclusion: Monotherapy with oral antidiabetic drugs was the predominant procedure, and the doses were not individualized according to age. Arq Bras Endocrinol Metab. 2012;56(2):120-7

Prevalence and Predictors of Potential Drug-Drug Interactions in the Elderly: A Cross-Sectional Study in the Brazilian Primary Public Health System

Purpose. The primary objective of this study was to investigate the prevalence of clinically important potential drug-drug interactions (DDIs) in elderly patients attending the public primary health care system in Brazil. The secondary objective was to investigate possible predictors of potential DDIs. Methods. A cross-sectional study was carried out in 5 Brazilian cities located in the Ourinhos Micro-region, Sao Paulo State, between November 2010 and April 2011. The selected sample was divided according to the presence (exposed) or absence (unexposed) of one or more potential DDIs (defined as the presence of a minimum 5-day overlap in supply of an interacting drug pair). Data were collected from medical prescriptions and patients' medical records. Potential DDIs (rated major or moderate) were identified using 4 DDI-checker programs. Logistic regression analysis was used to study potential DDI predictors. Results. The prevalence of clinically important potential DDIs found during the study period was 47.4%. Female sex (OR = 2.49 [95% CI 2.29-2.75]), diagnosis of = 3 diseases (OR = 6.43 [95% CI 3.25-12.44]), and diagnosis of hypertension (OR = 1.68 [95% CI 1.23-2.41]) were associated with potential DDIs. The adjusted OR increased from 0.90 [95% CI 0.82-1.03] in patients aged 60 - 64 years to 4.03 [95% CI 3.79 - 4.28] in those aged 75 years or older. Drug therapy regimens involving = 2 prescribers (OR = 1.39 [95% CI 1.17-1.67]), = 3 drugs (OR = 3.21 [95% CI 2.78-3.59]), = 2 ATC codes (OR = 1.19 [95% CI 1.12-1.29]), = 2 drugs acting on cytochrome P450 (OR = 2.24 [95% CI 2.07-2.46]), and ATC codes B (OR = 1.89 [95% CI 1.05-2.08]) and C (OR = 4.01 [95% CI 3.55-4.57]) were associated with potential DDIs. Conclusion. Special care should be taken with the prescription and therapeutic follow-up of patients who present characteristics identified as predictors. Knowledge of potential DDI predictors could aid in developing preventive practices and policies that allow public health services to better manage this situation.

Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria

Objective-The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. Methods and Results-DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-gamma levels, and ameliorated clinical score (day 5) with a trend for increased survival. Conclusion-Therapeutic use of DF in malaria is proposed. (Arterioscler Thromb Vasc Biol. 2012; 32:786-798.)

Interchangeability among therapeutic equivalents of lamotrigine: evaluation of quality of life

Epilepsy is the most common serious neurological disorder worldwide. Approximately 70% of patients with epilepsy have their seizures controlled by clinical and pharmacological treatment. This research evaluated the possible influence of interchangeability among therapeutic equivalents of LTG on the clinical condition and quality of life of refractory epileptic patients. The study was divided into three periods of 42 days, and an equivalent therapeutic LTG randomly dispensed for each period (two similars - formulations A and B, and the reference product - formulation C). The mean dose of LTG was 5.5 mg/kg/day. The presence of side effects tends to have a greater deleterious effect on quality of life of refractory epileptics compared to variations in number of seizures or changes in plasma concentrations. The results showed that independently of the drug prescribed, interchangeability among therapeutic equivalents can negatively impact epilepsy control.

Is there a therapeutic window for pentoxifylline after the onset of acute pancreatitis?

PURPOSE: To investigate the effects of pentoxifylline (PTX) in experimental acute pancreatitis (AP) starting drug administration after the induction of the disease. METHODS: One hundred male Wistar rats were submitted to taurocholate-induced AP and divided into three groups: Group Sham: sham-operated rats, Group Saline: AP plus saline solution, and Group PTX: AP plus PTX. Saline solution and PTX were administered 1 hour after induction of AP. At 3 hours after AP induction, peritoneal levels of tumor necrosis factor (TNF)-alpha, and serum levels of interleukin (IL)-6 and IL-10 levels were assayed by Enzyme-Linked Immunosorbent Assay (ELISA). Determinations of lung myeloperoxidase activity (MPO), histological analysis of lung and pancreas, and mortality study were performed. RESULTS: PTX administration 1 hour after induction of AP caused a significant decrease in peritoneal levels of TNF-alpha and in serum levels of IL-6 and IL-10 when compared to the saline group. There were no differences in lung MPO activity between the two groups with AP. A decrease in mortality was observed in the PTX treatment compared to the saline group. CONCLUSIONS: Administration of PTX after the onset of AP decreased the systemic levels of proinflammatory cytokines, raising the possibility that there is an early therapeutic window for PTX after the initiation of AP.

Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion

Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 mu mol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group. LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.

A New Method to Predict the Epidemiology of Fungal Keratitis by Monitoring the Sales Distribution of Antifungal Eye Drops in Brazil

Purpose: Fungi are a major cause of keratitis, although few medications are licensed for their treatment. The aim of this study is to observe the variation in commercialisation of antifungal eye drops, and to predict the seasonal distribution of fungal keratitis in Brazil. Methods: Data from a retrospective study of antifungal eye drops sales from the only pharmaceutical ophthalmologic laboratory, authorized to dispense them in Brazil (Opthalmos) were gathered. These data were correlated with geographic and seasonal distribution of fungal keratitis in Brazil between July 2002 and June 2008. Results: A total of 26,087 antifungal eye drop units were sold, with a mean of 2.3 per patient. There was significant variation in antifungal sales during the year (p < 0.01). A linear regression model displayed a significant association between reduced relative humidity and antifungal drug sales (R-2 = 0.17, p < 0.01). Conclusions: Antifungal eye drops sales suggest that there is a seasonal distribution of fungal keratitis. A possible interpretation is that the third quarter of the year (a period when the climate is drier), when agricultural activity is more intense in Brazil, suggests a correlation with a higher incidence of fungal keratitis. A similar model could be applied to other diseases, that are managed with unique, or few, and monitorable medications to predict epidemiological aspects.

Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption

Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted.

Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug

Objectives: To review and describe studies of the non-psychotomimetic constituent of Cannabis sativa, cannabidiol (CBD), as an anxiolytic drug and discuss its possible mechanisms of action. Method: The articles selected for the review were identified through searches in English,articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints. Results: Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. like", and "cannabidiol and anxiety". The reference lists of the publications included, review Portuguese, and Spanish in the electronic databases ISI Web of Knowledge, SciELO, PubMed, and PsycINFO, combining the search terms "cannabidiol and anxiolytic", "cannabidiol and anxiolytic-articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints. Results: Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder. Conclusion: like", and "cannabidiol and anxiety". The reference lists of the publications included, review Future clinical trials involving patients with different anxiety disorders are warranted, especially of panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorders. The adequate therapeutic window of CBD and the precise mechanisms involved in its anxiolytic action remain to be determined.

Interchangeability among therapeutic equivalents of lamotrigine: evaluation of quality of life

Epilepsy is the most common serious neurological disorder worldwide. Approximately 70% of patients with epilepsy have their seizures controlled by clinical and pharmacological treatment. This research evaluated the possible influence of interchangeability among therapeutic equivalents of LTG on the clinical condition and quality of life of refractory epileptic patients. The study was divided into three periods of 42 days, and an equivalent therapeutic LTG randomly dispensed for each period (two similars - formulations A and B, and the reference product - formulation C). The mean dose of LTG was 5.5 mg/kg/day. The presence of side effects tends to have a greater deleterious effect on quality of life of refractory epileptics compared to variations in number of seizures or changes in plasma concentrations. The results showed that independently of the drug prescribed, interchangeability among therapeutic equivalents can negatively impact epilepsy control.

Anticancer drug screening from images of zebrafish embryogenesis

During the previous 10 years, global R&D expenditure in the pharmaceuticals and biotechnology sector has steadily increased, without a corresponding increase in output of new medicines. To address this situation, the biopharmaceutical industry's greatest need is to predict the failures at the earliest possible stage of the drug development process. A major key to reducing failures in drug screenings is the development and use of preclinical models that are more predictive of efficacy and safety in clinical trials. Further, relevant animal models are needed to allow a wider testing of novel hypotheses. Key to this is the developing, refining, and validating of complex animal models that directly link therapeutic targets to the phenotype of disease, allowing earlier prediction of human response to medicines and identification of safety biomarkers. Morehover, well-designed animal studies are essential to bridge the gap between test in cell cultures and people. Zebrafish is emerging, complementary to other models, as a powerful system for cancer studies and drugs discovery. We aim to investigate this research area designing a new preclinical cancer model based on the in vivo imaging of zebrafish embryogenesis. Technological advances in imaging have made it feasible to acquire nondestructive in vivo images of fluorescently labeled structures, such as cell nuclei and membranes, throughout early Zebrafishsh embryogenesis. This In vivo image-based investigation provides measurements for a large number of features at cellular level and events including nuclei movements, cells counting, and mitosis detection, thereby enabling the estimation of more significant parameters such as proliferation rate, highly relevant for investigating anticancer drug effects. In this work, we designed a standardized procedure for accessing drug activity at the cellular level in live zebrafish embryos. The procedure includes methodologies and tools that combine imaging and fully automated measurements of embryonic cell proliferation rate. We achieved proliferation rate estimation through the automatic classification and density measurement of epithelial enveloping layer and deep layer cells. Automatic embryonic cells classification provides the bases to measure the variability of relevant parameters, such as cell density, in different classes of cells and is finalized to the estimation of efficacy and selectivity of anticancer drugs. Through these methodologies we were able to evaluate and to measure in vivo the therapeutic potential and overall toxicity of Dbait and Irinotecan anticancer molecules. Results achieved on these anticancer molecules are presented and discussed; furthermore, extensive accuracy measurements are provided to investigate the robustness of the proposed procedure. Altogether, these observations indicate that zebrafish embryo can be a useful and cost-effective alternative to some mammalian models for the preclinical test of anticancer drugs and it might also provides, in the near future, opportunities to accelerate the process of drug discovery.

Rare and complicated forms of infantile hemangiomas: new therapeutic outlooks

Infantile hemangiomas (IHs) are the most common benign neoplastic pathology of childhood; their natural history generally involves three phases: after the onset, which usually occurs in the first weeks of life, there is the proliferation phase where the IH reaches its maximum development and it is followed by the spontaneous involution which leads to the IH regression. The duration and the extent of these phases may vary widely even though in most of the cases the involution process begins around twelve months of life and the regression, complete or partial, is completed around seventh-ninth year of life. The majority of the IHs does not require any treatment. However, 10%-20% is likely to develop serious complications, functional impairments or aesthetic alterations and entail a timely treatment. Although there is no treatment protocol currently shared, therapies usually used in cases with a complication risk consist in: systemic or intralesional steroids as a first choice; interferon α, vincristine and/or bleomicin as second or third choice and/or surgical treatment. Propranolol, a non-selective beta-blocker, has been used for cardiovascular diseases even in childhood for decades. Since 2008 it has been widely used in the IHs treatment, although it is still "off-label". In literature there are hundreds of cases and some clinical studies that show the effectiveness and safety of this drug for this indication. Thanks to a multidisciplinary team (Dermatologists, Cardiologists, Paediatricians, and Radiologists) of S. Orsola-Malpighi Hospital, a clinical study, which has been previously approved by the ethics committee, is carried out in order to evaluate the efficacy and safety of systemic propranolol in the treatment of IHs in paediatric age. At the end of 2012, 78 patients underwent this treatment: the results we have obtained so far show a good efficacy and safety profile in agreement with the data provided by the literature.

Optimierung der Phenprocoumon-Dosierung durch intensivierte medizinisch-pharmazeutische Betreuung

Ein sorgfältiges INR-Monitoring ist wichtig für eine sichere und effektive Vitamin-K-antagonistische Therapie (VKA). Einer von vielen Faktoren, welcher die Einhaltung des INR-ZSB beeinflusst, ist die Compliance. Im Rahmen der vorliegenden Arbeit wurde erstmals die Effektivität einer intensiven medizinisch-pharmazeutischen Betreuung von Patienten mit Phenprocoumon-Therapie, unter besonderer Berücksichtung der Compliance, untersucht. 71 Patienten mit VKA-Therapie (Interventionsgruppe (IG) und Kontrollgruppe (KG)) wurden in die prospektive Studie eingeschlossen und über 6 Monate beobachtet. Patienten der IG erfuhren eine intensive medizinisch-pharmazeutische Betreuung im Thrombosedienst. Die Patienten der Kontrollgruppe wurden vom Hausarzt betreut. Zusätzlich fand eine Compliance-Messung mittels OtCM-Blistern (Objective-therapy-compliance-measurement-system) statt. Während die Compliance der Kontrollgruppe retrospektiv am Ende des Beobachtungszeitraums ausgewertet wurde, erfuhren die Patienten der Interventionsgruppe ein „real-time“ Monitoring der Phenprocoumon-Entnahme aus den Blistern. Nach per Protokoll-Analyse konnten die Daten von 58 Patienten ausgewertet werden. Patienten der IG zeigten eine signifikant bessere INR-Einhaltung im ZSB (Time in Therapeutic Range (TTR) 74%) im Vergleich zur Kontrollgruppe (TTR 53%; p= 0,001). Die verschiedenen gemessenen Compliance-Raten (Dosing-, Taking-, Timing Compliance und Drug Holidays) waren in der IG höher als in der KG. Patienten mit einer höheren TTR waren tendenziell besser compliant. Spezialisierte medizinisch-pharmazeutische Betreuung hat einen positiven Effekt auf das Outcome der VKA-Therapie.rnrn

Sindrome di cushing nel cane: Nuove prospettive diagnostiche e terapeutiche

La sindrome di Cushing (SC) è una delle endocrinopatie più comuni nel cane. La diagnosi richiede l'integrazione di anamnesi, segnalamento, segni clinici, esami ematobiochimici, test endocrini specifici e diagnostica per immagini . Nel corso degli anni diversi sono i principi attivi testati per la terapia della SC del cane. In passato, il mitotane è stato il farmaco più utilizzato, sebbene il suo uso risulti complicato e non privo di potenziali effetti collaterali. Recentemente, il trilostano ha dimostrato di essere un trattamento efficace per il controllo dei sintomi ed è stato approvato per tale uso nel cane. Al fine di testare metodiche non invasive per la diagnosi di SC nel cane abbiamo valutato le concentrazioni di cortisolo nel pelo (HCC) .Queste risultavano significativamente più elevate nei cani con SC rispetto ai cani sani e malati. Questo test può essere quindi considerato una procedura diagnostica non invasiva in cani con un elevato sospetto di SC. Inoltre, a causa della difficile reperibilità dell’ACTH esogeno sono state valutate le concentrazioni di cortisolo basale come strumento di monitoraggio in cani con SC trattati con trilostano. Tuttavia la singola valutazione del cortisolo basale non rappresenta un parametro efficace ed accurato per il monitoraggio della terapia con trilostano. Sono stati inoltre valutati i fattori prognostici in cani con SC alla diagnosi. L' iperfosfatemia è risultata un riscontro comune nei cani SC, rappresentando un fattore prognostico negativo. La terapia chirurgica non è una procedura di routine nella SC del cane, tuttavia abbiamo descritto l'approccio di ipofisectomia transsfenoidale in un Galgo spagnolo di 8 anni con SC . Il cane è stato sottoposto per due volte ad ipofisectomia transsfenoidale che ha permesso di rimuovere completamente il macroadenoma ipofisario. In conclusione, questi studi ci hanno permesso di indagare alcuni aspetti patogenetici, clinici e diagnostici della SC del cane.