From recipe to research: introducing undergraduate students to the nature of science using a hybrid practical course centred on drug discovery for neglected diseases

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Role of AT2 receptors in the cardioprotective effect of AT1 antagonists in mice

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT1 and AT2. Most of the known biological actions of Ang II are mediated by AT1 receptors; however, the role of AT2 receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT1 receptor antagonists (AT1-ant) after myocardial infarction (MI) are partially mediated by activation of AT2 receptors; thus in AT2 receptor gene knockout mice (AT2-/Y), the effect of AT1-ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT2-/Y and their wild-type littermates (AT2+/Y) were started on vehicle, AT1-ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT2+/Y and AT2-/Y. AT1-ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT2+/Y, and these effects were significantly diminished in AT2-/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT2 during AT1 blockade plays an important role in the therapeutic effect of AT1-ant and (2) the AT2 receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.     

Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena

Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune-related disorders are rare complications of MCD. We report on an MCD case in a 23-year-old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8). After 8 courses of the anti-CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti-CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune-related disorders are associated.     

The influence of polymorphisms of VKORC1 and CYP2C9 on major gastrointestinal bleeding risk in anticoagulated patients

The VKORC1 c.-1639G>A and CYP2C9 c.430C>T and c.1075A>C polymorphisms have been associated with increased sensitivity to oral anticoagulants. However, their role in gastrointestinal bleeding is unknown. We studied the risk of gastrointestinal bleeding associated with these polymorphisms, and how this risk was influenced by the anticoagulant dose and the use of common drugs. Eighty-nine patients with gastrointestinal bleeding during acenocoumarol therapy and 177 patients free of bleeding during acenocoumarol therapy were studied. None of the three polymorphisms constituted a serious gastrointestinal bleeding risk factor. However, patients bearing at least one of these polymorphisms were at high risk, when they simultaneously met one of the following conditions: a weekly dose of acenocoumarol higher than 15 mg [adjusted Odds Ratio (OR) (95% confidence interval (CI) = 4.19 (1.59-11.04)]; amiodarone use [adjusted OR (95% CI) = 9.97 (1.75-56.89)]; or aspirin use [adjusted OR (95% CI) = 8.97 (1.66-48.34)]. The consumption of statins was associated with a lower risk of gastrointestinal bleeding [adjusted OR = 0.50 (0.26-0.99)]. The risk of gastrointestinal bleeding during acenocoumarol therapy in carriers of any of the studied polymorphisms is severely increased with exposure to weekly doses of acenocoumarol higher than 15 mg or the use of amiodarone or aspirin.     

Peritoneal and intestinal tuberculosis: an ancestral disease that poses new challenges in the technological era. Case report and review of the literature

Tuberculosis is a public health problem. The most common presentation is pulmonary disease. The diagnosis of any extrapulmonary forms are quite difficult. Clinical manifestations of gastrointestinal tuberculosis are non-specific and compatible with pathologies such as inflammatory bowel disease, advanced ovarian cancer, deep mycosis, yersinia infection and amebomas. Abdominal form is located at 6th place of the extrapulmonary forms, after lymphatic, genitourinary, osteoarticular, miliary and meningeal infections. Eventually, 25 to 75% of patients with abdominal tuberculosis will require surgery. These procedures should be limitated with the purpose to preserve small bowel. Resection should be limitated for complicated cases. The surgical indications include: Intestinal occlusion (15-60%), perforation (1-15%), abscesses and fistulas (2-30%) and hemorrhage (2%). CONCLUSIONS: In most of the cases, the diagnosis of peritoneal or intestinal tuberculosis is made during a laparoscopy or laparotomy even during surgery performed by different purposes. Excessive manipulation of the intraabdominal organs may produced unexpected bowel lesions, increasing morbidity and mortality. Medical treatment is highly effective in the resolution of moderate complications such as bowel obstruction. Resectional procedures should be reserved for complications like perforation, bleeding or stenosis non-suitable for stricturoplasty.     

Model-based prediction of the acute and long-term safety profile of naproxen in rats

Background and Purpose

Despite the increasing importance of biomarkers as predictors of drug effects, toxicology protocols continue to rely on the experimental evidence of adverse events (AEs) as a basis for establishing the link between indicators of safety and drug exposure. Furthermore, biomarkers may facilitate the translation of findings from animals to humans. Combined with a model-based approach, biomarker data have the potential to predict long-term effects arising from prolonged drug exposure. Here, we used naproxen as a paradigm to explore the feasibility of a biomarker-guided approach for the prediction of long-term AEs in humans.

Experimental Approach

An experimental toxicology protocol was set up for evaluating the effects of naproxen in rats, in which four active doses were tested (7.5, 15, 40 and 80 mg·kg⁻¹). In addition to AE monitoring and histology, a few blood samples were also collected for the assessment of drug exposure, TXB₂ and PGE₂ levels. Non-linear mixed effects modelling was used to analyse the data and identify covariate factors on the incidence and severity of AEs.

Key Results

Modelling results showed that besides drug exposure, maximum PGE₂ inhibition and treatment duration were also predictors of gastrointestinal ulceration. Although PGE₂ levels were clearly linked to the incidence rates, it appeared that ulceration severity is better predicted by measures of drug exposure.

Conclusions and Implications

These results show that the use of a model-based approach provides the opportunity to integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling optimization of the design, analysis and interpretation of toxicology experiments.     

Neuropsychological Deficits in Alcoholics: Facts and Fancies

Five facts and complementary “fancies” have been examined. Brain damage is found in alcoholics but whether alcohol directly causes the damage is not clear at this time. Cortical and subcortical atrophy is found in 50%-70% of unselected alcoholics coming for treatment but a substantial minority of alcoholics do not have such changes. Brain changes in alcoholics are associated significantly with neuropsychological deficits but the magnitude of the correlations leaves much of the variance unexplained. Neuropsychological deficits in alcoholics (who do not have “mental deterioration”) are relatively specific and in most instances functions can be recovered but there are some suggestions of more permanent, if limited, deficits. While specific neuropsychological deficits in alcoholics have been recurrently established, their relationship to therapeutic strategies and therapeutic outcome remains to be explored. Finally, it is abundantly clear that implicit and explicit criteria for patient selection in neuropsychological studies are major, if not critical, variables in work in this field.