Effect of Irbesartan on Glucose Tolerance in a Type 2 Diabetes Mellitus Mouse Model

Background: Angiotensin receptor blockers (ARBs) have been reported to affect glycaemic control in both animals and humans. A few studies have evaluated the effects of irbesartan on blood glucose levels and ARBs are recommended in patients with comorbid diabetes and hypertension. However, the effect of irbesartan on insulin resistance and glucose tolerance is inconclusive and contradicting. Objectives: To evaluate the effect of irbesartan on blood glucose levels and glucose tolerance in diabetic and non-diabetic mice. Materials and methods: Diabetes was induced in 18 obese BALB/c mice fed on high fat diet using alloxan monohydrate 150mg/kg via the intra-peritoneal route. Non-diabetic mice were assigned to three treatment groups (n=6/group) and each group received either of the following treatments: 20mg/kg irbesartan or 75mg/kg irbesartan or vehicle. Diabetic mice were also divided into three groups and each group received one of the three treatments mentioned above. Drug administration was done daily via oral gavage for 14 days. Blood glucose levels were measured on day 1 (baseline values), day 8, and day 13 of treatment.  An oral glucose tolerance test was carried out on day 14 after administration of 50% dextrose at the dose of 1g/kg body weight. Blood glucose levels at 15, 30, 60 and 120 minutes were measured during the oral glucose tolerance test. Results: Irbesartan at the dose of 20mg/kg (-39.44% ±8.96, p=0.0177) and 75mg/kg (-40.07% ±6.27, p=0.0111) significantly lowered blood glucose levels in diabetic mice. However, irbesartan 20mg/kg (-14.87% ±10.13, p>0.9999) and 75mg/kg (-9.07%±3.77, p>0.9999) did not significantly change blood glucose levels in non-diabetic mice. In non-diabetic mice there was only a modest difference in AUC in the irbesartan20mg/kg (AUC=28.73mmol/Lmin, p=0.6435), 75mg/kg (AUC=26.66mmol/Lmin, p>0.9999) compared to the non-diabetic control (AUC=26.63 mmol/Lmins). Although there was a slight improvement in glucose tolerance in diabetic mice, irbesartan 20mg/kg (AUC=55.35mmol/Lmin, p>0.9999) and 75mg/kg (AUC=45.54mmol/Lmin, p=0.1737) had no significant effect on glucose tolerance compared to the diabetic control group (AUC=63.53mmol/Lmin). Conclusion: At standard treatment doses, irbesartan had a significant hypoglycaemic effect without significantly improving glucose tolerance in diabetic mice. Key words: Irbesartan, glycemic effects, glucose tolerance, Type 2 diabetes, mouse mode

An analysis of the trends, characteristics, scope, and performance of the Zimbabwean pharmacovigilance reporting scheme

We aimed to determine the reporting trends and characteristics of Individual Case Safety Reports (ICSRs) from the Zimbabwean national pharmacovigilance system. ICSRs submitted to VigiBaseTM, the World Health Organisation's ICSR database between January 1993 and December 2017 were retrospectively reviewed with respect to the suspected medicine, System Organ Class (SOC), adverse drug reaction (ADR) type and seriousness, Anatomic Therapeutic Chemical (ATC) group, age, and gender. In total, 4071 ICSRs were submitted to VigiBaseTM from targeted spontaneous reporting (n = 2909; 71.5%), vaccine surveillance (n = 679; 16.7%), and passive spontaneous reporting (n = 483; 11.9%), respectivel

The Impact of Herbal Drug Use on Adverse Drug Reaction Profiles of Patients on Antiretroviral Therapy in Zimbabwe

Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076–0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292–0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles

A retrospective analysis of applications for registration of generic medicines processed by the medicines control authority of Zimbabwe

Many applications for registration of medicines are rejected because applicants fail to submit or resolve critical deficiencies in the quality, efficacy, and safety of the medicines. The study aimed to establish approval rates, processing timelines, and common deficiencies of generic medicines applications processed by the Medicines Authority of Zimbabwe (MCAZ). A retrospective study of applications finalized by MCAZ between 2018 and 2020 was conducted. Data were collected from the assessment reports and verified with copies of letters sent to the applicants. Deficiencies were classified as administrative, quality, efficacy, and safety. Other characteristics collated included time to finalization, dosage form, region of origin, and therapeutic class

Situation analysis on the regulation of nanomedicines in Southern Africa

Medical products incorporating nanoparticle drug delivery systems (nanomedicines) are therapeutic or imaging agents, which comprise a delivery system within the nanometer size range (1 – 1000 nm). As medical products, nanomedicines meet definitions of medicines according to various national legislations for regulation of medicines. However, for the regulation of nanomedicines, additional assessments including toxicological issues have to be considered. These complexities require extra regulatory effort. In the resourcelimited context of low- and middle-income countries, many National Medicines Regulatory Authorities (NMRAs) lack resources and capacities to effectively assure the quality of medicinal products in their countries. With emerging trends in innovative technologies, including nanotechnology, this burden is worsened. The need to overcome regulatory challenges drove the formation of a work sharing initiative in the Southern African Development Community (SADC), ZaZiBoNA in 2013. Regulatory agencies participating in this initiative cooperate in the assessment of applications for registration of medicines

Exploring the utility of a spontaneous adverse drug reaction reporting system in identifying drug–drug interactions between antiretrovirals, antitubercular drugs, and cotrimoxazole: a case/non-case analysis

Background: Drug–drug interactions (DDIs) cause significant morbidity and mortality, especially in patients with HIV with opportunistic infections such as tuberculosis. However, the literature on quantitative signal detection analyses for DDIs within the national spontaneous reporting systems (SRSs) of countries with high HIV/tuberculosis burdens is lacking. Objective: Our objective was to explore the utility of using post-marketing SRSs in quantitative signal detection analyses of DDIs. Methods: A case/non-case analysis using the Zimbabwean adverse drug reaction (ADR) database obtained from VigiBase® was utilized for quantitative signal detection using 2 × 2 contingency table calculations. Cases were defined as individual case safety reports (ICSRs) with the ADR of interest, and non-cases included the rest of the ICSRs

An Interesting Case of Carbamazepine-Induced Stevens-Johnson Syndrome.

A 29-year-old Black female patient was admitted to a psychiatric ward with symptoms of major depressive disorder with psychosis. The patient was started on amitriptyline 50 mg/day and haloperidol 10 mg/day. On day 4 post-admission, the preferred first-line antidepressant, fluoxetine, became available and the patient was switched from amitriptyline to fluoxetine 20 mg/day. On the same day, the dose of haloperidol was reduced to 5 mg/day. Thirteen days post-initiation of these medications the patient became talkative, associated with emotional lability, an expansive mood, irritability and restlessness. The working diagnosis was changed to bipolar affective disorder in the manic phase. Fluoxetine was discontinued and carbamazepine 600 mg/day was added to the patient's treatment regimen. Her manic symptoms started to resolve; however, 14 days post-initiation of carbamazepine, the patient had a fever; itchy, discharging eyes; respiratory distress; generalised symmetrical erythematosus rash; buccal ulceration; and conjunctival injection with difficulty opening her eyes. Carbamazepine was immediately discontinued and the patient received intravenous fluid resuscitation. The patient recovered considerably after 12 days of symptomatic and supportive management, and was transferred back to the psychiatric ward for the continuation of bipolar disorder management. Lithium therapy was instituted and the patient was subsequently discharged. Using the Algorithm of Drug causality for Epidermal Necrolysis (ALDEN) Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) drug causality scoring system, carbamazepine and fluoxetine were evaluated as 'very probable' and 'possible' causes of SJS, respectively, in this patient. Fluoxetine-induced SJS was considered on account of previous case reports, however no evidence of causality was found in this patient. Consecutive administration with a potential increase in carbamazepine due to inhibition of cytochrome P450 (CYP) 3A4 metabolism by fluoxetine was also not ruled out. A diagnosis of carbamazepine-induced SJS was made and was considered an idiosyncratic adverse drug reaction

CYP2D6*17 polymorphism and tardive dyskinesia in black psychotic patients on typical antipsychotics

Background: Tardive dyskinesia is a debilitating, intractable, hyperkinetic movement disorder which contributes to an increase in psychiatric morbidity. Reduced function CYP2D6 alleles have been associated with tardive dyskinesia pathogenesis amongst Caucasians and Asians, with CYP2D*4 and *6 and CYP2D6*10 being implicated in these races respectively. No similar study has been successfully conducted in black Africans. Objective: To determine the relationship between tardive dyskinesia and CYP2D6*17 (the major reduced function CYP2D6 allele in Africans). Methodology: Abnormal Involuntary Movements Scale (AIMS) scoring and CYP2D6 genotyping were carried out on psychiatric patients exposed to typical antipsychotic medications in an unmatched case control study. A case of tardive dyskinesia was defined as a patient with an AIMS score ≥ 2 in two body areas OR ≥ 3 in one body area Results: A total of 18 cases and 32 controls made up the study sample.The sample’s mean age was 36.9±12.0 years with median treatment duration of 7.0 years (range: 0.25 to 38 years). Multiple logistic regression revealed no significant association between tardive dyskinesia and CYP2D6*17 (OR=0.252; 95% CI: 0.038 to 1.647; p=0.150). However, use of chlorpromazine (OR=5.754; 95% CI: 1.024 to 32.328; p=0.047) and age at treatment initiation (OR=1.146; 95% CI: 1.021 to 1.287; p=0.021) were independent predictors of tardive dyskinesia. Discussion: These findings suggest that there is no association between CYP2D6*17and tardive dyskinesia in African psychotic patients on typical antipsychotics. However, more studies with larger sample sizes are required to provide more definitive conclusions regarding the nature of the relationship betweenCYP2D6*17 and tardive dyskinesia. Key words: Tardive dyskinesia, CYP2D*17, typical antipsychotic

Use of antidepressant agents and the incidence of type 2 diabetes mellitus : a methodological comparison

textThe main study purposes were to determine: whether antidepressant (AD) use increases the risk of type 2 diabetes mellitus; and whether results differ when using different methodological designs: retrospective cohort design and nested case-control design. A retrospective Texas Medicaid database analysis of new AD (exposed cohort) and benzodiazepine (unexposed cohort [BZ]) users from January 1, 2002 to December 31, 2009 was conducted. Patients aged 18-64 years without diabetes at cohort entry were included. The primary outcome was incident diabetes and the main independent variable was AD vs. BZ use. Covariates included age, gender, race/ethnicity, medication adherence, persistence, number of concomitant diabetogenic medications, Chronic Disease Score, treatment duration, year of cohort entry, and use of both AD and BZ at index. Regression analyses (adjusted) were used to address the study purposes. Of the study cohort (N=44,715), 35,552 (79.5%) were AD users and 9,163 (20.5%) were BZ users. Patients were followed for an average of 2.3±1.9 years (Median=1.8 years), were on average 38.6±14.2 years old, and 69.3% were female. Using the retrospective cohort design, AD use was associated with a 48.9% increase (logistic regression) and 60.0% increase (Cox regression) in the risk of diabetes compared to BZ use (logistic regression analysis: RR[subscript adj]. =1.489; 95% CI: 1.331-1.667; Cox regression analysis: HR[subscript adj]. =1.600; 95% CI: 1.437 - 1.783). Using a nested case-control design within the entire study cohort, AD use was associated with a 54.1% increase in the risk of diabetes compared to BZ use (OR[subscript adj]. =1.541; 95% CI: 1.368 - 1.735). Using a nested case-control design within the exposed cohort, current AD use was associated with a two-fold higher risk of diabetes compared to former AD use (OR[subscript adj]. =1.995; 95% CI: 1.759 - 2.264). Among antidepressant classes, TCAs, SSRIs, SNRIs, and Other ADs were associated with a higher diabetes risk compared with BZs. The results from the present study suggest that AD use is associated with an increased risk of diabetes. Clinicians may need to take this into account when choosing treatment for depression in patients at high risk of diabetes.Pharmac