Situation analysis on the regulation of nanomedicines in Southern Africa.

Background: 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 resource-limited 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. Methods: A cross-sectional exploratory study design with qualitative techniques was used to investigate the status of the regulation of nanomedicines in Southern African countries in particular those participating in the ZaZiBoNA initiative. Results: The study found that in general, NMRAs are aware of the existence of nanomedicines and they apply legislation applicable to other medical products. The NMRAs however neither have specific definition for nanomedicines and technical guidance documents, nor technical committees specific for consideration of nanomedicines. Collaboration with external experts or organisations in the regulation of nanomedicines was also found to be lacking. Discussion: Capacity building and collaboration in the area of regulation of nanomedicines is strongly encouraged.

A Retrospective Analysis of Applications for Registration of Generic Medicines Processed by the Medicines Control Authority of Zimbabwe.

BACKGROUND: 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). METHOD: 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. RESULTS: Of the 579 finalized applications, 74.1% were approved while 25.9% were refused. Approved applications had more review cycles (median = 3 cycles) compared to refused applications (median = 2 cycles). However, refused applications had longer review times (median = 25 months) compared to approved applications (median = 18 months). The majority of applications (83.0%) were from Asian manufacturers and intended for oral administration (66.1%). Medicines for the endocrine system (50.0%) and rheumatism/gout (53.3%) had lower approval rates compared to other therapeutical classes (p < 0.001). The most common reasons for refusal of applications included failure to respond to review queries (52.6%), deficiencies in the API information (54.7%), FPP specifications (42.7%), FPP stability data (36.0%), and pharmaceutical development (31.3%). CONCLUSION: To improve the quality of applications and evaluation outcomes, there may be a need for the regulatory authority to engage applicants through training and pre-submission meetings.

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%), respectively. The median age, ICSR completeness score and timeliness of reporting were 34.0 years (IQR: 14.0; 43.0), 0.90 (IQR: 0.70; 1.00), and 548.0 days (IQR: 266:1131), respectively. More than half of the ICRS were from female patients (n = 2233; 54.9%). Antiretrovirals, antibiotics, vaccines, and anti-tubercular medicines were reported in 62.9%, 27.9%, 16.7%, and 13.3% of submitted ICSRs, respectively. The most frequent ADRs involved the skin and subcutaneous systems (n = 1111; 20.5%), nervous system (n = 733; 13.5%), and gastrointestinal disorders system (n = 654; 12.1%). The number of ADRs reported for each patient was significantly related to the reported medicine's ATC category (P = .001. The number of ADRs was significantly related to the use of antiretroviral agents. In conclusion, Zimbabwe has made significant progress in establishing a functional pharmacovigilance system. However, the present system reports on a limited therapeutic spectrum of medicines and potentially underestimates the national ADR burden. Further work is required to strengthen the more sustainable spontaneous reporting system which potentially captures a variety of therapeutic classes.

Adverse events following immunisation (AEFI) reports from the Zimbabwe expanded programme on immunisation (ZEPI): an analysis of spontaneous reports in Vigibase® from 1997 to 2017.

BACKGROUND: Vaccine safety surveillance is an essential requirement in vaccination programmes. It supports signal identification, hypothesis generation, and the identification and rectification of gaps in vaccine pharmacovigilance systems. The objectives of this study were to determine the characteristics and trends of adverse events following immunisation (AEFI) and to assess the performance of the Zimbabwe Expanded Immunisation Programme safety surveillance system. METHODS: We carried out a descriptive study of passively collected vaccine-related Individual Case Safety Report (ICSR) data submitted to the World Health Organization global adverse drug reaction database (VigiBase®) from Zimbabwe during the period 1997 to 2017. We extracted AEFI/ICSR data using VigiLyze® for analysis with respect to the demographic distribution, AEFI characteristics, reporting trends over time, ICSR timeliness and case completeness. RESULTS: A total of 272 vaccine-related ICSRs were included in the analyses with a median completeness score of 0.90 interquartile range, IQR (0.63; 0.90). The overall annual reporting rate was 0.58 per 100,000 vaccine doses and the AEFI reporting ratio ranged between 0 and 30.2 AEFI reports per 100,000 surviving infants. The majority of ICSRs were male (55.3%; p value = 0.641) and the median age was 12 (0-168) months. The majority of ICSRs were reported in children who had received measles (n = 133; 48.9%) and OPV/DTP-Hib-HepB (n = 107; 39.3%) vaccines. Of the 387 observed AEFIs, 301 (77.8%) were systemic events and 86 (22.2%) were local reactions. Systemic events were more frequently reported with doses containing the measles antigen (n = 190; 49.1%) while local events were associated with the multiple antigen OPV/DTP-Hib-HepB (n = 62; 16.0%). The multiple antigen OPV/DTP-Hib-HepB was associated with higher rates for injection site abscess (n = 57), pyrexia (n = 27), diarrhea (n = 15), vomiting (n = 12), and seizures (n = 6). The measles antigen was associated with higher rates for rash (n = 44), ocular disorders (n = 26), pyrexia (n = 26), urticaria (n = 22), diarrhea (n = 8), and vomiting (n = 12). CONCLUSIONS: Most of the ICSRs were associated with measles and OPV/DTP-Hib-HepB vaccines. Zimbabwe's vaccine safety surveillance system is still developing and is not yet fully functional. However, the current system provides a reference point for the monitoring of the ongoing AEFI reporting trends and characteristics.

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.

A Comparison of Adverse Drug Reaction Profiles in Patients on Antiretroviral and Antitubercular Treatment in Zimbabwe.

INTRODUCTION: Few studies describe the adverse drug event profiles in patients simultaneously receiving antiretroviral and anti-tubercular medicines in resource-limited countries. OBJECTIVES: To describe and compare the adverse drug reaction profiles in patients on highly active antiretroviral therapy only (HAART), HAART and isoniazid preventive therapy (HHART), and HAART and antitubercular treatment (ATTHAART). METHODS: We analysed individual case safety reports (ICSRs) for patients on antiretroviral therapy and antitubercular treatment submitted to the national pharmacovigilance centre during the targeted spontaneous reporting (TSR) programme from 1 September 2012 through 31 August 2016. All reports considered certain, probable or possible were included in the analysis. RESULTS: A total of 1076 ICSRs were included in the analysis. Most of the reports were from the HAART only group (n = 882; 82.0%), followed by patients on HHART (n = 132; 12.3%), and ATTHAART (n = 62; 5.7%). The ATTHAART (35.5%) and HHAART (34.1%) had a higher frequency of hepatic disorders than the HAART group (5.0%) (p < 0.0001). A higher frequency of rash was reported in the HHAART (35.6%) and HAART groups (29.4%) than the ATTHAART group (14.5%) (p = 0.011). Peripheral neuropathy occurred more frequently in the ATTHAART group (19.3%) than other groups (p = 0.001) while Stevens-Johnson syndrome (14.7%; p < 0.001), gynaecomastia (18.2%; p < 0.001), and lipodystrophy (4.5%; p = 0.012) occurred more frequently in the HAART group. The HHAART group was associated with a higher frequency of psychosis (4.5%; p = 0.002). CONCLUSION: Antiretroviral therapy was associated with a higher frequency of Stevens-Johnson syndrome, gynaecomastia, and lipodystrophy. Co-administration of antiretroviral and antitubercular medicines was associated with a higher frequency of drug-induced liver injury and peripheral neuropathy. Similarly, co-administration of isoniazid preventive therapy and antiretroviral drugs was associated with a higher risk for psychosis. There is a need to carefully manage TB/HIV co-infected patients, due to the higher risk of adverse drug reactions which may lead to poor treatment adherence and outcomes.

Wound Healing Properties of Selected Plants Used in Ethnoveterinary Medicine.

Plants have arrays of phytoconstituents that have wide ranging biological effects like antioxidant, anti-inflammatory and antimicrobial properties key in wound management. In vivo wound healing properties of ointments made of crude methanolic extracts (10% extract w/w in white soft paraffin) of three plant species, Cissus quadrangularis L. (whole aerial plant parts), Adenium multiflorum Klotzsch (whole aerial plant parts) and Erythrina abyssinica Lam. Ex DC. (leaves and bark) used in ethnoveterinary medicine were evaluated on BALB/c female mice based on wound area changes, regular observations, healing skin's percentage crude protein content and histological examinations. White soft paraffin and 3% oxytetracycline ointment were used as negative and positive controls, respectively. Wound area changes over a 15 day period for mice treated with C. quadrangularis and A. multiflorum extract ointments were comparable to those of the positive control (oxytetracycline ointment). Wounds managed with the same extract ointments exhibited high crude protein contents, similar to what was observed on animals treated with the positive control. Histological evaluations revealed that C. quadrangularis had superior wound healing properties with the wound area completely returning to normal skin structure by day 15 of the experiment. E. abyssinica leaf and bark extract ointments exhibited lower wound healing properties though the leaf extract exhibited some modest healing properties.

Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels (p = 0.0017) and AST levels (p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment (p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

Pattern and Epidemiology of Poisoning in the East African Region: A Literature Review.

The establishment and strengthening of poisons centres was identified as a regional priority at the first African regional meeting on the Strategic Approach to International Chemicals Management (SAICM) in June 2006. At this meeting, the possibility of a subregional poisons centre, that is, a centre in one country serving multiple countries, was suggested. The WHO Headquarters following consultation with counterparts at the WHO Regional Office for Africa (AFRO) and the SAICM Africa Regional Focal Point successfully submitted a proposal to the SAICM Quick Start Programme (QSP) Trust Fund Committee for a feasibility study into a subregional poisons centre in the Eastern Africa subregion. However, before such a study could be conducted it was deemed necessary to carry out a literature review on the patterns and epidemiology of poisoning in this region so as to inform the feasibility study. The current paper presents the results of this literature review. The literature search was done in the months of June and July 2012 by two independent reviewers with no language or publication date restrictions using defined search terms on PUBMED. After screening, the eventual selection of articles for review and inclusion in this study was done by a third reviewer.

Cost effectiveness of adding nucleic acid testing to hepatitis B, hepatitis C, and human immunodeficiency virus screening of blood donations in Zimbabwe.

BACKGROUND: The aim of this study was to assess the cost effectiveness of introducing individual-donation nucleic acid testing (ID-NAT), in addition to serologic tests, compared with the exclusive use of serologic tests for the identification of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) I and II among blood donors in Zimbabwe. STUDY DESIGN AND METHODS: The costs, health consequences, and cost effectiveness of adding ID-NAT to serologic tests, compared with serologic testing alone, were estimated from a health care perspective using a decision-analytic model. RESULTS: The introduction of ID-NAT in addition to serologic tests would lower the risk of HBV, HCV, and HIV transmission to 46.9, 0.3, and 2.7 per 100,000 donations, respectively. ID-NAT would prevent an estimated 25, 6, and 9 HBV, HCV, and HIV transfusion-transmitted infections per 100,000 donations, respectively. The introduction of this intervention would result in an estimated 212 quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio is estimated at US$17,774/QALY, a value far more than three times the gross national income per capita for Zimbabwe. CONCLUSION: Although the introduction of NAT could further improve the safety of the blood supply, current evidence suggests that it cannot be considered cost effective. Reducing the test costs for NAT through efficient donor recruitment, negotiating the price of reagents, and the efficient use of technology will improve cost effectiveness.

The costs of producing a unit of blood in Zimbabwe.

BACKGROUND: There is lack of published data on the costs of blood and blood transfusion in sub-Saharan Africa. This study aimed to assess the unit costs of producing blood in Zimbabwe using an activity-based costing (ABC) method. STUDY DESIGN AND METHODS: A management accounting approach, based on the ABC method, was used to develop a cost model for blood. The production of blood was broken down into recruitment, collection, testing, processing, and storage plus distribution. Data for the year 2013 were collected retrospectively from budgets, financial and expenditure reports, databases, and interviews with transfusion personnel and managers. All direct and indirect costs, in 2013 US$, were allocated, accordingly, to the activities of blood acquisition. RESULTS: The total cost of producing safe blood in Zimbabwe for the year 2013 was US$8.6 million. Variable costs accounted for 51.2% of the total cost of production. The unit production costs for red blood cells (RBCs) were US$15.94 for recruitment, US$34.62 for collection, US$17.88 for testing, US$11.49 for processing, and US$3.06 for storage plus distribution. The overall cost of production of one unit of whole blood was US$118.42 and RBCs was US$130.94 constituting 12.4 and 13.7% of the country's annual GDP per capita. CONCLUSIONS: The high unit cost of producing blood relative to the annual GDP per capita demonstrates that acquiring safe blood is a burden on the health care sector in Zimbabwe. Introducing additional safety measures, such as nucleic acid amplification testing and pathogen reduction technology, although desirable, will further increase this burden.

Experiences and Lessons From Implementing Cohort Event Monitoring Programmes for Antimalarials in Four African Countries: Results of a Questionnaire-Based Survey.

INTRODUCTION: Cohort event monitoring (CEM) is an intensive method of post-marketing surveillance for medicines safety. The method is based on prescription event monitoring, which began in the 1970s, and has since been adapted by WHO for monitoring the safety of medicines used in Public Health Programmes. CEM aims to capture all adverse events that occur in a defined group of patients after starting treatment with a specific medicine during the course of routine clinical practice. OBJECTIVE: The aims of this study were to describe the experiences of National Pharmacovigilance Centres (NCs) that have used CEM to monitor artemisinin-based combination therapy (ACT) for uncomplicated malaria in the African setting, to raise awareness of some of the challenges encountered during implementation and to highlight aspects of the method that require further consideration. METHOD: A questionnaire-based survey was conducted to capture the experiences of NCs that have implemented CEM for active post-marketing surveillance of antimalarial medicines in sub-Saharan Africa. Six NCs were identified as having implemented CEM programmes and were invited to participate in the survey; five NCs indicated willingness to participate and were sent the questionnaire to complete. RESULTS: Four NCs responded to the survey-Ghana, Kenya, Nigeria and Zimbabwe-providing information on the implementation of a total of six CEM programmes. Their experiences indicate that CEM has helped to build pharmacovigilance capacity within the participating NCs and at the monitoring sites, and that healthcare providers (HCPs) are generally willing to participate in implementing the CEM method. All of the programmes took longer than expected to complete: contributing factors included a prolonged enrolment period and unexpectedly slow data entry. All of the programmes exceeded their budget by 11.1-63.2 %. Data management was identified as a challenge for all participating NCs. CONCLUSIONS: The reported experiences of four NCs that have undertaken CEM studies on ACTs indicate that CEM has helped to build pharmacovigilance capacity within NCs and monitoring sites and that HCPs are willing to participate in CEM programmes; however, the method was found to be labour intensive and data management was identified as a challenge. Reducing the workload associated with CEM, particularly in relation to data management, and integrating the method into the routine work of HCPs and NCs should be considered for future implementation.

Profiles of blood and blood component transfusion recipients in Zimbabwe.

BACKGROUND: There are limited published data on the characteristics of blood transfusion recipients in sub-Saharan Africa. This study describes the demographic characteristics of blood transfusion recipients and patterns of blood and blood component use in Zimbabwe. MATERIALS AND METHODS: Data on the characteristics of the blood transfusion recipients (age, sex, blood group), blood components received (type, quantity), discharge diagnoses and outcomes following transfusion (discharge status, duration of stay in hospital), were retrospectively collected from four major hospitals for the period from January 1, 2012 to December 31, 2012. Diagnoses were grouped into broad categories according to the disease headings of the International Classification of Diseases (ICD-10). Surgical procedures were grouped into broad categories according to organ system using ICD-9. RESULTS: Most of the 1,793 transfusion recipients studied were female (63.2%) and in the reproductive age group, i.e. 15-49 years (65.3%). The median age of the recipients was 33 years (range, 0-93). The majority of these recipients (n=1,642; 91.6%) received a red blood cell transfusion. The majority of the patients were diagnosed with conditions related to pregnancy and childbirth (22.3%), and diseases of blood and blood-forming organs (17.7%). The median time spent in hospital was 8 days (range, 0-214) and in-hospital mortality was 15.4%. DISCUSSION: Our sample of blood transfusion recipients were fairly young and most of them received red blood cell transfusions. The majority of patients in the reproductive age group received blood transfusions for pregnancy and childbirth-related diagnoses.

Incidence and pattern of 12 years of reported transfusion adverse events in Zimbabwe: a retrospective analysis.

BACKGROUND: Haemovigilance hinges on a systematically structured reporting system, which unfortunately does not always exist in resource-limited settings. We determined the incidence and pattern of transfusion-related adverse events reported to the National Blood Service Zimbabwe. MATERIALS AND METHODS: A retrospective review of the transfusion-event records of the National Blood Service Zimbabwe was conducted covering the period from 1 January 1999 to 31 December 2011. All transfusion-related event reports received during the period were analysed. RESULTS: A total of 308 transfusion adverse events (0.046%) were reported for 670,625 blood components distributed. The majority (61.6%) of the patients who experienced an adverse event were female. The median age was 36 years (range, 1-89 years). The majority (68.8%) of the adverse events were acute transfusion reactions consisting of febrile non-haemolytic transfusion reactions (58.5%), minor allergies (31.6%), haemolytic reactions (5.2%), severe allergic reactions (2.4%), anaphylaxis (1.4%) and hypotension (0.9%). Two-thirds (66.6%) of the adverse events occurred following administration of whole blood, although only 10.6% of the blood was distributed as whole blood. Packed cells, which accounted for 75% of blood components distributed, were associated with 20.1% of the events. DISCUSSION: The incidence of suspected transfusion adverse events was generally lower than the incidences reported globally in countries with well-established haemovigilance systems. The administration of whole blood was disproportionately associated with transfusion adverse events. The pattern of the transfusion adverse events reported here highlights the probable differences in practice between different settings. Under-reporting of transfusion events is rife in passive reporting systems.

The state of health economic research in South Africa: a systematic review.

BACKGROUND: Economic factors are a limiting factor toward the implementation of many health programmes and interventions. Economic evaluation has a great potential to contribute toward cost-effective healthcare delivery in South Africa. Little is known about the characteristics and quality of health economic (including pharmacoeconomic) research in South Africa. OBJECTIVE AND METHODS: This study assessed the state of health economic (including pharmacoeconomic) research in South Africa. PUBMED, MEDLINE, HealthSTAR, EconLit and PsycINFO databases were searched to identify health economic articles pertaining to South Africa published between 1 January 1977 and 30 April 2010. The searches used the following Medical Subject Headings (MeSH) terms and text words alone and in combination: 'costs', 'health' and 'South Africa'. Our study included only original economic studies/analyses that pertained to South Africa, addressed a health-related topic, and had a statement or word in the title, abstract or keywords that indicated that an economic (including cost) analysis had been conducted. The study only included complete peer-reviewed publications (e.g. abstracts were excluded) that were reported in the English language. Two reviewers independently scored each article in the final sample using the data collection form designed for the study. RESULTS: In total, 108 studies investigating a wide variety of diseases were included in the study. These articles were published in 39 different journals mostly based outside of South Africa between 1977 and 2010. On average, each article was written by three authors. Most first authors had medical/clinical training and resided in South Africa at the time of publication of their study. Based on a 1-10 scale, with 10 indicating the highest quality, the mean quality score for all studies was 7.59 (SD 1.42) and half of the articles were of good quality (score 8-10) The quality of studies was related to the country in which the journal publishing the article was based (outside South Africa = higher); current residence of the primary author (outside South Africa = higher); method of economic analysis (economic evaluations higher than cost studies); type of data used (secondary higher than primary); primary training of the first author (health economics/pharmacoeconomics = higher); type of medical function (diagnosis = higher); study perspective (societal = higher); primary health intervention (pharmaceuticals = higher); study design (modelling = higher); number of authors (more = higher); and year of publication (more recent = higher) [p ≤ 0.05]. CONCLUSION: Half of the articles were of poor or fair quality. Measures are needed to promote the commissioning of more and better quality health economic and pharmacoeconomic studies in South Africa.

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.

Use of antidepressants and the risk of type 2 diabetes mellitus: a nested case-control study.

BACKGROUND: Recent evidence from case reports, observational studies, and randomized trials suggests that long-term use of antidepressants increases the risk of developing diabetes. However, the nature of the relationship between antidepressants and diabetes remains unclear. OBJECTIVE: To determine whether there is an association between antidepressant use and the risk of developing type 2 diabetes mellitus. METHODS: A nested case-control study using the Texas Medicaid prescription claims database was conducted. Data were extracted for new users of either antidepressant agents (exposed) or benzodiazepines (unexposed) from January 1, 2002 through December 31, 2009. Patients aged 18-64 years without a history of diabetes were included in the cohort. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the risk of diabetes associated with antidepressant exposure was computed using conditional logistic regression, controlling for demographic and clinical covariates. MAIN OUTCOME MEASURE: Development of type 2 diabetes mellitus. RESULTS: Among the total sample (N = 44,715), the majority were in the exposed (N = 35,552) vs. the unexposed (N = 9,163) group. A total of 2,943 cases of type 2 diabetes mellitus and 11,748 matched controls (1:4) were identified using risk-set sampling. Cases and controls were matched using age and gender. Antidepressant use was associated with an increase in the risk of (type-2) diabetes when compared to benzodiazepine use [Adjusted Odds Ratio (OR) = 1.512; 95% CI 1.345-1.700]. The association was observed with serotonin-norepinephrine reuptake inhibitors (OR = 1.742; 95% CI 1.472-2.060), tricyclic antidepressants (OR = 1.533; 95% CI 1.295-1.814), selective serotonin reuptake inhibitors (OR = 1.457; 95% CI 1.279-1.659), "Other" antidepressants (OR = 1.318; 95% CI 1.129-1.540). CONCLUSIONS: Antidepressant use was associated with an increased risk of (type-2) diabetes. This association was observed for tricyclic antidepressants, serotonin-reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other antidepressants.

ADHD medication use, adherence, persistence and cost among Texas Medicaid children.

OBJECTIVES: (1) Describe ADHD medication use, adherence and persistence. (2) Determine factors (e.g., medication type, demographics, concomitant medication use) associated with ADHD medication adherence and persistence. (3) Compare ADHD medication costs. METHODS: Continuously enrolled Texas Medicaid children (3-18 years) with ≥ 2 ADHD prescription claims (July 2002-December 2008) were included. Prescription claims were grouped by medication type (i.e., immediate-release, extended-release, prodrug, non-stimulant); medication class (i.e., stimulant, non-stimulant); and duration of action (i.e., long-acting, short-acting). Adherence, using medication possession ratio, was measured continuously and dichotomously (80% cut-off). Persistence was days of continuous therapy without a 30-day gap and medication costs were reimbursement amount paid to dispensing pharmacies. RESULTS: The study sample (n = 62,789) was primarily 6-12 years (61.7%) and male (69.2%). The majority of the subjects were prescribed extended-release agents (70.3%), stimulant agents (86.4%), and long-acting agents (84.5%). Adherence and persistence (adherence mean ± SD; adherence dichotomous; persistence mean ± SD) varied among medication type and was highest for non-stimulants (52.5 ± 30.9; 25.8%; 153.3 ± 124.3), followed by extended-release stimulants (52.1 ± 30.2; 24.1%; 143.7 ± 120.8), prodrug stimulants (47.6 ± 30.9; 21.1%; 113.3 ± 100.5) and immediate-release stimulants (37.2 ± 27.1; 9.8%; 95.4 ± 92.6). Logistic regression showed immediate-release stimulant users were 67% less adherent than non-stimulant users (p < 0.0001) and linear regression showed immediate-release, extended-release and long-acting users (p < 0.0001) were significantly less persistent than non-stimulant users. Females, increase in total number of medications, and comorbid medications were associated with better adherence and persistence. Non-stimulant agents ($4.04 ± $2.15) had the highest mean medication cost per patient per day and immediate-release stimulants had the lowest ($1.24 ± $0.97). CONCLUSIONS: ADHD medication adherence and persistence was suboptimal. Although there was no difference in adherence between long-acting stimulant and non-stimulant users, non-stimulant users were more persistent compared to stimulant users. This study was limited due to the use of retrospective prescription claims data, which cannot capture actual patient use patterns, ICD-9 diagnoses, family history and support, or side effect profiles. Because ADHD can be effectively treated with pharmacotherapy, providers should be proactive in identifying patients with poor adherence and intervene to address barriers to medication adherence and persistence.

Glucose dysregulation associated with antidepressant agents: an analysis of 17 published case reports.

AIM OF THE REVIEW: Although there are several case reports in literature linking use of antidepressants and disturbances in glucose control, it is difficult to identify risk factors for serious adverse drug events from individual case reports. The aim of this review is to provide a descriptive analysis of the demographic and clinical characteristics of published glucose dysregulation case reports following initiation of antidepressant agents. METHODS: Published case reports of glucose dysregulation associated with antidepressants were accessed through PubMed (Medline), PsycINFO, and Web of Science (WOS) between January 1, 1970 and April 30, 2010. The following key words were used: antidepressant agents, glucose dysregulation, hypoglycemia, hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Case reports were excluded if glucose dysregulation occurred after a drug overdose/improper dosing or after the patient was prescribed drugs known to cause glucose disturbances in addition to antidepressant agents. RESULTS: Out of the 17 cases reports reviewed, nine (53%) were of hyperglycemia while eight (47%) were of hypoglycemia. Hyperglycemia was reported following treatment with clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline. Hypoglycemia was reported following treatment with doxepine, fluoxetine, imipramine, nefazodone, nortriptyline, maprotiline, and sertraline. Fourteen out of the seventeen patients were female (82%) while ten had a history of diabetes mellitus (59%). The average age of the patients was 53.9 (SD = 17.5) years (range: 24-84 years). The time to onset of glucose dysregulation ranged from 4 days to 5 months after initiation of antidepressant therapy. More than two-thirds (68%) of the cases (n = 11) reported glucose control disturbances within 1 month of therapy. CONCLUSIONS: It is not clear from published case reports whether changes in glucose regulation, following antidepressant therapy initiation are due to antidepressants or changes in mood and lifestyle. Nonetheless, healthcare providers should be aware of the potential changes in glucose regulation especially in the first month of antidepressant therapy, and use appropriate clinical and laboratory monitoring to prevent serious adverse events in patients at risk.