Adverse Drug Reaction Reporting by Doctors in a Developing Country: A Case Study from Ghana

Background: Spontaneous adverse drug reaction reporting is the most widely used and cost effective method of monitoring the safety of drugs. This method is heavily afflicted by underreporting by healthcare professionals. The study aims at assessing adverse drug reaction (ADR) reporting rate by doctors; knowledge of the reporting system and attitudes to SADR in the Greater Accra region. Methods: This was a cross sectional survey of 259 doctors randomly selected from 23 hospitals classified as government 199 (76.8); quasi-governmental 43(16.6) and private 17 (6.6) hospitals in the Greater Accra Region of Ghana. Data collection was by self-administered questionnaire from May 5; 2012- July 6; 2012. Descriptive statistics was used to describe the background characteristics of the doctors and the outcome measures like training and reasons for ADR reporting were summarized as frequencies and percentages. Results: One-third (27.4) of doctors surveyed had received previous training on drug safety monitoring and ADR reporting; training and knowledge of the reporting system was found to improve reporting. More than half 154 (59.5) of the doctors had seen a patient with suspected ADR in the past one year although only 31 (20) had reported it by completing the SADR reporting form. Doctors working in government hospitals were about 5 times more likely to report than those in private hospitals [OR=4.94; 95CI (1.55-15.69)]. Conclusion: Training and knowledge of the ADR reporting system were found to be associated with the likelihood of reporting an ADR. Most of the doctors had not previously received training on ADR reporting

Pharmacoepidemiology of antiretroviral drugs in a teaching hospital in Lagos, Nigeria.

OBJECTIVE: Prescribing, adherence, and adverse drug events to HAART in a large antiretroviral programme in Lagos was evaluated. DESIGN: A retrospective 5 year open cohort study. SETTING: The AIDS Prevention Initiative in Nigeria (APIN) clinic at LUTH is one of the United States Presidential Emergency Plan for AIDS Relief (PEP-FAR) funded centers for HIV relief program in Nigeria Participants The case files of 390 patients on HAART and attending the APIN clinic were reviewed sequel to random selection. MAIN OUTCOME MEASURES: Demographics of the patients and pattern of antiretroviral (ARV) combination drugs prescribed were extracted from their case files. The details of the adverse drug events (ADEs) were extracted from drug toxicity forms regularly filled for each patient. A Chi-square test with Yates correction was used to determine the association between adherence and therapeutic outcome. RESULTS: A total of 2944 prescriptions were assessed. Zidovudine + lamivudine + nevirapine (35.87%) and stavudine + lamivudine + nevirapine (35.63%) were the most frequently prescribed combinations. Over 2000 ADEs were reported with cough (13.3%), fever (8.75%) and skin rashes (8.01%) being the most frequently reported. Drug adherence was associated with good therapeutic outcome (χ(2) = 115.60, p<0.0001). CONCLUSIONS: Zidovudine + lamivudine + nevirapine was the most frequently prescribed ARV combination. Cough was the most frequently reported ADE. Interventions aimed at rational prescribing of ARV drugs and improving adherence to antiretroviral drugs is essential for good therapeutic outcome in the treatment of HIV infection.

Adverse drug reaction reporting by doctors in a developing country: a case study from Ghana.

BACKGROUND: Spontaneous adverse drug reaction reporting is the most widely used and cost effective method of monitoring the safety of drugs. This method is heavily afflicted by underreporting by healthcare professionals. The study aims at assessing adverse drug reaction (ADR) reporting rate by doctors, knowledge of the reporting system and attitudes to SADR in the Greater Accra region. METHODS: This was a cross sectional survey of 259 doctors randomly selected from 23 hospitals classified as government 199 (76.8%), quasi-governmental 43(16.6%) and private 17 (6.6%) hospitals in the Greater Accra Region of Ghana. Data collection was by self-administered questionnaire from May 5, 2012-July 6, 2012. Descriptive statistics was used to describe the background characteristics of the doctors and the outcome measures like training and reasons for ADR reporting were summarized as frequencies and percentages. RESULTS: One-third (27.4%) of doctors surveyed had received previous training on drug safety monitoring and ADR reporting; training and knowledge of the reporting system was found to improve reporting. More than half 154 (59.5%) of the doctors had seen a patient with suspected ADR in the past one year although only 31 (20%) had reported it by completing the SADR reporting form. Doctors working in government hospitals were about 5 times more likely to report than those in private hospitals [OR=4.94, 95%CI (1.55-15.69)]. CONCLUSION: Training and knowledge of the ADR reporting system were found to be associated with the likelihood of reporting an ADR. Most of the doctors had not previously received training on ADR reporting.

The role of generic medicines and biosimilars in oncology in low-income countries.

Cancer cases are rising in developing countries which are already grappling with high levels of infectious diseases including human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), tuberculosis (TB) and malaria. The United Nations (UN) including the World Health Organisation (WHO) have called on member states to establish strategies to deal with the increasing burden of non-communicable diseases, including cancer, in developing countries. The complexity of cancer care and management calls for innovative approaches in low resource settings especially since these settings are already grappling with huge challenges in healthcare including lack of funds, weak human resource base and lack of treatment guidelines. Whilst the cost of medications is by no means the only high cost in cancer care, the availability of affordable anti-cancer generic drugs and biologically similar therapeutic agents (biosimilars) will go a long way to reduce overall cost of cancer care. The high cost of anticancer medicines has been cited among the reasons whilst patients default in treatment. Non-proprietary anti-cancer agents--generics and biosimilars--often cost several times lower than their innovator branded counterparts. They can reduce the cost of care significantly and their multi-source origin often provide guarantee in supply. The use of generic and biosimilar products is hinged on the assumption that they are of assured quality and of the same pharmaceutical integrity as their innovator counterparts. The use of these products however is associated with challenges that must be understood and addressed. The quality of all generics and biosimilars should be rigorously controlled and assured. Measures to prevent counterfeit and sub-standard generics and biosimilars should be developed and the cold-chain must be maintained for all biosimilars. In addition to these, the WHO is encouraged to develop a prequalification scheme to assist countries without strong regulatory systems to procure anticancer generics and biosimilars of assured quality.

The concept of vaccination failure.

Despite remarkable success of immunization programmes on a global perspective, vaccines are neither 100% efficacious nor 100% effective. Therefore, vaccination failure, i.e. occurrence of a specific disease in an individual despite previous vaccination, may occur. Vaccination failure may be due to actual vaccine failure or failure to vaccinate appropriately. Universally accepted concepts and definitions of vaccination failure are required to assess and compare the benefit of vaccines used in populations. Here we propose general definitions for types of vaccination failure. In the future, these should be complemented by specific definitions for specific vaccines as needed depending on public health considerations.

Pharmacogenetics in Ghana: reviewing the evidence.

Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.

High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria.

Although the roles played by systemic tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta), and their upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, in the pathogenesis of human cerebral malaria (CM) are well established, the role of local cytokine release, in the brain, remains unclear. Immunohistochemistry was therefore used to compare the expression of ICAM-1, VCAM-1, E-selectin, IL-1beta, TNF and transforming growth factor beta (TGF-beta) at light-microscope level, in cryostat sections of cerebral, cerebellar and brainstem tissues collected, post-mortem, from Ghanaian children. Among the 21 children investigated were 10 cases of CM, five of severe malarial anemia (SMA), one of purulent bacterial meningitis (PBM), two of non-central-nervous-system infection (NCNSI) and three children who had no infection (NI) when they died. Parasitised erythrocytes were detected in all of the sections from the cases of fatal malaria (CM and SMA), and sequestered leucocytes were present in most of the sections from the CM cases (but none of the sections from the SMA cases). Significantly elevated vascular expression of all three adhesion molecules investigated was detected in the brains of the 15 cases of fatal malaria and one of the cases of NCNSI (a child with Salmonella septicaemia), and in the malaria cases this showed highly significant co-localization with the areas of erythrocyte sequestration. In terms of the levels of expression of ICAM-1, VCAM-1 and E-selectin, there were, however, negligible differences between the CM and SMA cases. Although TGF-beta showed intravascular and perivascular distribution in all the subjects, its expression was most intense in the PBM case and the CM group. Only in the sections from the PBM and CM cases did TNF and IL-1beta show prominent brain parenchymal staining, in addition to the intravascular and perivascular staining seen in all subjects. The highest observed expression of each of the six antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation in the brain therefore appears to be a feature of fatal malaria and Salmonella sepsis, and in cases of fatal malaria is closely associated with leucocyte sequestration. In the present study, IL-1beta and TNF were only up-regulated in the brains of children with neurodegenerative lesions, whereas TGF-beta was present in all cases.

Findings from a buruli ulcer mouse model study.

SUMMARY INTRODUCTION: Buruli ulcer disease is endemic in many developing countries in Africa. It is caused by Mycobacterium ulcerans, a toxin-producing bacterium with predilection for the skin and its deeper tissues. The exact mode of transmission is unclear and the pathogenesis is also not well understood, necessitating further elucidation through animal studies. OBJECTIVE: The study assessed the infectivity of a Ghanaian Mycobacterium ulcerans isolate and the dose-response pattern in BALB/c mice. METHOD: Ten standardized bacterial suspensions of different concentrations were prepared from the M. ulcerans isolate and inoculated into the foot-pads of the mice. Thereafter they were observed for clinical signs of Buruli ulcer, upon which they were serially euthanised and evaluated for pathological and microbiological changes. RESULTS: Irrespective of the inoculum dose, all the experimentally infected mice developed similar clinical lesions, from erythema to foot ulceration (3.1 to 6.7 weeks after inoculation). However, the higher the inoculum dose the earlier the onset of the lesions. After the development of foot ulceration, mice that had received between 1 to 4 doses developed gangrene (5.7 to 7.2 weeks after inoculation) and died within a week, while those that had received 5 to 10 doses lost their limbs spontaneously (5.6 to 6.1 weeks after inoculation), followed by sudden clinical recovery. Eight weeks after the spontaneous amputation the amputees relapsed with concomitant metastasis, anasarca and death. Acid-fast bacilli (AFBs) were detected in inoculated and non-inoculated limbs, tails, visceral organs, faecal pellets and caecal contents of the mice. The AFBs detected in the caecal samples were innumerable and unusually long. Though AFBs were consistently detected in lymph nodes they were never detected in blood samples. CONCLUSION: The findings suggest that the progression and final outcome of an M. ulcerans infection maybe dose related. The unequivocal absence of AFBs in the blood, but their consistent presence in lymph nodes located in the lower limbs right up to the neck, suggests that the microbes are disseminated through the lymphatic system rather than through the blood.

Systematic investigations of the influence of molecular structure on the transport of peptides across cultured alveolar cell monolayers.

PURPOSE: To determine how the structures of peptides influence their alveolar permeability. METHODS: The studies were performed using 14 synthetic 'model' peptides, labelled with a novel, non-intrusive amino acid fluorophore, and their transport studied using rat alveolar cell monolayers cultured on permeable supports. RESULTS: The passage of the peptides across the epithelial cell monolayers is shown to be primarily paracellular, with an inverse dependence on molecular size, and an enhanced flux observed for cationic peptides. The apparent permeability coefficients (Papp) for the peptides (together with those for other organic solutes, taken from the literature) are shown to be well-modelled assuming two populations of 'pores' in the monolayers, modelled as cylindrical channels of radii 15 A and 22 nm. The former pores are shown to be numerically equitable with the monolayer tri-junctional complexes, and the latter are taken as monolayer defects. CONCLUSIONS: The various monolayer Papp values correlate well with the results from in vivo transport experiments, and the conclusion is drawn that the pulmonary delivery of peptide drugs is perfectly exploitable.

Use of alveolar cell monolayers of varying electrical resistance to measure pulmonary peptide transport.

The apparent permeability coefficient (P(app)) of two fluorescently tagged model hydrophilic peptides, acXASNH(2) and acXAS(GAS)(7)NH(2), and (14)C-mannitol across monolayers of cultured rat alveolar epithelial cells of varying transepithelial electrical resistance (TER) has been examined. In line with their design features, the peptides were not degraded under the conditions of the test. Furthermore, no concentration dependence of transport of the tripeptide acXASNH(2) was observed over the concentration range studied, nor was any directional transport seen for either of the model peptides, indicating that under the conditions of the test they were not substrates for any transporters or efflux pumps. From the hydrophilic nature of the peptides (as assessed by their log P), and their inverse dependence of transport with molecular weight and TER, it was assumed that the peptides were transported across the cell monolayer passively via the paracellular route. The observed P(app) for the transport of (14)C-mannitol and the peptides across rat alveolar epithelial cell monolayers were found to be inversely (though not linearly) related to the measured TER and could be well-modeled assuming the presence of two populations of "pores" in the cell monolayer, namely, cylindrical pores of diameter 1.5 nm and large pores of diameter 20 nm. The relative populations of the two types of pores varied with the TER of the monolayer, with the number of large pores decreasing with an increase in TER (and the number of small pores taken as fixed). These results suggest that if the cell monolayer is well characterized with respect to the passage of a range of probe molecules across monolayers of varying electrical resistance, it should be possible to predict the P(app) of any hydrophilic peptide or drug crossing the membrane by the paracellular route at any desired TER using a monolayer of any electrical resistance, above a minimum value.

Synthesis and properties of (6,7-dimethoxy-4-coumaryl)alanine: a fluorescent peptide label.

The synthesis of racemic and l-(6,7-dimethoxy-4-coumaryl)alanine (Dmca) is described and some spectral and physicochemical properties are reported. The utility of Dmca as a highly sensitive and specific label for the quantitative detection of synthetic peptides in HPLC and in minimal essential media (MEM) is also described.

Seasonality of rotavirus infection in Ghana.

Human rotavirus (HRV) infection and its seasonal distribution was studied over a 12-month period in Ghana. A total of 561 stool samples, 447 diarrhoea stools and 114 non-diarrhoea stools (controls), were obtained from children attending three polyclinics in Accra. Rotavirus was detected during 10 of the 12 months and showed a seasonal trend. It was high during the relatively cool dry months and low during the wet season. Peaks of infection were in February (26.2%) and September (24.5%). HRV was detected in 67 of 447 of the diarrhoea stools (15.0%) and in eight of 114 controls (7.0%). The HRV isolation rate was highest (20.2%) in the under-18-months age group. The RNA electropherotype of the HRV isolates was predominantly (83.6%) of the long type. Non-group A HRV was detected in 14.9% of the HRV-positive samples.