Drug discovery and developments in developing countries: bottlenecks and way forward

Infectious and parasitic diseases continue to threaten the health of million of people throughout the world, with the major burden being in developing countries. Many of the currently available drugs for the treatment of these diseases face setbacks such as insufficient efficacy, increasing loss of effectiveness due to emergence of resistance, high levels of toxicity, inaccessibility and/or high costs. The driving force for drug discovery and development by pharmaceutical firms has been the foreseeable profit from drug sells. Since most infectious diseases prevail in developing countries and the fact that people living in these countries have poor purchasing power, the market for such drugs are unattractive to these firms. Thus, there has been reluctance for the pharmaceutical companies to engage in the development of drugs addressing diseases that mainly affect developing countries. Although a lot of research to discover new effective and cheap drugs is in progress in the disease endemic countries, it is not yet possible to fully develop leads and drug candidates from natural products, hence people in these countries continue to rely on traditional medicines. Poor economies and technological capabilities, lack of human resources and good management in these countries are the major constraints to progress in research and development work for new drugs. This paper discusses these major bottlenecks in drug discovery and development and suggests the way forward. Keywords: drug discovery, traditional medicine, infectious diseases, developing countries Tanzania Health Research Bulletin Vol. 7(3) 2005: 154-15

In vitro multistage malaria transmission blocking activity of selected malaria box compounds

Purpose: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. Methods: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. Results: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07\u20130.13 \ub5M. They were also active against mature stage V gametocytes with IC50 values below 5 \ub5M (range: 3.43\u20134.42 \ub5M). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 \ub5M. Conclusion: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials

In vitro multistage malaria transmission blocking activity of selected Malaria Box compounds

Purpose: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. Methods: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. Results: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07-0.13 µM. They were also active against mature stage V gametocytes with IC50 values below 5 µM (range: 3.43-4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 µM. Conclusion: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials

Self-Reported Occupational Exposure to HIV and Factors Influencing its Management Practice: A Study of Healthcare Workers in Tumbi and Dodoma Hospitals, Tanzania.

Blood borne infectious agents such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immune deficiency virus (HIV) constitute a major occupational hazard for healthcare workers (HCWs). To some degree it is inevitable that HCWs sustain injuries from sharp objects such as needles, scalpels and splintered bone during execution of their duties. However, in Tanzania, there is little or no information on factors that influence the practice of managing occupational exposure to HIV by HCWs. This study was conducted to determine the prevalence of self-reported occupational exposure to HIV among HCWs and explore factors that influence the practice of managing occupational exposure to HIV by HCWs in Tanzania. Self-administered questionnaire was designed to gather information of healthcare workers' occupational exposures in the past 12 months and circumstances in which these injuries occurred. Practice of managing occupational exposure was assessed by the following questions: Nearly half of the HCWs had experienced at least one occupational injury in the past 12 months. Though most of the occupational exposures to HIV were experienced by female nurses, non-medical hospital staff received PEP more frequently than nurses and doctors. Doctors and nurses frequently encountered occupational injuries in surgery room and labor room respectively. HCWs with knowledge on the possibility of HIV transmission and those who knew whom to contact in event of occupational exposure to HIV were less likely to have poor practice of managing occupational exposure. Needle stick injuries and splashes are common among HCWs at Tumbi and Dodoma hospitals. Knowledge of the risk of HIV transmission due to occupational exposure and knowing whom to contact in event of exposure predicted practice of managing the exposure. Thus provision of health education on occupational exposure may strengthen healthcare workers' practices to manage occupational exposure

Estimated Risk of HIV Acquisition and Practice for Preventing Occupational Exposure: A Study of Healthcare Workers at Tumbi and Dodoma Hospitals, Tanzania.

Health care workers (HCWs) are at risk of acquiring human immuno-deficiency virus (HIV) and other infections via exposure to infectious patients' blood and body fluids. The main objective of this study was to estimate the risk of HIV transmission and examine the practices for preventing occupational exposures among HCWs at Tumbi and Dodoma Hospitals in Tanzania. This study was carried out in two hospitals, namely, Tumbi in Coast Region and Dodoma in Dodoma Region. In each facility, hospital records of occupational exposure to HIV infection and its management were reviewed. In addition, practices to prevent occupational exposure to HIV infection among HCWs were observed. The estimated risk of HIV transmission due to needle stick injuries was calculated to be 7 cases per 1,000,000 HCWs-years. Over half of the observed hospital departments did not have guidelines for prevention and management of occupational exposure to HIV infections and lacked well displayed health and safety instructions. Approximately, one-fifth of the hospital departments visited failed to adhere to the instructions pertaining to correlation between waste materials and the corresponding colour coded bag/container/safety box. Seventy four percent of the hospital departments observed did not display instructions for handling infectious materials. Inappropriate use of gloves, lack of health and safety instructions, and lack of use of eye protective glasses were more frequently observed at Dodoma Hospital than at Tumbi Hospital. The poor quality of the hospital records at the two hospitals hampered our effort to characterise the risk of HIV infection acquisition by HCWs. Greater data completeness in hospital records is needed to allow the determination of the actual risk of HIV transmission for HCWs. To further reduce the risk of HIV infection due to occupational exposure, hospitals should be equipped with sufficient personal protective equipment (PPE) and HCWs should be reminded of the importance of adhering to universal precautions

Acceptability of Condom Promotion and Distribution Among 10-19 Year-Old Adolescents in Mpwapwa and Mbeya Rural Districts, Tanzania.

\ud The HIV/AIDS pandemic remains a leading challenge for global health. Although condoms are acknowledged for their key role on preventing HIV transmission, low and inappropriate use of condoms persists in Tanzania and elsewhere in Africa. This study assesses factors affecting acceptability of condom promotion and distribution among adolescents in Mpwapwa and Mbeya rural districts of Tanzania. Data were collected in 2011 as part of a larger cross-sectional survey on condom use among 10-19 year-olds in Mpwapwa and Mbeya rural districts of Tanzania using a structured questionnaire. Associations between acceptability of condom promotion and distribution and each of the explanatory variables were tested using Chi Square. Multivariate logistic regression model was used to examine independent predictors of the acceptability of condom promotion and distribution using STATA (11) statistical software at 5% significance level. Mean age of the 1,327 adolescent participants (50.5% being males) was 13.5 years (SD = 1.4). Acceptance of condom promotion and distribution was found among 37% (35% in Mpwapwa and 39% in Mbeya rural) of the adolescents. Being sexually active and aged 15-19 was the strongest predictor of the acceptability of condom promotion and distribution (OR = 7.78, 95% CI 4.65-12.99). Others were; not agreeing that a condom is effective in preventing transmissions of STIs including HIV (OR = 0.34, 95% CI 0.20-0.56), being a resident of Mbeya rural district (OR = 1.67, 95% CI 1.28-2.19), feeling comfortable being seen by parents/guardians holding/buying condoms (OR = 2.20, 95% CI 1.40-3.46) and living with a guardian (OR = 1.48, 95% CI 1.08-2.04). Acceptability of condom promotion and distribution among adolescents in Mpwapwa and Mbeya rural is low. Effect of sexual activity on the acceptability of condom promotion and distribution is age-dependent and was the strongest. Feeling comfortable being seen by parents/guardians buying or holding condoms, perceived ability of condoms to offer protection against HIV/AIDS infections, district of residence and living arrangements also offered significant predictive effect. Knowledge of these factors is vital in designing successful and sustainable condom promotion and distribution programs in Tanzania.\u

Role of traditional healers in the management of severe malaria among children below five years of age: the case of Kilosa and Handeni Districts, Tanzania

BACKGROUND: The current malaria control strategy of WHO centres on early diagnosis and prompt treatment using effective drugs. Children with severe malaria are often brought late to health facilities and traditional health practitioners are said to be the main cause of treatment delay. In the context of the Rectal Artesunate Project in Tanzania, the role of traditional healers in the management of severe malaria in children was studied. METHODOLOGY: A community cross-sectional study was conducted in Kilosa and Handeni Districts, involving four villages selected on the basis of existing statistics on the number of traditional health practitioners involved in the management of severe malaria. A total of 41 traditional health practitioners were selected using the snowballing technique, whereby in-depth interviews were used to collect information. Eight Focus Group Discussions (FGDs) involving traditional health practitioners, caregivers and community leaders were carried out in each district. RESULTS: Home management of fever involving sponging or washing with warm water at the household level, was widely practiced by caregivers. One important finding was that traditional health practitioners and mothers were not linking the local illness termed degedege, a prominent feature in severe malaria, to biomedically-defined malaria. The majority of mothers (75%) considered degedege to be caused by evil spirits. The healing process was therefore organized in stages and failure to abide to the procedure could lead to relapse of degedege, which was believed to be caused by evil spirits. Treatment seeking was, therefore, a complex process and mothers would consult traditional health practitioners and modern health care providers, back and forth. Referrals to health facilities increased during the Rectal Artesunate Project, whereby project staff facilitated the process after traditional medical care with the provision of suppositories. This finding is challenging the common view that traditional healers are an important factor of delay for malaria treatment, they actually play a pivotal role by giving "bio-medically accepted first aid" which leads to reduction in body temperature hence increasing chances of survival for the child. Increasing the collaboration between traditional healers and modern health care providers was shown to improve the management of severe malaria in the studied areas. INTERPRETATION AND CONCLUSION: Traditional health care is not necessarily a significant impediment or a delaying factor in the treatment of severe malaria. There is a need to foster training on the management of severe cases, periodically involving both traditional health practitioners and health workers to identify modalities of better collaboration

To what extent can traditional medicine contribute a complementary or alternative solution to malaria control programmes?

Recent studies on traditional medicine (TM) have begun to change perspectives on TM effects and its role in the health of various populations. The safety and effectiveness of some TMs have been studied, paving the way to better collaboration between modern and traditional systems. Traditional medicines still remain a largely untapped health resource: they are not only sources of new leads for drug discoveries, but can also provide lessons and novel approaches that may have direct public-health and economic impact. To optimize such impact, several interventions have been suggested, including recognition of TM's economic and medical worth at academic and health policy levels; establishing working relationships with those prescribing TM; providing evidence for safety and effectiveness of local TM through appropriate studies with malaria patients; spreading results for clinical recommendations and health policy development; implementing and evaluating results of new health policies that officially integrate TM

Neuromuscular disease genetics in under-represented populations: increasing data diversity

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% ‘solved’ and ∼13% ‘possibly solved’ outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally