ghanaopendata/ghanaian-research-english huggingface dataset:
Pharmacogenetics and rational drug use around the world

The WHO embraces evidence-based medicine to formulate an essential medicines list (EML) considering disease prevalence, drug efficacy, drug safety and cost-effectiveness. The EML is used by developing countries to build a national formulary. As pharmacogenetics in developed countries evolves, the Pharmacogenetics for Every Nation Initiative (PGENI) convened with representatives from China, Mexico, Ghana and South Africa in August 2009 to evaluate the use of human pharmacogenetics to enhance global drug use policy. The diseases causing mortality, the lack of integration of pharmacovigilance at the national formulary level, the pharmacogenetics research agenda and pharmacogenetics clinician education did not differ greatly among the countries. While there are many unanswered questions, systematically incorporating pharmacogenetics at the national formulary level promises to improve global drug use.

Source: UG
Pharmacogenetics of catechol-O-methyltransferase: Frequency of low activity allele in a Ghanaian population

Catechol-O-methyltransferase (COMT) catalyses the O-methylation of neurotransmitters, catechol hormones and drugs such as levodopa and methyldopa. Ethnic differences in COMT activity have been observed in several populations. Previous studies suggest that the g1947G>A low activity allele is less common in individuals of African origin. COMT genotyping was performed using a mini-sequencing method in 195 healthy Ghanaians with a frequency of the homozygous g1947G>A of 6%. This study provides confirmation that the low activity COMT allele is less common in individuals of African origin. This finding may be important clinically with regards to the treatment of many neuropsychiatric disorders and in the pathophysiology of various human disorders including estrogen-induced cancers, Parkinson's disease, depression and hypertension. Copyright 2000 Wiley-Liss, Inc.

Source: UG
Pharmacoinformatics-based identification of potential bioactive compounds against Ebola virus protein VP24

Background: The impact of Ebola virus disease (EVD) is devastating with concomitant high fatalities. Currently, various drugs and vaccines are at different stages of development, corroborating the need to identify new therapeutic molecules. The VP24 protein of the Ebola virus (EBOV) plays a key role in the pathology and replication of the EVD. The VP24 protein interferes with the host immune response to viral infections and promotes nucleocapsid formation, thus making it a viable drug target. This study sought to identify putative lead compounds from the African flora with potential to inhibit the activity of the EBOV VP24 protein using pharmacoinformatics and molecular docking. Methods: An integrated library of 7675 natural products originating from Africa obtained from the AfroDB and NANPDB databases, as well as known inhibitors were screened against VP24 (PDB ID: 4M0Q) utilising AutoDock Vina after energy minimization using GROMACS. The top 19 compounds were physicochemically and pharmacologically profiled using ADMET Predictor™, SwissADME and DataWarrior. The mechanisms of binding between the molecules and EBOV VP24 were characterised using LigPlot+. The performance of the molecular docking was evaluated by generating a receiver operating characteristic (ROC) by screening known inhibitors and decoys against EBOV VP24. The prediction of activity spectra for substances (PASS) and machine learning-based Open Bayesian models were used to predict the anti-viral and anti-Ebola activity of the molecules, respectively. Results: Four natural products, namely, ZINC000095486070, ZINC000003594643, ZINC000095486008 and sarcophine were found to be potential EBOV VP24-inhibitiory molecules. The molecular docking results showed that ZINC000095486070 had high binding affinity of −9.7 kcal/mol with EBOV VP24, which was greater than those of the known VP24-inhibitors used as standards in the study including Ouabain, Nilotinib, Clomiphene, Torimefene, Miglustat and BCX4430. The area under the curve of the generated ROC for evaluating the performance of the molecular docking was 0.77, which was considered acceptable. The predicted promising molecules were also validated using induced-fit docking with the receptor using Schrödinger and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The molecules had better binding mechanisms and were pharmacologically profiled to have plausible efficacies, negligible toxicity as well as suitable for designing anti-Ebola scaffolds. ZINC000095486008 and sarcophine (NANPDB135) were predicted to possess antiviral activity, while ZINC000095486070 and ZINC000003594643 to be anti-Ebola compounds. Conclusion: The identified compounds are potential inhibitors worthy of further development as EBOV biotherapeutic agents. The scaffolds of the compounds could also serve as building blocks for designing novel Ebola inhibitors.

Source: UG
Pharmacokinetic and biodistribution studies of Amphotericin B microspheres

The pharmacokinetics of Amphotericin B (AmB) from polyethylene glycol 2000 (PEG 2000) entrapped cross-linked bovine serum albumin (BSA) microsphere formulations were investigated and compared with solution formulation. The microsphere preparations were characterized for particle size using electron microscopy, zeta potential and encapsulation efficiency. The microsphere formulations demonstrated a sustained release of AmB for a longer period of time, with no rise in plasma creatinine and potassium levels. The enhanced AmB accumulation in lungs was observed which could be of importance since lungs are the primary target in most fungal infections. The stealth property of submicron cross-linked BSA microspheres in formulations containing PEG 2000 (formulation F-2N) and without PEG 2000 (formulation F-1N) was also evaluated. There was no evidence that microspheres embedded with PEG remained longer in circulation; however, it was noticed that the internalization of formulation F-2N microspheres was delayed when compared with microspheres from formulation F-1N.

Source: UG
Pharmacokinetics and in vivo chemosuppressive activity studies on cryptolepine hydrochloride and cryptolepine hydrochloride-loaded gelatine nanoformulation designed for parenteral administration for the treatment of malaria

The Epidemiology Department contributes to the mission of the institute through basic and applied epidemiological research on, but not limited to, malaria and other diseases of public health importance. It is also home to the Social Science Unit of the Institute, including the Health Support Centre for HIV/AIDS and other communicable and noncommunicable health problems.

Source: UG
Pharmacokinetics of enrofloxacin given by the oral, intravenous and intramuscular routes in broiler chickens

Enrofloxacin was given to broiler chickens, 3 groups of 6 birds each, at a dose of 5 mg/kg. Routes of administration were intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) and blood samples were collected from the jugular vein for determination of serum drug levels over a 54-hour period after administration. Drug levels were determined using Bacillus subtilis spore suspension on Meuller-Hinton antibiotic medium. Intravenous administration produced drug levels which followed a bi-exponential decay according to the model C = 101e(-1.84(t)) + 1.30e(-0.06(t)). After i.m. administration, the mean Cmax observed (2.01 microg/mL) occurred at 1 h and levels were detected for up to 48 h. The mean time to maximum concentration (Tmax) for the birds occurred at 0.79 h. The model describing serum concentrations after i.m. administration was C = 1.35e(-0.48(t)) + 1.27e(-0.07(t)) - 2.06e(-2.1(t)). Serum concentrations after oral administration were lower and the mean +/- standard error of mean, of the maximum concentrations (Cmax) was 0.99 microg/mL at 2 h after administration. The mean residence times after the 3 routes of administration were not significantly different and ranged from 12.5-13.7 h. Bioavailability by the oral route was 80.1%. Dialysis of chicken plasma vs saline indicated that the protein binding was 22.7%.

Source: UG
Pharmacokinetics of Sulfadoxine-Pyrimethamine in HIV-Infected and Uninfected Pregnant Women in Western Kenya

Background. Sulfadoxine-pyrimethamine (SP) is among the most commonly used antimalarial drugs during pregnancy, yet the pharmacokinetics of SP are unknown in pregnant women. HIV-infected (HIV+) women require more frequent doses of intermittent preventive therapy with SP than do HIV-uninfected (HIV-) women. We investigated whether this reflects their impaired immunity or an HIV-associated alteration in the disposition of SP. Methods. Seventeen pregnant HIV- women and 16 pregnant HIV+ women received a dose of 1500 mg of sulfadoxine and 75 mg of pyrimethamine. Five HIV- and 6 HIV+ postpartum women returned 2–3 months after delivery for another dose. The pharmacokinetics of sulfadoxine and pyrimethamine were compared between these groups. Results. HIV status did not affect the area under the curve (AUC0→∞) or the half-lives of sulfadoxine or pyrimethamine in prepartum or postpartum women, although partum status did have a significant affect on sulfadoxine pharmacokinetics. Among prepartum women, the median half-life for sulfadoxine was significantly shorter than that observed in postpartum women (148 vs 256 h; P < .001), and the median AUC0→∞ was ∼40% lower (22,816 vs 40,106 μg/mL/h, P < .001). HIV status and partum status did not show any significant influence on pyrimethamine pharmacokinetics. Conclusion. Pregnancy significantly modifies the disposition of SP, whereas HIV status has little influence on pharmacokinetic parameters in pregnant women.

Source: UG
Pharmacokinetics of the oral iron chelatordeferiprone (L1) in patients with iron overload

Single oral dose pharmacokinetics of the iron chelator deferiprone (L1) were studied in 24 patients with chronic iron overload and correlated with 24 h urinary iron excretion (UIE) and creatinine clearance. Absorption of L1 was rapid with a t1/2 of 22.2 +/- 17.7 (mean +/- SD) min. The elimination half-life (elt1/2) of the drug was 91.1 +/- 33.1 min and of its metabolite, L1-glucuronide (L1G) 147.7 +/- 52.0 min. Creatinine clearance of the patients correlated significantly with the elimination t1/2 of L1G (r = -0.79, P = 0.002). There was also a significant correlation between 24 h UIE in the 14 patients studied and L1 versus time area under the curve (AUC) (P = 0.007). The total amount of L1 recovered in urine in 24 h comprised 77.9 +/- 13.3% of the L1 dose. L1 efficiency (the 24 h UIE divided by the amount of iron the oral dose of L1 is capable of binding) in the 14 patients was 3.8 +/- 1.9%. These data show for the first time that the urinary elimination of L1G is influenced by the renal function of the patient. Although no significant accumulation of L1 and L1G will occur in most of the patients if L1 is given more than once daily, in some patients with impaired renal function, L1G may accumulate.

Source: UG
Pharmacological Inhibition of Endogenous Hydrogen Sulfide Production Slows Bladder Cancer Progression in an Intravesical Murine Model.

: Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

Source: UG
The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways

Type 1 interferons (IFN-1) are pleiotropic cytokines with well-established anticancer and antiviral properties, particularly in mucosal tissues. Hence, natural IFN-1-inducing treatments are highly sought after in the clinic. Here, we report for the first time that cryptolepine, a pharmacoactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, is a potent IFN-1 pathway inducer. Cryptolepine increased the transcript levels of JAK1, TYK2, STAT1, STAT2, IRF9, and OAS3, as well as increased the accumulation of STAT1 and OAS3 proteins, similar to recombinant human IFN-α. Cryptolepine effects were observed in multiple cell types including a model of human macrophages. This response was maintained in MAVS and STING-deficient cell lines, suggesting that cryptolepine effects are not mediated by nucleic acids released upon nuclear or organelle damage. In agreement, cryptolepine did not affect cell viability in concentrations that triggered potent IFN-1 activation. In addition, we observed no differences in the presence of a pharmacological inhibitor of TBK1, a pleiotropic kinase that is a converging point for Toll-like receptors (TLRs) and nucleic acid sensors. Together, our results demonstrate that cryptolepine is a strong inducer of IFN-1 response and suggest that cryptolepine-based medications such as C. sanguinolenta extract could be potentially tested in resource-limited regions of the world for the management of chronic viral infections as well as cancers.

Source: UG
Pharmacophore-Guided Identification of Natural Products as Potential Inhibitors of Mycobacterium ulcerans Cystathionine γ-synthase MetB

Abstract: Buruli ulcer caused by Mycobacterium ulcerans (M. ulcerans) is identified by a pain-free cyst or edema which develops into a massive skin ulcer if left untreated. There are reports of chemore sistance, toxicity, noncompliance, and poor efficacy of current therapeutic options. Previously, we used cheminformatics approaches to identify potential antimycobacterial compounds targeting major receptors in M. ulcerans. In this paper, we sought to identify potential bioactive compounds by targeting Cystathionine gamma-synthase (CGS) MetB, a key receptor involved in methionine syn thesis. Inhibition of methionine synthesis restricts the growth of M. ulcerans. Two potent inhibitors Juglone (IC50 0.7 +/− 0.7 µmol/L) and 9-hydroxy-alpha-lapachone (IC50 0.9 +/− 0.1 µmol/L) were used to generate 3D chemical feature pharmacophore model via LigandScout with a score of 0.9719. The validated model was screened against a pre-filtered library of 2530 African natural products. Compounds with fit scores above 66.40 were docked against the structure of CGS to generate hits. Three compounds, namely Gentisic 5-O glucoside (an isolate of African tree Alchornea cordifolia), Isos cutellarein (an isolate of Theobroma plant) and ZINC05854400, were identified as potential bioactive molecules with high binding affinities of −7.1, −8.4 and −8.4 kcal/mol against CGS, respectively. Novel structural insight into the binding mechanisms was elucidated using LigPlot+ and molecular dynamics simulations. All three molecules were predicted to possess antibacterial, anti-ulcerative, and dermatological properties. These compounds have the propensity to disrupt the methionine synthesis mechanisms with the potential of stagnating the growth of M. ulcerans. As a result of rea sonably good pharmacological profiling, the three drug-like compounds are potential novel scaffolds that can be optimized into antimycobacterial molecules.

Source: UG
Pharmacovigilance in Africa

The last 20 years have seen seismic shifts in the political, civil, and healthcare environment in Africa. Currently, 33 national pharmacovigilance (PV) centers in Africa are full members of the WHO Programme for International Drug Monitoring, whilst another six are associate members. A recent analysis showed that the challenges facing African PV centers include the lack of human and financial resources. The total number of spontaneous reports from African countries is extremely low even for drugs that are used heavily within the region. Despite this low reporting, a safety signal - that is, extrapyramidal reactions with the antimalarial drug combination of amodiaquine + artesunate - has been generated entirely due to PV efforts in Africa. PV in Africa is evolving, and key stakeholders like the pharmaceutical industry are being brought on board. Indicators for PV exist (Strengthening Pharmaceutical Systems (SPS) Program, 2009) or are being developed. © 2014 by John Wiley & Sons, Ltd. All rights reserved.

Source: UG
Pharmacovigilance of malaria intermittent preventive treatment in infants coupled with routine immunizations in 6 african countries

BACKGROUND: Intermittent preventive treatment in infants (IPTi) is a new malaria control strategy coupled with the delivery of routine immunizations recommended by the World Health Organization since 2009 for countries with moderate to high endemicity. To evaluate its safety profile and identify potential new adverse events (AEs) following simultaneous administration of sulfadoxine-pyrimethamine (SP-IPTi) with immunizations, we measured AE incidence and evaluated spontaneous AE reporting. METHODS: A cohort event monitoring study was conducted on 24 000 infants in 2 countries after administration of SP-IPTi during routine immunizations. Additional pharmacovigilance training and supervision were conducted to stimulate AE passive reporting in 6 African countries. RESULTS: No serious AEs were found by active follow-up, representing 95% probability that the rate does not exceed 1 per 8000. No serious AEs were found by retrospective review of hospital registers. The rate of moderate AEs probably linked to immunization and/or SP-IPTi was 1.8 per 1000 doses (95% confidence interval, 1.50-2.00). Spontaneous reporting of AEs remained <1% of cases collected by active follow-up. CONCLUSIONS: Simultaneous administration of SP-IPTi and immunizations is a safe strategy for implementation with a low risk of serious AEs to infants. Strategies toward strengthening spontaneous reporting in Africa should include not only the provider but also beneficiaries or their caregivers.

Source: UG
Pharmacy premises licensing policy formulation: experience from Ghana

Background: Licences to operate pharmacy premises are issued by statutory regulatory bodies. The Health Institutions and Facilities Act (Act 829) and Health Professions Regulatory Bodies Act (Act 857) regulate pharmacy premises and the business of supplying restricted medicines by retail, respectively, and this could create a potential regulatory overlap for pharmacy practice in Ghana. We theorise that the potential overlap of regulation duties stems from how law-makers framed issues and narratives during the formulation of these Acts. Objective: To describe the policy actors involved, framing of narratives and decision-making processes relating to pharmacy premises licensing policy formulation. Methods: A qualitative study was conducted and data gathered through interviewing eight key informants and reviewing Hansards, reports, bills, memoranda and Acts 829 and 857. Data were analysed to map decision-making venues, processes, actors and narratives. Results: The Ministry of Health drafted the bills in July 2010 with the consensus of internal stakeholders. These were interrogated by the Parliament Select Committee on Health (with legislative power) during separate periods, and decisions made in Parliament to alter propositions of pharmacy premises regulations. Parliamentarians framed pharmacies as health facilities and reassigned their regulation from the Pharmacy Council to a new agency. The Pharmacy Council and the Pharmaceutical Society of Ghana could not participate in the decision-making processes in Parliament to oppose these alterations. The laws’ contents rested with parliamentarians as they made decisions in venues restricted to others. Legislative procedure limited participation, although non-legislative actors had some level of influence on the initial content. Conclusion: Implementation of these laws would have implications for policy and practice and therefore understanding how the laws were framed and formulated is important for further reforms. We recommend additional research to investigate the impact of the implementation of these Acts on pharmacy practice and business in Ghana and the findings can serve as bargaining information for reforms.

Source: UG
Pharmacy premises licensing policy formulation: experience from&nbsp;Ghana

Background: Licences to operate pharmacy premises are issued by statutory regulatory bodies. The Health Institu- tions and Facilities Act (Act 829) and Health Professions Regulatory Bodies Act (Act 857) regulate pharmacy premises and the business of supplying restricted medicines by retail, respectively, and this could create a potential regulatory overlap for pharmacy practice in Ghana. We theorise that the potential overlap of regulation duties stems from how law-makers framed issues and narratives during the formulation of these Acts. Objective: To describe the policy actors involved, framing of narratives and decision-making processes relating to pharmacy premises licensing policy formulation. Methods: A qualitative study was conducted and data gathered through interviewing eight key informants and reviewing Hansards, reports, bills, memoranda and Acts 829 and 857. Data were analysed to map decision-making venues, processes, actors and narratives. Results: The Ministry of Health drafted the bills in July 2010 with the consensus of internal stakeholders. These were interrogated by the Parliament Select Committee on Health (with legislative power) during separate periods, and decisions made in Parliament to alter propositions of pharmacy premises regulations. Parliamentarians framed phar- macies as health facilities and reassigned their regulation from the Pharmacy Council to a new agency. The Pharmacy Council and the Pharmaceutical Society of Ghana could not participate in the decision-making processes in Parlia- ment to oppose these alterations. The laws’ contents rested with parliamentarians as they made decisions in venues restricted to others. Legislative procedure limited participation, although non-legislative actors had some level of inﬂuence on the initial content. Conclusion: Implementation of these laws would have implications for policy and practice and therefore under- standing how the laws were framed and formulated is important for further reforms. We recommend additional research to investigate the impact of the implementation of these Acts on pharmacy practice and business in Ghana and the ﬁndings can serve as bargaining information for reforms.

Source: UG