Publications

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2016
Njogu PM, Guantai EM, Pavadai E, Chibale K. "Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis." ACS Infectious Diseases. 2016;2:8-31. Abstract

Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010−2014).

2014
Mecca LW, Riungu J, Guantai EM. "Financing and Availability of Essential Medicines Before and After Introduction of the National Hospital Insurance Fund Civil Servants and Disciplined Services Medical Scheme At Webuye District Hospital, Kenya." Afr. J. Pharmacol. Ther.. 2014;3(4):128-133. Abstract

Background:
Financing is an important determinant of access to essential medicines. In Kenya, the National Hospital Insurance Fund Civil Servants and Disciplined Services Medical Scheme is a key contributor to financing the
procurement of essential medicines.

Main Objective:
To compare availability and funding of essential medicines at Webuye District Hospital, Kenya before and after implementation of the new National Hospital Insurance Fund Medical Scheme.

Methods:
This was a longitudinal before-after study of four years (January 2010-December 2013); the latter two of which the scheme was in operation.

Results:
After introduction of the scheme, there was a higher allocation for the medicines budget from the Facility Improvement Fund, which hosts finances from the National Hospital Insurance Fund (p=0.008). The actual expenditure on essential medicines was also higher. Expenditure on essential medicines by the government, reduced (p<0.0001). The stock out rate decreased by 2.28% though this change was not statistically significant (p=0.099). The Facility Improvement Fund expenditure on essential medicines was a significant negative predictor of stock out rate.

Conclusion:
Although financing of medicines through the facility improvement fund increased after introduction of the new scheme, there was no change in the stock-out rate.

Key words: financing, availability, essential medicines, insurance

Nkonge NG, Opanga SA, Guantai EM, Karimi PN. "Knowledge of Correct Use among Hormonal Contraceptive Users in a Kenyan Referral Hospital." Afr. J. Pharmacol. Ther.. 2014;3(4):105-111. Abstract

Background:
Contraception is the intentional use of temporary, long-term or permanent methods to prevent
pregnancy. The consistent and correct use of contraceptives ensures that unintended pregnancies and pregnancy-related health risks are prevented.

Objectives:
To assess the prevalence, types and level of knowledge on the correct use of hormonal contraceptives among women of reproductive age at Kenyatta National Hospital.

Methodology:
A cross-sectional study was carried out targeting 400 women in their reproductive age at Kenyatta National Hospital, Nairobi, Kenya. Data was collected using an interviewer administered questionnaire and analyzed
using SPSS version 20 into descriptive and inferential statistics.

Results:
The prevalence of contraceptive use was 42.8%. Contraceptive use was associated with number of children [OR 1.7 (1.3-2.1)] p<0.001. 56.1% of contraceptive users were on hormonal contraceptives. Injectable contraceptives were the most preferred followed by implants and pills. The choice of contraceptive methods was associated with age [OR 2.003 (1.330-3.017)] p=0.001 and level of education [OR 1.697 (1.135-2.539)] p=0.010. The level of knowledge on the correct use of hormonal contraceptive use was limited and was associated with the level of education [OR 1.389 (1.144-2.051)] p=0.000.

Conclusion:
Contraceptive use is low compared to knowledge of contraceptives. Injectable contraceptives are the most preferred hormonal contraceptives. The level of knowledge on the correct use of hormonal contraceptive is low.

Key words: contraceptive use, hormonal contraceptives, knowledge, correct use

Kerama SK, Okalebo FA, Nyamu DG, Guantai EM, Ndwigah SN, Maru SM. "Risk Factors and Management of Stress Ulcers in the Critical Care Unit in a Kenyan Referral Hospital." Afr. J. Pharmacol. Ther.. 2014;3(2):51-61. Abstract

Background:
Stress ulcers develop due to extreme physiological stress among critically ill patients. Data on it management is scant in resource limited settings.

Objectives:
To determine the incidence, risk factors and management of stress ulcers among adult patients admitted to the Critical Care Unit of a Kenyan referral hospital, Kenyatta National Hospital. The outcome of the prophylaxis was also evaluated.

Methodology:
This was a retrospective cohort study among 186 critically ill adult patients admitted between January and December, 2012. The data was extracted from patient files. Logistic regression was performed to determine the risk factors for development of stress ulcers by manual forward stepwise model building.

Results:
Ninety percent of the patients received prophylaxis and this was done within 72 hours of admission. Twenty patients did not qualify for prophylaxis but received it. Most (76.4%) patients received prophylaxis with histamine 2 receptor blockers. The incidence of stress ulcers was 36.6% which was mainly treated with ranitidine (57.4% of cases) and omeprazole (38.8% of cases). The only diagnostic criteria were presence of the following clinical signs: epigastric tenderness (60 patients, 36.6%) and melena (3, 4.4%) and hematemesis (5, 7.4%). Mechanical ventilation of patients was the most important risk factor for stress ulcer development (adjusted OR: 43.76, 95% CI [5.067, 377.9]; followed by hospital stay for more than 7 days (adjusted OR: 11.88, 95% CI [3.923, 36.9]). Antibiotics (adjusted OR: 0.044, 95% CI [0.002, 0.936]) and benzodiazepines (adjusted OR: 0.074, 95% CI [0.013, 0.419] appeared to confer protection. Prophylaxis with histamine receptor antagonists did not seem to confer protection.

Conclusion:
The incidence of stress ulcers was high and methods for prophylaxis of stress ulcer need to be improved.

Key words: Stress ulcers, Critical care, antibiotics, benzodiazepines, antibiotics, CNS depressants

2012
M. DRGUANTAIERIC, Chibale K. "Natural product-based drug discovery in Africa: the need for integration into modern drug-discovery paradigms.". In: Drug Discovery in Africa. Springer: Germany. (Pp. 101-126). Springer: Germany; 2012.
Tacon C, M. DRGUANTAIERIC, Smith PJ, Chibale K. "Synthesis, Biological Evaluation and Mechanistic Studies of Totarol Amino Alcohol Derivatives as Potential Antimalarial Agents." Bioorg. Med. Chem.. 2012;20:893-902. Abstract

Herein we report on the semisynthesis and biological evaluation of b-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All beta-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC50: 11.69 microM (K1, chloroquine and multi-drug resistant strain), and 11.78 microM (D10, chloroquine sensitive strain)]—12e was the most active [IC50: 0.63 microM (K1), and 0.61 microM (D10)]. The phenyl and naphthyl b-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the b-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.

2011
T-S. F, M. DRGUANTAIERIC, M. N, et al. "Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction." Bioorg. Med. Chem. Lett.. 2011;21 :2882-2886. Abstract

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC50 values of 610 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC50 of 0.37 lM and the highest tumor specificity.

T-S F, M. DRGUANTAIERIC, M. N, et al. "Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum. ." Biochem. Pharmacol. . 2011;82 :236-247. Abstract

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a–c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent b-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials.

M. DRGUANTAIERIC, Ncokazi K, Egan T, et al. "Enone- and Chalcone-Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies." J. Med. Chem. . 2011;54 :3637-3649. Abstract

Analogues of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogues, particularly at low pH; they retained acceptable predicted permeability properties but were predicted to be susceptible to hepatic metabolism. These analogues were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogues. In vitro metabolism studies indicated susceptibility of the analogues to hepatic metabolism. There was also evidence of primary glucuronidation for analogues 24-27. Presumed cis-trans isomerism of 12, 22, and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogues.

M. DRGUANTAIERIC, Chibale K. "How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?" Malaria J. . 2011;10((Suppl 1) ):S2. Abstract

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds.

2010
Hans RH, Guantai EM, Carmen L, Smith PJ, Baojie W, Gut J, Franzblau SG, Rosenthal PJ, Chibale K. "Synthesis, antimalarial and antitubercular activity of acetylenic chalcones.". 2010. Abstract

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H37Rv, an unusual pattern with respect to existing anti-TB agents

M. DRGUANTAIERIC. "Chloroquine Resistance: Proposed Mechanisms and Countermeasures.". In: Current Drug Delivery. DMW; 2010. Abstract
Malaria has been, and remains, one of the biggest global health concerns as far as infectious diseases are concerned, with yearly incidence and mortality figures running into millions. One of the major drawbacks to the control of this disease has been the emergence of drug resistant strains of the causative agent, which limits the successful use of many clinically available antimalarial drugs. This review discusses chloroquine resistance; it highlights some of the proposed molecular mechanisms of chloroquine resistance, but dwells more on efforts at reversing chloroquine resistance and the concept of chloroquine resistance-reversal agents.
M. DRGUANTAIERIC. "Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds.". In: Bioorganic & Medicinal Chemistry. DMW; 2010. Abstract
A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC50 values against the D10, Dd2 and W2 strains of Plasmodium falciparum.
2007

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