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BACKGROUND: Pre-eclampsia is the second leading cause of maternal death in Uganda. However, mothers report to the hospitals late due to health care challenges. Therefore, we developed and validated the prediction models for prenatal screening for pre-eclampsia. METHODS: This was a prospective cohort study at St. Mary's hospital lacor in Gulu city. We included 1,004 pregnant mothers screened at 16-24 weeks (using maternal history, physical examination, uterine artery Doppler indices, and blood tests), followed up, and delivered. We built models in RStudio. Because the incidence of pre-eclampsia was low (4.3%), we generated synthetic balanced data using the ROSE (Random Over and under Sampling Examples) package in RStudio by over-sampling pre-eclampsia and under-sampling non-preeclampsia. As a result, we got 383 (48.8%) and 399 (51.2%) for pre-eclampsia and non-preeclampsia, respectively. Finally, we evaluated the actual model performance against the ROSE-derived synthetic dataset using K-fold cross-validation in RStudio. RESULTS: Maternal history of pre-eclampsia (adjusted odds ratio (aOR) = 32.75, 95% confidence intervals (CI) 6.59-182.05, p = 0.000), serum alkaline phosphatase(ALP) < 98 IU/L (aOR = 7.14, 95% CI 1.76-24.45, p = 0.003), diastolic hypertension ≥ 90 mmHg (aOR = 4.90, 95% CI 1.15-18.01, p = 0.022), bilateral end diastolic notch (aOR = 4.54, 95% CI 1.65-12.20, p = 0.003) and body mass index of ≥ 26.56 kg/m2 (aOR = 3.86, 95% CI 1.25-14.15, p = 0.027) were independent risk factors for pre-eclampsia. Maternal age ≥ 35 years (aOR = 3.88, 95% CI 0.94-15.44, p = 0.056), nulliparity (aOR = 4.25, 95% CI 1.08-20.18, p = 0.051) and white blood cell count ≥ 11,000 (aOR = 8.43, 95% CI 0.92-70.62, p = 0.050) may be risk factors for pre-eclampsia, and lymphocyte count of 800 - 4000 cells/microliter (aOR = 0.29, 95% CI 0.08-1.22, p = 0.074) may be protective against pre-eclampsia. A combination of all the above variables predicted pre-eclampsia with 77.0% accuracy, 80.4% sensitivity, 73.6% specificity, and 84.9% area under the curve (AUC). CONCLUSION: The predictors of pre-eclampsia were maternal age ≥ 35 years, nulliparity, maternal history of pre-eclampsia, body mass index, diastolic pressure, white blood cell count, lymphocyte count, serum ALP and end-diastolic notch of the uterine arteries. This prediction model can predict pre-eclampsia in prenatal clinics with 77% accuracy.
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Preeclampsia , Embarazo , Femenino , Humanos , Adulto , Preeclampsia/diagnóstico , Preeclampsia/epidemiología , Estudios Prospectivos , Uganda/epidemiología , Edad Materna , Hospitales , Ultrasonografía PrenatalRESUMEN
BACKGROUND: Women of Afro-Caribbean and Asian origin are more at risk of stillbirths. However, there are limited tools built for risk-prediction models for stillbirth within sub-Saharan Africa. Therefore, we examined the predictors for stillbirth in low resource setting in Northern Uganda. METHODS: Prospective cohort study at St. Mary's hospital Lacor in Northern Uganda. Using Yamane's 1967 formula for calculating sample size for cohort studies using finite population size, the required sample size was 379 mothers. We doubled the number (to > 758) to cater for loss to follow up, miscarriages, and clients opting out of the study during the follow-up period. Recruited 1,285 pregnant mothers at 16-24 weeks, excluded those with lethal congenital anomalies diagnosed on ultrasound. Their history, physical findings, blood tests and uterine artery Doppler indices were taken, and the mothers were encouraged to continue with routine prenatal care until the time for delivery. While in the delivery ward, they were followed up in labour until delivery by the research team. The primary outcome was stillbirth 24 + weeks with no signs of life. Built models in RStudio. Since the data was imbalanced with low stillbirth rate, used ROSE package to over-sample stillbirths and under-sample live-births to balance the data. We cross-validated the models with the ROSE-derived data using K (10)-fold cross-validation and obtained the area under curve (AUC) with accuracy, sensitivity and specificity. RESULTS: The incidence of stillbirth was 2.5%. Predictors of stillbirth were history of abortion (aOR = 3.07, 95% CI 1.11-8.05, p = 0.0243), bilateral end-diastolic notch (aOR = 3.51, 95% CI 1.13-9.92, p = 0.0209), personal history of preeclampsia (aOR = 5.18, 95% CI 0.60-30.66, p = 0.0916), and haemoglobin 9.5 - 12.1 g/dL (aOR = 0.33, 95% CI 0.11-0.93, p = 0.0375). The models' AUC was 75.0% with 68.1% accuracy, 69.1% sensitivity and 67.1% specificity. CONCLUSION: Risk factors for stillbirth include history of abortion and bilateral end-diastolic notch, while haemoglobin of 9.5-12.1 g/dL is protective.
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Aborto Espontáneo , Mortinato , Embarazo , Femenino , Humanos , Mortinato/epidemiología , Estudios Prospectivos , Uganda/epidemiología , Factores de Riesgo , Nacimiento VivoRESUMEN
Backgroundand Aim. Diabetes mellitus is a metabolic disorder that has no known cure with continuous endeavors to find a therapy for the condition. According to some studies, traditional leafy vegetables could prevent and manage diabetes by modifying the carbohydrate and lipid metabolism. In this study, a phytochemical analysis, acute toxicity, as well as antihyperglycemic and antidiabetic activity testing of the methanolic, diethyl ether, and aqueous leaf extracts of Corchorus olitorius L. was performed. Materials and Methods. Methanolic, diethyl ether, and aqueous leaf extracts of Corchorus olitorius L. were prepared by serial extraction. Phytochemical analysis was performed following standard methods. 52 mice were separated into 13 groups (A-M) of 4 and received extracts' doses ranging from 1000 mg/kg to 5000 mg/kg for the acute toxicity testing. For the antihyperglycemic and antidiabetic activities testing, 48 rats were divided into 8 groups of 6 and received 500 mg/kg of each extract. 10 mg/kg of glibenclamide and distilled water were used as controls. Data were analyzed using Prism GraphPad version 8.0.2 (263). Results. Phytochemical analysis revealed the presence of alkaloids, reducing sugars, saponins, and terpenoids. There were no acute toxicity signs observed in this study. Corchorus olitorius L. extracts demonstrated moderate antihyperglycemic and antidiabetic activities. The methanolic extract exhibited the highest degree of antihyperglycemic activity. However, there was no statistically significant difference between the extracts and the negative control (p > 0.05), but with glibenclamide (p < 0.01). Conclusion. Corchorus olitorius L. is a safe and potential postprandial antidiabetic vegetable that could minimize the rise in blood glucose after a meal. We therefore recommend further investigations into the antidiabetic properties of the vegetable using purified extracts.
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Corchorus , Fitoquímicos , Extractos Vegetales , Hojas de la Planta , Animales , Corchorus/química , Éter , Gliburida , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Ratones , Fitoquímicos/análisis , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/toxicidad , Ratas , VerdurasRESUMEN
Results: Crude extracts of Corchorus olitorius L leaves and their TLC-separated components demonstrated bioactivity against Staphylococcus aureus (14 mm), Streptococcus pneumoniae (16 mm), and Escherichia coli (11 mm) but neither against Candida albicans nor Mycobacteria tuberculosis. However, the overall zones of inhibition were smaller compared to the positive control (≥18 mm). GC-MS analysis of the active components revealed the presence of methyl esters. Conclusion: Corchorus olitorius L is bioactive against both Gram-negative and Gram-positive bacteria but neither against fungi nor mycobacteria. The bioactivity is attributable to the presence of methyl esters. Since methyl esters already have proven bioactivity in some studies, they could be further studied and optimized for possible pharmaceutical use. Further, to provide a more comprehensive antimicrobial spectrum of Corchorus olitorius L in Uganda, purified active components could be investigated using a wider range of organisms.
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Antiinfecciosos , Corchorus , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Ésteres , Cromatografía de Gases y Espectrometría de Masas , Extractos Vegetales/farmacología , Hojas de la PlantaRESUMEN
BACKGROUND: In the absence of an effective vaccine, malaria treatment and eradication is still a challenge in most endemic areas globally. This is especially the case with the current reported emergence of resistance to artemisinin agents in Southeast Asia. This study therefore explored the prevalence of K13-propeller gene polymorphisms among Plasmodium falciparum parasites in northern Uganda. METHODS: Adult patients (≥18 years) presenting to out-patients department of Lira and Gulu regional referral hospitals in northern Uganda were randomly recruited. Laboratory investigation for presence of plasmodium infection among patients was done using Plasmodium falciparum exclusive rapid diagnostic test, histidine rich protein-2 (HRP2) (Pf). Finger prick capillary blood from patients with a positive malaria test was spotted on a filter paper Whatman no. 903. The parasite DNA was extracted using chelex resin method and sequenced for mutations in K13-propeller gene using Sanger sequencing. PCR DNA sequence products were analyzed using in DNAsp 5.10.01software, data was further processed in Excel spreadsheet 2007. RESULTS: A total of 60 parasite DNA samples were sequenced. Polymorphisms in the K13-propeller gene were detected in four (4) of the 60 parasite DNA samples sequenced. A non-synonymous polymorphism at codon 533 previously detected in Cambodia was found in the parasite DNA samples analyzed. Polymorphisms at codon 522 (non-synonymous) and codon 509 (synonymous) were also found in the samples analyzed. The study found evidence of positive selection in the Plasmodium falciparum population in northern Uganda (Tajima's D = -1.83205; Fu and Li's D = -1.82458). CONCLUSIONS: Polymorphism in the K13-propeller gene previously reported in Cambodia has been found in the Ugandan Plasmodium falciparum parasites. There is need for continuous surveillance for artemisinin resistance gene markers in the country.
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Antígenos de Protozoos/genética , Malaria Falciparum/diagnóstico , Plasmodium falciparum/genética , Adulto , Animales , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Codón , ADN Protozoario/química , ADN Protozoario/aislamiento & purificación , ADN Protozoario/metabolismo , Resistencia a Medicamentos/genética , Haplotipos , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Plasmodium falciparum/aislamiento & purificación , Polimorfismo de Nucleótido Simple , Prevalencia , Análisis de Secuencia de ADN , Uganda/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Antimicrobial self-medication is common in most low and middle income countries (LMICs). However there has been no systematic review on non-prescription antimicrobial use in these settings. This review thus intended to establish the burden, risk factors and effects of antimicrobial self-medication in Low and Middle Income Countries. METHODS: In 2012, we registered a systematic review protocol in PROSPERO (CRD42012002508). We searched PubMed, Medline, Scopus, and Embase databases using the following terms; "self-medication", "non-prescription", 'self-treatment', "antimicrobial", "antimalarial", "antibiotic", "antibacterial" "2002-2012" and combining them using Boolean operators. We performed independent and duplicate screening and abstraction of study administrative data, prevalence, determinants, type of antimicrobial agent, source, disease conditions, inappropriate use, drug adverse events and clinical outcomes of antibiotic self-medication where possible. We performed a Random Effects Meta-analysis. RESULTS: A total of thirty four (34) studies involving 31,340 participants were included in the review. The overall prevalence of antimicrobial self-medication was 38.8 % (95 % CI: 29.5-48.1). Most studies assessed non-prescription use of antibacterial (17/34: 50 %) and antimalarial (5/34: 14.7 %) agents. The common disease symptoms managed were, respiratory (50 %), fever (47 %) and gastrointestinal (45 %). The major sources of antimicrobials included, pharmacies (65.5 %), leftover drugs (50 %) and drug shops (37.5 %). Twelve (12) studies reported inappropriate drug use; not completing dose (6/12) and sharing of medicines (4/12). The main determinants of antimicrobial self-medication include, level of education, age, gender, past successful use, severity of illness and income. Reported negative outcomes of antimicrobial self-medication included, allergies (2/34: 5.9 %), lack of cure (4/34: 11.8 %) and causing death (2/34: 5.9 %). The commonly reported positive outcome was recovery from illness (4/34: 11.8 %). CONCLUSION: The prevalence of antimicrobial self-medication is high and varies in different communities as well as by social determinants of health and is frequently associated with inappropriate drug use.
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Antibacterianos/administración & dosificación , Actitud Frente a la Salud , Infecciones Bacterianas/tratamiento farmacológico , Países en Desarrollo , Medicamentos sin Prescripción/administración & dosificación , Automedicación/estadística & datos numéricos , Antibacterianos/efectos adversos , Antiinfecciosos/administración & dosificación , Conductas Relacionadas con la Salud , Humanos , Medicamentos sin Prescripción/efectos adversos , Prevalencia , Factores de Riesgo , Autocuidado/estadística & datos numéricos , Automedicación/efectos adversosRESUMEN
BACKGROUND: Medicines are kept in households Worldwide for first aid, treatment of chronic or acute disease conditions. This promotes inappropriate use of medicines and hence the associated risks. The study explored the factors which predict availability and utilization of medicines in households of Northern Uganda. METHOD: A cross sectional survey of 892 households was performed from November-to-December 2012. Five data collectors administered the questionnaires, respondents were requested to bring out any medicines present in their households. Demographic characteristics, drug name, quantity, source, formulation, legibility of drug labels and reasons why the medicines were being kept at home was collected. Data was analyzed using STATA 12.0 at 95% level of significance. RESULTS: Of the households visited, 35.1% (313/892) had drugs. Paracetamol (11.8%), coartem (11.3%), cotrimoxazole (10%), amoxicillin (9.2%) and metronidazole (8.2%) were the major medicines found. Antibacterial drugs were the most commonly (40.1%) kept type of drugs. The medicines present in households were for on-going treatment (48%); 'leftover' (30.5%) and anticipated future use (21.6%). Symptoms of malaria (34.1%) were common in households which had drugs. The medicines kept in homes were mainly from the private sector 60.5% (497/821). The rate of home drug storage was higher 85.3% (267/313) amongst the educated individuals. There was high prevalence 76% (238/313) of self-medication among respondents in households which stored drugs. The average number of medicines in each household was 6 ± 5 with majority (68.1%) having between 1-10 drugs. Previous successful treatment (OR: 1.3; 95% CI: 0.95-1.77), regular income (OR: 1.8; 95% CI: 1.2-2.6) and sex (OR: 0.63; 95% CI: 0.5-0.9) predicted storage of medicines in households in northern Uganda. CONCLUSION: Over a third of households in Northern Uganda store medicines with antibacterial agents being the most common. Self-medication is common among individuals in households which keep drugs. Past successful treatment, regular income and sex predict community home drug storage.
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Almacenaje de Medicamentos , Composición Familiar , Automedicación , Acetaminofén , Adolescente , Adulto , Antiinfecciosos , Combinación Arteméter y Lumefantrina , Artemisininas , Estudios Transversales , Recolección de Datos , Combinación de Medicamentos , Etanolaminas , Femenino , Fluorenos , Humanos , Malaria/complicaciones , Masculino , Metronidazol , Persona de Mediana Edad , Factores Socioeconómicos , Encuestas y Cuestionarios , Combinación Trimetoprim y Sulfametoxazol , Uganda , Adulto JovenRESUMEN
Although the roles of Medicines and therapeutic committees (MTCs) have been expanding, there is limited information on the role of their structure in optimal antibacterial use in hospitals, especially in low-and-middle-income countries. Our study explored the structure and role of MTC in supporting antibacterial use in regional referral, general hospitals and tertiary private not-for-profit (PNFP) hospitals in Uganda. We conducted an explanatory sequential mixed-method approach with triangulation to explore the structure and functional role of MTCs from August 2019 to February 2020 in hospitals in Uganda. Quantitative data was collected using an interviewer-administered questionnaire among chairpersons or secretaries of MTCs and was analysed using descriptive statistics. We conducted key informant interviews using an interview guide among long-term serving members of MTCs to collect qualitative data which triangulated the quantitative data. The study revealed that sixteen hospitals had successfully established MTCs with an average duration of the MTCs' existence of 5.6 (+2.7) years. The membership of the MTCs varied between 7 and 14, with a median value of 10, and the majority of members in MTCs were pharmacists (15 out of 16) and clinical specialists (13 out of 16). The most frequent subcommittees of the 16 hospitals MTC were supply chain (n = 14), antimicrobial stewardship (n = 13), and infection control (n = 12). Majority (14 out of 16) of the MTCs supported availability and access of antibacterial use by selecting and evaluating antibacterials agents for their formulary lists using established criteria. Additionally, 15 out 16 MTCs conducted antimicrobial stewardship activities to support optimal antimicrobial use. In our study, MTC membership and subcommittees were critical structural components that aided the selection and evaluation antibacterials on hospital formulary lists and they supported optimal antibacterial use through implementing various antimicrobial stewardship activities. There is a need for the Ministry of Health to conduct more training on operationalising MTCs structures in all hospitals.
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Hospitales , Comité Farmacéutico y Terapéutico , Humanos , Uganda , Antibacterianos/uso terapéutico , FarmacéuticosRESUMEN
BACKGROUND: HIV infection, anti-tuberculosis and efavirenz therapy are associated with neuropsychological effects. We evaluated the influence of rifampicin cotreatment, efavirenz pharmacokinetics and pharmacogenetics on neuropsychiatric disorders in Ugandan HIV patients with or without tuberculosis coinfection. METHODS: 197 treatment naïve Ugandan HIV patients, of whom 138 were TB co-infected, enrolled prospectively and received efavirenz based HAART. TB-HIV confected patients received concomitant rifampicin based anti-TB therapy. Genotypes for CYP2B6 (*6, *11), CYP3A5 (*3, *6, *7), ABCB1 (c.3435C>T and c.4036 A/G rs3842), CYP2A6 (*9, *17) and NR1I3 rs3003596 T/C were determined. Efavirenz plasma concentrations were serially quantified at 3rd day, 1st, 2nd, 4th, 6th, 8th and 12th weeks during therapy. Efavirenz neuropsychiatric symptoms were evaluated in terms of sleep disorders, hallucinations and cognitive effects at baseline, at two and twelve weeks of efavirenz treatment using a modified Mini Mental State Examination (MMSE) score. RESULTS: During the first twelve weeks of ART, 73.6% of the patients experienced at least one efavirenz related neuropsychiatric symptom. Commonest symptoms experienced were sleep disorders 60.5% (n=124) and hallucination 30.7% (n=63). Neuropsychiatric symptoms during HAART were significantly predicted by efavirenz plasma concentrations consistently. Rifampicin cotreatment reduced plasma efavirenz concentrations significantly only during the first week but not afterwards. There was no significant difference in the incidence of neuropsychiatric symptoms between patients receiving efavirenz with or without rifampicin cotreatment. CYP2B6*6 and ABCB1 c.4036 A/G genotype significantly predicted efavirenz concentrations. The tendency of CYP2B6*6 genotype association with higher incidence of having vivid dream (p=0.05), insomnia (p=0.19) and tactile hallucination (p=0.09) was observed mainly at week-2. CONCLUSIONS: Efavirenz related neuropsychiatric symptoms are common among Ugandan HIV patients receiving ART and is mainly predicted by higher efavirenz plasma concentrations and CYP2B6 genotype but not by rifampicin based anti-TB co-treatment.
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Fármacos Anti-VIH/sangre , Benzoxazinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/metabolismo , Tuberculosis/metabolismo , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Antibióticos Antituberculosos/uso terapéutico , Terapia Antirretroviral Altamente Activa , Hidrocarburo de Aril Hidroxilasas/genética , Benzoxazinas/efectos adversos , Benzoxazinas/sangre , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/virología , Receptor de Androstano Constitutivo , Ciclopropanos , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/genética , Femenino , Frecuencia de los Genes , Infecciones por VIH/microbiología , Infecciones por VIH/psicología , Alucinaciones/tratamiento farmacológico , Alucinaciones/metabolismo , Alucinaciones/virología , Humanos , Estimación de Kaplan-Meier , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/virología , Trastornos Mentales/microbiología , Trastornos Mentales/virología , Estudios Prospectivos , Rifampin/uso terapéutico , Trastornos del Despertar del Sueño/tratamiento farmacológico , Trastornos del Despertar del Sueño/metabolismo , Trastornos del Despertar del Sueño/virología , Tuberculosis/tratamiento farmacológico , Tuberculosis/virología , Uganda/epidemiologíaRESUMEN
BACKGROUND: A wide range of indigenous vegetables grow in Uganda especially during rainy seasons but scarcely during droughts, except those that are commercially grown. Although a number of these vegetables have medicinal values, they have not been satisfactorily studied besides conservation. Therefore, we conducted a cross-sectional ethnobotanical survey in Northern Uganda in order to document traditional medicinal vegetables and their uses. METHODS: Qualitative and quantitative approaches of data collection and analysis were employed using semistructured, interviewer-administered questionnaires as well as key informant interviews following international ethical codes. Fidelity levels and informant consensus factors were also calculated. RESULTS: 13 traditional vegetables belonging to 10 families were reported to serve as folk medicines. The most dominant families were Fabaceae (23.08%) and Solanaceae (15.38%). The most often used vegetables were Corchorus spp., Hibiscus spp., and Asystasiagangeticafor musculoskeletal (51%), gastrointestinal (34.3%), and malaria (31.8%). The vegetables were cultivated in the backyard and the leaves stewed for the different ailments. The informant consensus factor was the highest for Corchorus spp., in the treatment of joint pain/stiffness (0.92-1) while the highest fidelity level was (60.42%) for Amaranthus spp., in the management of anemia. CONCLUSIONS: Northern Uganda has numerous traditional vegetables with medicinal benefits. Diseases treated range from gastrointestinal to reproductive through musculoskeletal abnormalities. The community obtains vegetable leaves from the backyard and stews them regularly for the medicinal purposes with no specific dosage. Therefore, we recommend studies to verify in laboratory models the efficacy of these vegetables and standardize the dosages.
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Quinine is one of the most effective antimalarial drugs, although its clinical use is limited as a result of its narrow safety margin. Quinine is a substrate of the polymorphic p-glycoprotein and CYP3A4/3A5. This study aimed to examine the effects of genetic variations in ABCB1 and CYP3A5 genes, sex, demographic, and biochemical variables (serum albumin, creatinine, alanine aminotransferase and albumin) on quinine disposition among Ugandans. Quinine (600 mg) was orally administered to 140 healthy volunteers. Quinine and its metabolite 3-hydroxyquinine concentrations were determined from 16-hour postdose plasma by high-performance liquid chromatography. CYP3A5 activity was measured using quinine/3-hydroxyquinine ratio (metabolic ratio). Genotyping for a total of 20 single nucleotide polymorphisms in ABCB1 (n = 13) and CYP3A5 (n = 7) was done using Taqman and minisequencing on microarray. There were 20.5- and 13-fold variations in body weight-adjusted plasma quinine concentrations (mean +/- standard deviation, 5.26 +/- 2.5 mumol/L; range, 0.88-18.10 mumol/L) and quinine-to-3-hydroxyquinine metabolic ratio (mean +/- standard deviation, 7.68 +/- 3.3 mumol/L; range, 1.66-22.3 mumol/L), respectively. Weight-adjusted plasma quinine concentration was significantly influenced by sex and ABCB1 haplotype. There was a significant sex difference in quinine metabolic ratio, women being faster metabolizers than men (P = 0.01). CYP3A5 genotype/haplotype significantly (P = 0.03) influenced quinine disposition with a clear CYP3A5*1 gene dose effect. The result confirms that quinine disposition is influenced mainly by sex as well as by ABCB1 and CYP3A5 genotypes. Despite being fast metabolizers, women display higher quinine bioavailability than men in Uganda. This may have clinical significance in determining an individual's susceptibility to quinine-associated adverse reactions such as cinchonism.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Inhibidores del Citocromo P-450 CYP3A , Variación Genética , Quinidina/análogos & derivados , Quinina/metabolismo , Factores Sexuales , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Población Negra , Peso Corporal , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Genes/fisiología , Haplotipos/genética , Haplotipos/fisiología , Humanos , Inmunosupresores/farmacología , Masculino , Polimorfismo Genético/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Quinidina/metabolismo , Quinina/farmacología , UgandaRESUMEN
Aspilia pruliseta Schweinf. (Asteraceae) is a medicinal plant indigenous to Uganda and the neighboring countries of East Africa. It has been used extensively by the rural population for the treatment of fevers and malaria. During the antimalarial evaluation of this plant, four nontoxic diterpenes were isolated that possessed moderate activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) clones of Plasmodium falciparum, with IC(50) values ranging from 14 to 23 µM. These moderately active compounds included the previously undescribed diterpene, ENT-15 ß-senecioyloxy-16,17-epoxy-kauran-18-oic acid that demonstrated an IC(50) value of 23.4 µM against clone D6, but was devoid of activity against clone W2. Four additional diterpenes were obtained from the aerial parts of A. pruliseta, but these known compounds were essentially inactive. The moderate activities of select diterpenes of A. pruliseta could account collectively for the historical and enduring use of this plant in traditional African medicine.
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Antimaláricos/farmacología , Asteraceae/química , Diterpenos/farmacología , Extractos Vegetales/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/aislamiento & purificación , Antimaláricos/uso terapéutico , Cloroquina , Diterpenos/aislamiento & purificación , Diterpenos/uso terapéutico , Concentración 50 Inhibidora , Malaria Falciparum/tratamiento farmacológico , Medicinas Tradicionales Africanas , Componentes Aéreos de las Plantas , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Plantas Medicinales/química , UgandaRESUMEN
BACKGROUND: Artemisinin combination therapy (ACT) has been widely adopted as first-line treatment for uncomplicated falciparum malaria. In Uganda, amodiaquine plus artesunate (AQ+AS), is the alternative first-line regimen to Coartem(R) (artemether + lumefantrine) for the treatment of uncomplicated falciparum malaria. Currently, there are few field-adapted analytical techniques for monitoring amodiaquine utilization in patients. This study evaluates the field applicability of a new method to determine amodiaquine and its metabolite concentrations in whole blood dried on filter paper. METHODS: Twelve patients aged between 1.5 to 8 years with uncomplicated malaria received three standard oral doses of AQ+AS. Filter paper blood samples were collected before drug intake and at six different time points over 28 days period. A new field-adapted sampling procedure and liquid chromatographic method was used for quantitative determination of amodiaquine and its metabolite in whole blood. RESULTS: The sampling procedure was successively applied in the field. Amodiaquine could be quantified for at least three days and the metabolite up to 28 days. All parasites in all the 12 patients cleared within the first three days of treatment and no adverse drug effects were observed. CONCLUSION: The methodology is suitable for field studies. The possibility to determine the concentration of the active metabolite of amodiaquine up to 28 days suggested that the method is sensitive enough to monitor amodiaquine utilization in patients. Amodiaquine plus artesunate seems effective for treatment of falciparum malaria.
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Amodiaquina/sangre , Antimaláricos/sangre , Artemisininas/sangre , Cromatografía Liquida/métodos , Amodiaquina/metabolismo , Amodiaquina/uso terapéutico , Animales , Antimaláricos/metabolismo , Antimaláricos/uso terapéutico , Artemisininas/metabolismo , Artemisininas/uso terapéutico , Niño , Preescolar , Combinación de Medicamentos , Femenino , Humanos , Lactante , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Masculino , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/aislamiento & purificación , Resultado del Tratamiento , UgandaRESUMEN
AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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Fármacos Anti-VIH/farmacocinética , Benzoxazinas/farmacocinética , Población Negra/genética , Polimorfismo Genético/genética , Adulto , Alquinos , Ciclopropanos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Modelos Biológicos , Modelos Genéticos , Factores Sexuales , Uganda , Adulto JovenRESUMEN
BACKGROUND: East African countries have in the recent past experienced a tremendous increase in the volume of antiretroviral drugs. Capacity to manage these medicines in the region remains limited. Makerere University, with technical assistance from the USAID supported Rational Pharmaceutical Management Plus (RPM Plus) Program of Management Sciences for Health (MSH) established a network of academic institutions to build capacity for pharmaceutical management in the East African region. The initiative includes institutions from Uganda, Tanzania, Kenya and Rwanda and aims to improve access to safe, effective and quality-assured medicines for the treatment of HIV/AIDS, TB and Malaria through spearheading in-country capacity. The initiative conducted a regional assessment to determine the existing capacity for the management of antiretroviral drugs and related commodities. METHODS: Heads and implementing workers of fifty HIV/AIDS programs and institutions accredited to offer antiretroviral services in Uganda, Kenya, Tanzania and Rwanda were key informants in face-to-face interviews guided by structured questionnaires. The assessment explored categories of health workers involved in the management of ARVs, their knowledge and practices in selection, quantification, distribution and use of ARVs, nature of existing training programs, training preferences and resources for capacity building. RESULTS: Inadequate human resource capacity including, inability to select, quantify and distribute ARVs and related commodities, and irrational prescribing and dispensing were some of the problems identified. A competence gap existed in all the four countries with a variety of healthcare professionals involved in the supply and distribution of ARVs. Training opportunities and resources for capacity development were limited particularly for workers in remote facilities. On-the-job training and short courses were the preferred modes of training. CONCLUSION: There is inadequate capacity for managing medicines and related commodities in East Africa. There is an urgent need for training in aspects of pharmaceutical management to different categories of health workers. Skills building activities that do not take healthcare workers from their places of work are preferred.
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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. WHAT THIS STUDY ADDS: * This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. * The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. * The study proposes dose modification to improve response with the CQ + SDx/PYR combination. AIMS: To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. METHODS: Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 microl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. RESULTS: A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V(C)/F) values were estimated to be 2.84 l h(-1) and 230 l. The typical CL/F for SDx was 0.023 l h(-1), while the factor relating its V(C)/F to normalized body weight was 1.6 l kg(-1). Post hoc parameter estimates for both drugs showed lower maximum concentrations (C(max)) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. CONCLUSIONS: The study results suggest that full-strength combination to all children would improve the cure rate.
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Antiinfecciosos/farmacocinética , Antimaláricos/farmacocinética , Cloroquina/farmacocinética , Malaria Falciparum/tratamiento farmacológico , Sulfadoxina/farmacocinética , Animales , Antiinfecciosos/sangre , Antimaláricos/sangre , Preescolar , Cloroquina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Malaria Falciparum/epidemiología , Masculino , Sulfadoxina/sangre , Resultado del Tratamiento , Uganda/epidemiologíaRESUMEN
The Home-Based Management of Fever/Malaria (HBMF) strategy in rural Uganda was evaluated in a quasi-experimental study. The intervention consisted of volunteers educating mothers and providing a 3-day course of pre-packaged chloroquine plus sulfadoxine/pyrimethamine tablets (HOMAPAK), free of charge, for the treatment of under-five fevers. Using a structured questionnaire, information was obtained on care-seeking and treatment practices before (n=498) and 18 months after the introduction of HBMF (n=587). Assessment of the intervention effect indicated 13.5% improvement in the accumulated proportion of patients (1) treated, (2) treated within 24h of illness onset, (3) treated with the recommended antimalarials, (4) treated at an adequate dosage and (5) treated for the correct duration. Combining this with the antimalarial drug efficacy resulted in a 10.4% improvement in the community effectiveness of malaria treatment. HOMAPAK use was reported in 25% of 156 febrile children; 23% in the most poor compared with 50% in the least poor. Using HOMAPAK instead of other allopathic antimalarials increased the likelihood of completing all steps (odds ratio 37, 95% CI 4.8-286). Similar to other large-scale public health interventions, this study demonstrates modest practice changes at the population level. However, practices improved markedly among HOMAPAK users, suggesting that intensifying implementation efforts to increase HOMAPAK use, especially among the poorest, would be beneficial.
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Antimaláricos/administración & dosificación , Fiebre/tratamiento farmacológico , Conocimientos, Actitudes y Práctica en Salud , Malaria/tratamiento farmacológico , Antimaláricos/uso terapéutico , Niño , Preescolar , Cloroquina/administración & dosificación , Cloroquina/uso terapéutico , Servicios de Salud Comunitaria , Combinación de Medicamentos , Quimioterapia Combinada , Atención Domiciliaria de Salud , Humanos , Madres/educación , Evaluación de Resultado en la Atención de Salud , Cooperación del Paciente , Pirimetamina/administración & dosificación , Pirimetamina/uso terapéutico , Salud Rural , Sulfadoxina/administración & dosificación , Sulfadoxina/uso terapéutico , Encuestas y Cuestionarios , UgandaRESUMEN
AIM: To assess genotype effect on efavirenz (EFV) pharmacokinetics, treatment outcomes and provide genotype-based EFV doses recommendations during for tuberculosis (TB)-HIV-1 cotreatment. MATERIALS & METHODS: EFV concentrations from 158 HIV-TB co-infected patients treated with EFV/lamivudine/zidovidine and rifampicin were analyzed. Genotype and CD4 and viral load data were analyzed using a population PK model. RESULTS: Simulated AUCs for 600 mg EFV dose were 1.2- and 2.4-times greater than the product label for Ugandans in general and CYP2B6*6/*6 genotypes respectively. EFV daily doses of 450 and 250 mg for Ugandans and CYP2B6*6/*6 genotypes, respectively, yielded simulated exposures comparable to the product label. CONCLUSIONS: Around 450 and 250 mg daily doses might meet EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6/*6 genotypes, respectively.
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Antituberculosos/administración & dosificación , Benzoxazinas/administración & dosificación , Citocromo P-450 CYP2B6/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Rifampin/administración & dosificación , Tuberculosis/tratamiento farmacológico , Adulto , África del Sur del Sahara , Alquinos , Fármacos Anti-VIH/administración & dosificación , Coinfección/tratamiento farmacológico , Ciclopropanos , Femenino , Genotipo , VIH-1/efectos de los fármacos , Humanos , Lamivudine/administración & dosificación , Masculino , Carga Viral/efectos de los fármacos , Zidovudina/administración & dosificaciónRESUMEN
OBJECTIVES: To explore the availability and utilization of the World Health Organization (WHO) recommended priority life-saving medicines for children under five in public health facilities in Uganda. METHODS: We conducted a cross sectional survey in 32 lower level public facilities in Jinja district of Uganda. A proportionate number of facilities were randomly selected in each stratum following a hierarchy of Health Centers (HC) defined according to the level of care they provide: 17 HC IIs, 10 HC IIIs and 5 HC IVs. In the facilities, we verified the availability of the WHO recommended priority medicines for diarrhea, sepsis, pneumonia and malaria. 81 health workers from the facilities reported what they prescribed for children with the above diseases. RESULTS: Oral rehydration salt (ORS) and zinc sulphate dispersible tablets for diarrhea were available in all HC IIs and IIIs and in only 60% of HC IVs. Procaine benzyl penicillin injection powder for treatment of sepsis was available in the majority of all HCs with: 100% of HC of IVs, 83% of HC IIIs and 82% of HC IIs. Medicines for pneumonia were limited across all the HCs with: Amoxicillin dispersible tablets in only 30% of the HC IIs and 40% of the HC IVs. The most uncommon were child-friendly priority medicines for malaria with: Artesunate injection in only 6% of HC IIs, 14% of HC IIIs and 20% of HC IVs; Artemether lumefantrine dispersible tablets and rectal artesunate were missing in all the 32 HCs. Less than a third of the health workers reported prescribing zinc sulphate and ORS for diarrhea, 86% reported procaine benzyl penicillin injection powder for sepsis, and 57% reported amoxicillin dispersible tablets for pneumonia. None reported prescribing Artemether lumefantrine dispersible tablets and rectal artesunate for malaria. CONCLUSIONS: There is low availability and utilization of life-saving priority medicines for pneumonia and malaria in public health facilities in Uganda. However, the priority medicines for diarrhea and sepsis are available and highly prescribed by the health workers.
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BACKGROUND: In 2007, the Sixtieth World Health Assembly (WHA) passed a resolution entitled "Better medicines for children" and subsequently the World Health Organization (WHO) recommended the inclusion of child-appropriate dosage formulations in the essential medicines lists of member countries. However, child-appropriate dosage formulations are not highlighted in the Essential Medicines and Health Supplies List of Uganda (EMHSLU) 2012 and they are still limited in availability in public health facilities. Several stakeholders influenced the status of child-appropriate dosage formulations in the EMHSLU 2012. OBJECTIVE: To explore stakeholders' views about the relevance of the globally recommended child-appropriate dosage formulations in the context of Uganda. METHODS: The findings derive from thirty three in-depth interviews with stakeholder representatives and the results of a follow up validation meeting where preliminary findings were shared with stakeholders. Policy analysis and policy transfer theories were used to guide a deductive analysis for manifest and latent content. RESULTS: According to stakeholders, the transition to the globally recommended child-appropriate dosage formulations has been slow in Uganda due to a number of factors. These factors include resource constraints at the global and national levels, lack of Ministry of Health (MOH) formal commitment to the adoption of the child-appropriate dosage formulations policy and a lack of consensus between those who advocated for the availability of liquid oral dosage formulations for easy administration and effectiveness and those who were more convinced by economic arguments and preferred the procurement of solid oral dosage formulations intended for adults. CONCLUSIONS: The global policy for child-appropriate dosage formulations still remains to be implemented in Uganda and other low income countries. This has been due to lack of resources that hindered formal transfer of the policy from the global to the local level. To achieve this transfer there is a need for resource mobilisation at both the international and local levels, together with the revitalisation of UMTAC to enable it to take on a leadership role of the coalitions supporting child-appropriate dosage formulations.