School of Bio-Medical Sciences (Bio-Medical) Collections
Permanent URI for this collection
Browse
Recent Submissions
1 - 5 of 457
-
ItemAssessment of pharmacokinetic profiles of hydroxyurea in children with sickle cell disease at sickle cell clinic, Mulago national referral hospital(Makerere University, 2025)Background: Hydroxyurea (HU), initially developed as an anticancer agent, has become a cornerstone in the management of sickle cell disease due to its ability to induce fetal hemoglobin (HbF), reduce red blood cell sickling and adhesion, and improve clinical outcomes. At the Mulago Sickle Cell Clinic, HU is widely used in both pediatric and adult patients with promising results; however, there remains a lack of pharmacokinetic (PK) data on its use across varying doses and schedules in children aged 0–12 years. Understanding HU’s PK profile in this population is crucial for optimizing individualized dosing, enhancing efficacy, and minimizing toxicity. This information is vital for guiding clinical decisions and shaping policy, especially in resource-limited settings. Objective: To assess the effects of varying dosing schedules of hydroxyurea on the steady state plasma concentration of hydroxyurea in children aged 0-12 years with sickle cell anemia attending Mulago Sickle Cell Clinic. Methods: A pharmacokinetic study was conducted on 66 children on HU regimen. Informed consent was obtained from the caregivers of participating children using a structured questionnaire. Participants were recruited for the study, and 3 mL of blood samples were collected from veins in the antecubital fossa (inner elbow area). Plasma from each sample were analyzed for drug levels using liquid chromatography-mass–mass spectrometry (LC-MS). The resulting concentration-time data were used to estimate pharmacokinetic parameters through non-compartmental data analysis. Results: A total of 66 children participated in the study, each receiving an oral dose of hydroxyurea and providing three blood samples for pharmacokinetic analysis. The majority of participants were male and of primary school age. Children were grouped based on standard and alternate dosing schedules, with a slight difference in average body weight between the groups. Analysis of plasma concentrations showed that both dosing regimens resulted in comparable drug exposure, as assessed by the area under the concentration-time curve (AUC), indicating similar pharmacokinetic profiles between the two groups. Conclusion: This study examined pharmacokinetic variability of hydroxyurea in children with sickle cell disease on standard versus alternate dosing. Key parameters (AUC, Cmax, Cmin, and Tmax) showed no significant differences, indicating comparable systemic exposure between regimens. Variability in absorption, particularly Tmax, highlighted interindividual differences. Both dosing strategies achieved therapeutic AUC levels, supporting their clinical effectiveness. These results underscore the value of individualized dosing and pharmacokinetic monitoring in pediatric sickle cell treatment.
-
ItemPhysiologically based pharmacokinetics model to assess the effect of food on absorption pharmacokinetics of metformin in adult type ii diabetic patients(Makerere University, 2025)ABSTRACT Background: Metformin, a biguanide-class oral hypoglycemic medication, has formed the cornerstone in the management of type 2 diabetes. However, MH exhibits a negative food effect that complicates its pharmacokinetics. This is concerning because, in clinical practice, patients taking metformin are usually advised to take the medication with food to alleviate GI symptoms. Available data indicate that a High-calorie diet lowered the overall absorption rate of metformin, with a profound decrease in Cmax, and a delayed Tmax. However, whether these food effects were related to drug dosages, formulations, or patient factors remains unanswered. PBPK modeling is a powerful bottom-up approach that can be used to predict and explain how food intake affects the absorption of oral medication. Methods: A PBPK model for metformin was developed utilizing GastroPlus™ software version 9.8.3. Initially, an absorption PBPK model was established by incorporating experimentally obtained dissolution data, permeability metrics, and population data from three study groups that received varying doses of 250 mg, 500 mg, and 850 mg. This oral model was subsequently validated to assess its predictive accuracy against different pharmacokinetic datasets. The validated model was applied to simulate different fed states, evaluating the impact of both high- and low-calorie diets under these conditions. Results: The absorption PBPK model accurately predicted metformin’s low bioavailability and indicated that absorption primarily occurs through the paracellular pathway, with an additional contribution from an active, saturable transcellular movement. Administration of a high-fat, high-calorie meal resulted in more than 30% reduction in the Cmax but without a significant change in AUC (12%) and a 1.5-hour delay in the Tmax compared to the fasted state. Conclusion: The findings of this study present a comprehensive mechanistic model for the pharmacokinetic absorption of metformin in the presence of food
-
ItemA comparison of inflammasome markers in people living with HIV, with and without polysubstance use(Makerere University, 2025)Despite the widespread use of antiretroviral therapy, systemic inflammation remains a hallmark of HIV-1 infection. This not only affects brain function, but may also promote immune cell exhaustion and persistence of HIV reservoirs, among other effects. Inflammasomes, key regulators of the innate immune response, are central to this inflammatory process. Polysubstance use, prevalent among people living with HIV (PLWH), can exacerbate HIV-induced inflammation. This study compared inflammasome marker levels in PLWH, with and without polysubstance use. To determine and compare the median of selected inflammasome markers (IL-1β, IL-18, IL-33, IL-6, IL-8, IL-15, TNF-α) in plasma between people living with HIV, with and without polysubstance use. To determine the factors (CD4+ T cell count, time on ART, Age, and sex) that are associated with statistically significant inflammasome markers in PLWH, with and without polysubstance use. Inflammasome marker levels in plasma were measured using Luminex assays. Median plasma concentrations of inflammasome markers were higher among PLWH with polysubstance use compared to non-users. Notably, IL-15 levels were 106.5 pg/mL (IQR: 82-118.3) in users vs. 78.4 pg/mL (IQR: 63.7-103) in non-users (p = 0.015), and IL-18 levels were 1573.8 pg/mL (IQR: 1136.1-1722.3) vs. 1195.1 pg/mL (IQR: 881.7-1573.4), respectively (p = 0.029).Multivariate analysis revealed that male sex was associated with a 30% higher IL-15 concentration relative to females (GMR = 1.30; 95% CI: 1.00–1.67; FDR = 0.095), suggesting a sex-specific pattern of immune activation in the context of polysubstance use. Altogether,this study demonstrates that elevated levels of inflammasome markers are associated with polysubstance use among PLWH,with IL-15 and IL-18 being significantly associated. Notably, multivariate analysis revealed that male polysubstance users exhibit disproportionately high IL-15 levels, suggesting a sex-specific immune activation pattern. These findings underscore the complex interplay between substance use, sex, and immune dysregulation in HIV-positive populations. IL-15 may serve as a potential biomarker for chronic immune stimulation in this subgroup, warranting further investigation into targeted interventions and sex-sensitive immunomodulatory strategies.
-
ItemMicrobial detoxification of aflatoxins in poultry feeds: Effects on nutrient stability and Detoxification capacity of freeze-dried Bacillus spp. (B285) and Saccharomyces spp. (Y833)(Makerere University, 2025)Microbial detoxification using Bacillus spp. (B285) and Saccharomyces spp. (Y833) offers a promising alternative to the use of chemical methods to degrade aflatoxins while preserving essential nutrients. This study evaluated the detoxification efficiency of Bacillus spp. (B285) and Saccharomyces spp. (Y833) in aflatoxin-contaminated poultry feeds, their effect on nutrient stability, and their detoxification capacity when freeze-dried. Five broiler starter feeds (four commercial and one lab-formulated) were artificially contaminated with 100 ppb each of AFB₁, AFB₂, AFG₁, and AFG₂. The feeds were subjected to four different treatment conditions, including microbial application of Bacillus spp. (B285) and Saccharomyces spp. (Y833) at 1.5×10⁸ CFU/mL, a chemical binder Bentonite (positive control), and normal saline (negative control). Residual Aflatoxin concentrations were quantified using Liquid Chromatography-Mass Spectrometry (LC-MS) to determine the efficacy of aflatoxin decontamination. Nutrient stability assessment was performed on treated samples to measure the profiles of crude protein, crude fat, fat-soluble vitamins (A, D3, and K1), and 18 amino acids. The detoxification performance of the freeze-dried Bacillus spp. (B285) and Saccharomyces spp. (Y833) incorporated into poultry feed was also assessed over three months. Data were analyzed using RStudio v4.4.2.2024-10-31. Both microbial strains significantly reduced aflatoxin levels by 78.2-81.3% compared with untreated controls (p ≤ 0.05), while Bentonite achieved up to 81.6%. Nutrient stability analysis revealed that crude fat remained unchanged (p > 0.05), whereas crude protein decreased by 18.9% under Bacillus B285 (p = 0.015) but increased by 8.1% under Saccharomyces Y833. Fat-soluble vitamins responded variably: vitamin A1 increased with Bacillus (+38%) and bentonite (+37%) but decreased with yeast (-54%); vitamin D3 was markedly elevated by Bentonite (+93%) and yeast (+82%) compared with baseline (p ≤ 0.05-0.001); and vitamin K1 remained stable across all treatments. Amino acid profiles showed sharp decline in case of alanine (72-81%) and histidine (65-97%), while branched-chain amino acids increased significantly, with leucine rising 27-53-fold (p ≤ 0.001) and isoleucine 9-22-fold (p ≤ 0.001). Freeze-dried Bacillus and Saccharomyces retained detoxification capacity during three months of storage, maintaining aflatoxin concentrations below 10 ppb. These findings demonstrate that while bentonite remains the most effective binder, Saccharomyces Y833 and Bacillus B285 offer biologically sustainable detoxification, with variable effects on nutrients. Their efficacy and storage stability highlighted potential for integration into safe feed production systems.
-
ItemPharmacokinetics of piperaquine co administered with ritonavir boosted lopinavir antiretroviral therapy in Ugandan children without malaria(Makerere University, 2025)Background: Dihydroartemisinin–piperaquine (DHA–PQ) is widely used for malaria treatment and prevention in children, including those living with HIV. Piperaquine (PQ) exposure, which determines both efficacy and safety, may be altered by drug–drug interactions with antiretroviral therapy (ART), particularly ritonavir-boosted lopinavir (LPV/r) leading to safety concerns. However, there is limited information on the PQ and LPV/r interaction in HIV infected children. Objective: This study evaluated PQ pharmacokinetics (PK) in HIV-uninfected Ugandan children and HIV-infected children receiving LPV/r-based ART. Methods: A retrospective analysis utilized data from a prospective, open-label study of DHA–PQ in children with and without HIV in Uganda. Pharmacokinetic parameters were assessed following a single dose in HIV-uninfected children and after a 3-dose regimen in both HIV-uninfected children and HIV-infected children on LPV/r-based ART. PQ concentrations were analyzed to estimate Cmax, area under the concentration–time curve (AUC), and terminal half-life (t½). Results: Among the HIV-uninfected children who received a single dose of DHA-PQ, the median age was 5.9 years (IQR: 4.9–7.1), and the majority were female (65%). The the median body weight and height were 20.6 kg (IQR: 18.1–23.4) and 115.7 cm (IQR: 108.7–123.2), respectively. The geometric mean AUC0-24hr was 1687 hr·ng/mL (95% CI: 1279.–2226), geometric mean Cmax was 197.9 ng/mL (95% CI: 141–278). The median Tmax was 2.1 hours (IQR: 2–3). Among the HIV-uninfected children who received three doses of DHA-PQ, the median age was 7.4 years (IQR: 6.0–8.7 years), weight was 23.6 kg (IQR: 21.4–27.9 kg), the geometric mean PQ Cmax was 218 ng/mL (90% CI: 175–272 ng/mL) and AUC0–day 42 was 14.6 hr·µg/mL (90% CI: 12.7–16.7 hr·µg/mL), with a terminal t½ of 435 hours (90% CI: 377–502 hours). In contrast, HIV-infected children on LPV/r-based ART, the median age was 7.1 years (IQR: 6.0–8.7 years), weight was 19.0 kg (IQR: 17.4–22.5 kg), and exhibited markedly higher exposures with a Cmax of 491 ng/mL (90% CI: 397–608 ng/mL) and AUC0–day 42 of 49700 hr·ng/mL (90% CI: 41700–59200 hr·ng/mL), representing a 3.3-fold increase compared to uninfected controls (GMR 3.40; p < 0.0001). The terminal t½ was slightly shorter at 414 hours (90% CI: 364–471 hours). Statistical analysis showed a highly significant increament in PQ exposure with a GMR of 3.40 (p < 0.0001). The present findings indicates significant differences in PQ pharmacokinetics among HIV-infected children on LPV/r and HIV-uninfected controls. Conclusions: LPV/r-based ART significantly increased PQ exposure in HIV-infected children, highlighting a strong drug–drug interaction with clinical implications for malaria chemoprevention and treatment. In contrast, PQ pharmacokinetics in HIV-uninfected children were consistent with standard dosing guidelines. These findings underscore the need for adjust dosing strategies to a lower dose and perform therapeutic monitoring to optimize malaria prevention and treatment in HIV-infected pediatric population