Browsing by Author "Howe, Rawleigh"

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    Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease
    (Journal of Infection, 2016) Awoniyi, Dolapo O.; Teuchert, Andrea; Sutherland, Jayne S.; Mayanja-Kizza, Harriet; Howe, Rawleigh; Mihret, Adane; Loxton, Andre G.; Sheehama, Jacob; Kassa, Desta; Crampin, Amelia C.; Dockrell, Hazel M.; Kidd, Martin; Rosenkrands, Ida; Geluk, Annemieke; Ottenhoff, Tom H.M.; Chegou, Novel N.; Walzl, Gerhard
    We investigated the accuracy of host markers detected in Mtb antigenstimulated whole blood culture supernatant in the diagnosis of TB. Methods: Prospectively, blood from 322 individuals with presumed TB disease from six African sites was stimulated with four different Mtb antigens (Rv0081, Rv1284, ESAT-6/CFP-10, and Rv2034) in a 24 h whole blood stimulation assay (WBA). The concentrations of 42 host markers in the supernatants were measured using the Luminex multiplex platform. Diagnostic biosignatures were investigated through the use of multivariate analysis techniques. Results: 17% of the participants were HIV infected, 106 had active TB disease and in 216 TB was excluded. Unstimulated concentrations of CRP, SAA, ferritin and IP-10 had better discriminating ability than markers from stimulated samples. Accuracy of marker combinations by general discriminant analysis (GDA) identified a six analyte model with 77% accuracy for TB cases and 84% for non TB cases, with a better performance in HIV uninfected patients. Conclusions: A biosignature of 6 cytokines obtained after stimulation with four Mtb antigens has moderate potential as a diagnostic tool for pulmonary TB disease individuals and stimulated marker expression had no added value to unstimulated marker performance.
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    Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients
    (Frontiers in Pharmacology, 2020) Ahmed, Jemal H.; Makonnen, Eyasu; Bisaso Kuteesa, Ronald; Kijumba Mukonzo, Jackson; Fotoohi, Alan; Aseffa, Abraham; Howe, Rawleigh; Hassan, Moustapha; Aklillu, Eleni
    Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or