Leading Paediatric Infectious Diseases-Current Trends, Gaps, and Future Prospects in Oral Pharmacotherapeutic Interventions.

Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they are regularly accompanied with long-standing disadvantages that negatively impact efficacy, thus necessitating the need for effective and child-friendly pharmacotherapeutic interventions. Recent advancements in drug delivery technologies, particularly oral formulations, have shown tremendous progress in enhancing the effectiveness of paediatric medicines. Generally, these delivery methods target, and address challenges associated with palatability, dosing accuracy, stability, bioavailability, patient compliance, and caregiver convenience, which are important factors that can influence successful treatment outcomes in children. Some of the emerging trends include moving away from creating liquid delivery systems to developing oral solid formulations, with the most explored being orodispersible tablets, multiparticulate dosage forms using film-coating technologies, and chewable drug products. Other ongoing innovations include gastro-retentive, 3D-printed, nipple-shield, milk-based, and nanoparticulate (e.g., lipid-, polymeric-based templates) drug delivery systems, possessing the potential to improve therapeutic effectiveness, age appropriateness, pharmacokinetics, and safety profiles as they relate to the paediatric population. This manuscript therefore highlights the evolving landscape of oral pharmacotherapeutic interventions for leading paediatric infectious diseases, crediting the role of innovative drug delivery technologies. By focusing on the current trends, pointing out gaps, and identifying future possibilities, this review aims to contribute towards ongoing efforts directed at improving paediatric health outcomes associated with the management of these infectious ailments through accessible and efficacious drug treatments.

Evaluating determinants of treatment outcomes among tuberculosis patients in the mining district of Butha Buthe, Lesotho.

Background: Before the COVID-19 pandemic, tuberculosis (TB) was the leading infectious cause of death globally. In low- and middle-income countries (LMIC) including Lesotho, treatment outcome is lower than the recommended rate and poor TB treatment outcomes remain a programmatic challenge. The aim of this study was to determine unfavourable treatment outcomes and associated risk factors among TB patients in Butha Buthe district. Methods: This was a retrospective record review of TB patients registered between January 2015 and December 2020. Data were collected from TB registers and patients' files and entered Microsoft Excel 2012. Analysis was conducted using R and INLA statistical software. Descriptive statistics were presented as frequencies and percentages. The differences between groups were compared using Pearson's X 2 test in bivariate analysis. Frailty Cox proportional hazards model was used to determine the risk of unfavourable outcomes among the variables. Results: A total of 1792 TB patients were enrolled in the study with about 70% males (1,257). Majority (71.7%) of the patients were between 20 and 59 years old, with 48% of the patients being unemployed. Almost a quarter of the patients (23.1%) had unfavourable outcomes with death (342 patients) being the most common unfavourable outcome. Our study has shown that patients older than 59 years, and unemployment increased the risk of having unfavourable treatment outcomes. Death was the most common unfavourable outcome followed by lost-to-follow up. We also observed that the patients in the initiation phase of treatment died at a faster rate compared to those in the continuation phase (p=0.02). Conclusion: TB treatment programs should have efficient follow-up methods geared more toward elderly patients. Active case finding to identify population at risk should be part of a TB program which would improve early diagnosis and treatment initiation. Patients in the intensive phase of the treatment program should be monitored more closely to determine adverse drug effects and nutritional requirement to prevent death during this phase of treatment.

Unintended pregnancies among HIV-positive women in sub-Saharan Africa: a scoping review protocol.

BACKGROUND: Unintended pregnancies pose a severe threat to the well-being of HIV-positive women and their unborn children. Factors contributing to the high incidence of unintended pregnancies include contraceptive failure, low uptake of contraceptives, and misuse of contraceptives. Despite various contraceptive options, an increased incidence of unintended pregnancies is rampant among HIV-positive women in the region of sub-Saharan Africa. This study seeks to present evidence of unintended pregnancies among women living with HIV in sub-Saharan Africa, including those using contraceptives. METHOD: This study entails a scoping review to survey and interrogate the literature to provide evidence for the incidence of unintended pregnancies among HIV-positive women in sub-Saharan Africa. A proposed framework by Arksey and O'Malley will guide this scoping review. Peer-reviewed articles which address the research questions will constitute the main search. Electronic databases such as EBSCOhost, Cochrane Library, World of Science, World Health Organization (WHO) library databases, Science Direct, Google Scholar PubMed, and gray literature search will be involved. Reference list from studies included will also be searched. The investigation of articles will be done employing keywords from the studies included. The inclusion and exclusion criteria will guide two separate reviewers with the screening of abstracts and full papers. To summarize the findings from this review, thematic content analysis will be done using NVivo version 11. DISCUSSION: We expect that this review will add to the current body of knowledge on the incidence of unintended pregnancies among HIV-positive women, identify gaps for further future research, and show evidence that may contribute to strengthening the health system's regulations, guidelines, and policies that may help prevent unintended pregnancies among HIV-positive women. SYSTEMATIC REVIEW REGISTRATION: 10.17605/OSF.IO/EY3R5.

Pediatric Tuberculosis Management: A Global Challenge or Breakthrough?

Managing pediatric tuberculosis (TB) remains a public health problem requiring urgent and long-lasting solutions as TB is one of the top ten causes of ill health and death in children as well as adolescents universally. Minors are particularly susceptible to this severe illness that can be fatal post-infection or even serve as reservoirs for future disease outbreaks. However, pediatric TB is the least prioritized in most health programs and optimal infection/disease control has been quite neglected for this specialized patient category, as most scientific and clinical research efforts focus on developing novel management strategies for adults. Moreover, the ongoing coronavirus pandemic has meaningfully hindered the gains and progress achieved with TB prophylaxis, therapy, diagnosis, and global eradication goals for all affected persons of varying age bands. Thus, the opening of novel research activities and opportunities that can provide more insight and create new knowledge specifically geared towards managing TB disease in this specialized group will significantly improve their well-being and longevity.

A Micro-Configured Multiparticulate Reconstitutable Suspension Powder of Fixed Dose Rifampicin and Pyrazinamide: Optimal Fabrication and In Vitro Quality Evaluation.

The scarcity of age-appropriate pharmaceutical formulations is one of the major challenges impeding successful management of tuberculosis (TB) prevalence in minors. To this end, we designed and assessed the quality of a multiparticulate reconstitutable suspension powder containing fixed dose rifampicin and pyrazinamide (150 mg/300 mg per 5 mL) which was prepared employing solid−liquid direct dispersion coupled with timed dehydration, and mechanical pulverization. The optimized formulation had a high production yield (96.000 ± 3.270%), displayed noteworthy powder flow quality (9.670 ± 1.150°), upon reconstitution the suspension flow property was non-Newtonian and was easily redispersible with gentle manual agitation (1.720 ± 0.011 strokes/second). Effective drug loading was attained for both pyrazinamide (97.230 ± 2.570%w/w) and rifampicin (97.610 ± 0.020%w/w) and drug release followed a zero-order kinetic model (R2 = 0.990) for both drugs. Microscopic examinations confirmed drug encapsulation efficiency and showed that the particulates were micro-dimensional in nature (n < 700.000 µm). The formulation was physicochemically stable with no chemically irreversible drug-excipient interactions based on the results of characterization experiments performed. Findings from organoleptic evaluations generated an overall rating of 4.000 ± 0.000 for its attractive appearance and colour 5.000 ± 0.000 confirming its excellent taste and extremely pleasant smell. Preliminary cytotoxicity studies showed a cell viability above 70.000% which indicates that the FDC formulation was biocompatible. The optimized formulation was environmentally stable either as a dry powder or reconstituted suspension. Accordingly, a stable and palatable FDC antimycobacterial reconstitutable oral suspension powder, intended for flexible dosing in children and adolescents, was optimally fabricated.

Factors associated with high HIV-related stigma among commuter populations in Johannesburg, South Africa.

Stigma remains an important barrier to seeking and staying in care among individuals infected with Human Immunodeficiency Virus (HIV). Despite continued widespread information, education and communication campaigns to raise awareness about the infection. The aim of the study was to identify factors related to HIV stigma among a commuter population in the inner-city Johannesburg. A self-administered closed-ended questionnaire was loaded onto personal tablet computers during a community outreach campaign. The outcome was measured by asking the respondents to rate their perceptions of stigma as 'high or low'. About 1146 participants were enrolled in the study of which 585 (51.0%) reported high stigma levels. Overall, being married/cohabiting (Adjusted Prevalence Ratio (APR): 1.14 95%CI: 1.02-1.28), divorced (APR: 1.38 95%CI: 1.07-1.78), were associated with high levels of stigma; while being aware of HCT services (APR: 0.85 95%CI: 0.75-0.97) and employment status (APR: 0.78 95%CI: 0.71-0.87) were less likely associated with a high level of stigma. High HIV stigma still exists among those affected in our communities. Enhancement of health promotion intervention and reinforcing the benefits of knowing HIV status is essential to mitigate factors shown to influence stigma in the commuter population. Such an approach would help overcome stigma, an obstacle for expanding access to HIV testing and counselling.

Dzherelo (Immunoxel) as adjunctive therapy to standard antituberculosis treatment in patients with pulmonary tuberculosis: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Dzherelo (Immunoxel) is one of the few approved immunomodulators that has been shown to produce positive treatment outcomes in patients with tuberculosis (TB). The aim of this review was to assess the effectiveness of Immunoxel used as adjunct therapy with conventional anti-TB therapy for the treatment of pulmonary TB. METHODS: Comprehensive search was conducted in different major databases: PubMed (MEDLINE), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus (Elsevier). We also searched Google Scholar along with trial registries and hand-searched the reference list of identified original research as well as review articles. Conference proceedings of relevant TB and lung disease annual conferences were also screened. Two independent authors extracted outcome data using a standardised extraction form. Relative risk (RR), mean difference (MD) and standardised mean difference (SMD) with a 95% confidence interval (CI) were used as measures of effect. We assessed certainty of evidence using GRADE. RESULTS: Six clinical trials, which met the criteria for the review, were identified, and these provided data for the review. Overall results from the six trials that compared antituberculosis treatment (ATT) alone versus ATT and Immunoxel, and ATT and placebo versus ATT and Immunoxel showed an increased number of patients becoming sputum-negative in the Immunoxel group (RR 3.19; 95% CI 2.44 to 4.17; 488 participants). There was also reduction in body temperature among patients receiving Immunoxel compared to ATT alone (MD -0.20, 95% CI -0.22 to -0.18, 345 participants). However, there were no differences in body weight changes across all the studies (MD 5.65; 95% CI -0.80 to 12.11; 382 participants). CONCLUSION: Current evidence indicates that the use of Immunoxel as an adjunctive treatment in patients with pulmonary tuberculosis has the potential to enhance the efficacy of antituberculosis treatment. However, well-designed, conducted and adequately powered clinical trials are needed to establish the effectiveness of this adjunctive treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42019127823.

An investigation of maternal anaemia among HIV infected pregnant women on antiretroviral treatment in Johannesburg, South Africa.

INTRODUCTION: maternal anaemia is a major public health problem in developing countries. Data suggests that anaemia contributes to the progression of Human Immunodeficiency Virus (HIV)-infection. The aim of this study was to investigate if pregnancy was an aggravating factor for anaemia among HIV-positive women on anti-retroviral treatment (ART). METHODS: we analyzed data of all HIV-positive women aged 18-49 years receiving ART at Themba Lethu Clinic, Helen Joseph Hospital, Johannesburg, South Africa, from 1st April 2004- 30t hApril 2011. HIV-positive pregnant women were matched with non-pregnant women using the year of initiation of treatment. The outcome of interest ´anaemia´ was defined as "no anaemia", "anaemia" and "moderate/severe anaemia". We fitted an ordered logistic regression model to predict the likelihood of having severe/moderate anaemia versus no anaemia. We included pregnancy status as a predictor of the outcome and controlled the effect of other covariates in the analysis. RESULTS: the study included 236 HIV positive patients, of which half (n=118, 50%) were pregnant. At baseline, about (n=143, 60%) of patients were anaemic. The proportion of pregnant women classified as anaemic (anaemia, moderate/severe) differed significantly (p=0.02) from that of non-pregnant women. The following characteristics were significantly associated with anaemia at baseline: Body mass index (BMI) category (p=0.01); World Health Organization (WHO) stage (p=0.001) and CD4 count (p=0.001). Seven months after initiation of treatment, the proportion of HIV positive women with anaemia decreased significantly. CONCLUSION: anaemia is a significant risk factor for untoward health outcomes, especially among HIV-positive pregnant women. Early ART access might result in a significant decrease in anaemia in pregnancy.

Interactions of 1-methyl-3-phenylpyrrolidine and 3-methyl-1-phenyl-3-azabicyclo[3.1.0]hexane with monoamine oxidase B.

The parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its corresponding five-membered ring analogue 1-methyl-3-phenyl-3-pyrroline are cyclic tertiary allylamines and good substrates of monoamine oxidase B (MAO-B). The MAO-B catalyzed 2-electron alpha-carbon oxidation of this class of substrates appears to be dependent on the presence of the allylic pi-bond since the corresponding saturated piperidinyl analogue of MPTP is reported not to be an MAO-B substrate. The only saturated cyclic tertiary amine known to act as an MAO-B substrate is the 3,4-cyclopropyl analogue of MPTP, 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane. As part of our ongoing studies we have examined the MAO-B substrate properties of the corresponding pyrrolidinyl analogue, 1-methyl-3-phenylpyrrolidine, and the 3,4-cyclopropyl analogue, 3-methyl-1-phenyl-3-azabicyclo[3.1.0]hexane. The results document that both the pyrrolidinyl analogue [K(m)=234microM; V(max)=8.37nmol/(min-mg mitochondrial protein)] and the 3,4-cyclopropyl analogue [K(m)=148microM; V(max)=16.9nmol/(min-mg mitochondrial protein)] are substrates of baboon liver mitochondrial MAO-B. We also have compared the neurotoxic potential of these compounds in the C57BL/6 mouse. The results led us to conclude that these compounds are not MPTP-type neurotoxins.

Deuterium isotope effects for the oxidation of 1-methyl-3-phenyl-3-pyrrolinyl analogues by monoamine oxidase B.

The parkinsonian inducing agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a cyclic tertiary allylamine exhibiting good monoamine oxidase B (MAO-B) substrate properties. MAO-B catalyzes the ring alpha-carbon 2-electron bioactivation of MPTP to yield the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP(+)). The corresponding 5-membered ring MPTP analogue, 1-methyl-3-phenyl-3-pyrroline, also undergoes MAO-B-catalyzed oxidation to give the 2-electron oxidation product, 1-methyl-3-phenylpyrrole. Here we report the kinetic deuterium isotope effects on V(max) and V(max)/K(m) for the steady-state oxidation of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4-fluorophenyl)-3-pyrroline by baboon liver MAO-B, using the corresponding pyrroline-2,2,4,5,5-d(5) analogues as the deuterated substrates. The apparent isotope effects for the two substrates were 4.29 and 3.98 on V(max), while the isotope effects on V(max)/K(m) were found to be 5.71 and 3.37, respectively. The values reported for the oxidation of MPTP by bovine liver MAO-B with MPTP-6,6-d(2), as deuterated substrate, are (D)(V(max))=3.55; (D)(V(max)/K(m))=8.01. We conclude that the mechanism of the MAO-B-catalyzed oxidation of pyrrolinyl substrates is similar to that of the tetrahydropyridinyl substrates and that a carbon-hydrogen bond cleavage step is, at least partially, rate determining.

Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles.

1-Methyl-3-phenyl-3-pyrrolines are structural analogues of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and like MPTP are selective substrates of monoamine oxidase B (MAO-B). As part of an ongoing investigation into the substrate properties of various 1-methyl-3-phenyl-3-pyrrolinyl derivatives, it is shown in the present study that their respective MAO-B catalyzed oxidation products act as reversible competitive inhibitors of the enzyme. The most potent inhibitor among the oxidation products considered was 1-methyl-3-(4-trifluoromethylphenyl)pyrrole with an enzyme-inhibitor dissociation constant (K(i) value) of 1.30 microM. The least potent inhibitor was found to be 1-methyl-3-phenylpyrrole with a K(i) value of 118 microM. The results of an SAR study established that the potency of MAO-B inhibition by the 1-methyl-3-phenylpyrrolyl derivatives examined here is dependent on the Taft steric parameter (E(s)) and Swain-Lupton electronic constant (F) of the substituents attached to C-4 of the phenyl ring. Electron-withdrawing substituents with a large degree of steric bulkiness appear to enhance inhibition potency. Potency was also found to vary with the substituents at C-3, again with E(s) and F being the principal substituent descriptors.

Neurotoxicity studies with the monoamine oxidase B substrate 1-methyl-3-phenyl-3-pyrroline.

The neurotoxic properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are dependent on its metabolic activation in a reaction catalyzed by centrally located monoamine oxidase B (MAO-B). This reaction ultimately leads to the permanently charged 1-methyl-4-phenylpyridinium species MPP(+), a 4-electron oxidation product of MPTP and a potent mitochondrial toxin. The corresponding 5-membered analogue, 1-methyl-3-phenyl-3-pyrroline, is also a selective MAO-B substrate. Unlike MPTP, the MAO-B-catalyzed oxidation of 1-methyl-3-phenyl-3-pyrroline is a 2-electron process that leads to the neutral 1-methyl-3-phenylpyrrole. MPP(+) is thought to exert its toxic effects only after accumulating in the mitochondria, a process driven by the transmembrane electrochemical gradient. Since this energy-dependent accumulation of MPP(+) relies upon its permanent charge, 1-methyl-3-phenyl-3-pyrrolines and their pyrrolyl oxidation products should not be neurotoxic. We have tested this hypothesis by examining the neurotoxic potential of 1-methyl-3-phenyl-3-pyrroline and 1-methyl-3-(4-chlorophenyl)-3-pyrroline in the C57BL/6 mouse model. These pyrrolines did not deplete striatal dopamine while analogous treatment with MPTP resulted in 65-73% depletion. Kinetic studies revealed that both 1-methyl-3-phenyl-3-pyrroline and its pyrrolyl oxidation product were present in the brain in relatively high concentrations. Unlike MPP(+), however, 1-methyl-3-phenylpyrrole was cleared from the brain quickly. These results suggest that the brain MAO-B-catalyzed oxidation of xenobiotic amines is not, in itself, sufficient to account for the neurodegenerative properties of a compound like MPTP. The rapid clearance of 1-methyl-3-phenylpyrroles from the brain may contribute to their lack of neurotoxicity.

Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues.

We have recently reported that a series of (E)-8-styrylcaffeines and (E)-2-styrylbenzimidazoles are moderate to very potent competitive inhibitors of monoamine oxidase B (MAO-B). The most potent member of the series was found to be (E)-8-(3-chlorostyryl)caffeine (CSC) with an enzyme-inhibitor dissociation constant (K(i) value) of 128 nM. In the present study, we have prepared additional caffeine and benzimidazole analogues in an attempt to identify compounds with improved MAO-B inhibition potency while still acting reversibly. The most potent inhibitor among the caffeine analogues was (E)-8-(3,4-dichlorostyryl)caffeine with a K(i) value of 36 nM, approximately 3.5 times more potent than CSC. The most potent inhibitor among the benzimidazole analogues was (E)-2-(4-trifluoromethylstyryl)-1-methylbenzimidazole with a K(i) value of 430 nM. An SAR analysis indicated that the potency of MAO-B inhibition by (E)-2-styryl-1-methylbenzimidazole analogues depended upon the Taft steric parameter (E(s)) of the substituents attached to C-4 of the styryl phenyl ring. Substituents with a large degree of steric hindrance appear to enhance inhibition potency. The proposal that potent MAO-B inhibition by (E)-8-styrylcaffeines and (E)-2-styrylbenzimidazoles can be explained by a mode of binding that involves traversing both the entrance and substrate cavities was supported by the finding that 1-methylbenzimidazole only weakly inhibited MAO-B with a K(i) value of 2084 microM. Without the styryl side chain, 1-methylbenzimidazole is not expected to be able to bind simultaneously to both the entrance and substrate cavities.