Antenatal corticosteroid therapy, delivery intervals and perinatal mortality in low-resource settings.

BACKGROUND: Uncertainty exists regarding the ideal interval between the administration of antenatal corticosteroids (ACS) and delivery. The study's objective was to assess the risks of perinatal mortality and respiratory distress syndrome (RDS) among preterm neonates whose mothers gave birth within 48 h of the administration of ACS and those whose mothers gave birth between 48 h and 7 days. METHODS: The study design was a secondary analysis of data from an observational prospective chart review study that was carried out in Tanzania in 2020. Preterm infants born to mothers who got at least one dose of ACS between 28 and 34 weeks of pregnancy were included. RESULTS: A total of 346 preterm neonates (294 singletons and 52 twins) were exposed to ACS. Compared to infants born 48 h following the first dose of ACS, those exposed to the drug between 48 h and 7 days had significantly decreased rates of perinatal mortality and RDS. Multivariable analysis revealed that infants exposed ACS between 48 h and 7 days prior to delivery had lower risk of perinatal mortality (aRR 0.30, 95% CI 0.14-0.66) and RDS (aRR 0.27, 95% CI 0.14-0.52). CONCLUSION: The first dose of ACS given between 48 h and 7 days before delivery was associated with a lower risk of perinatal mortality and RDS than when the first dose was given <48 h before delivery. To improve neonatal outcomes, healthcare providers should consider administering ACS to mothers at the appropriate time.

Preterm infants exposed to antenatal corticosteroids (ACS) have lower rates of perinatal mortality and morbidity. Uncertainty exists regarding the ideal interval between the administration of ACS and delivery. We conducted a secondary analysis of data from a study that included preterm infants born in four hospitals in Tanzania. We investigated whether there were differences in perinatal mortality and respiratory distress syndrome between preterm neonates whose mothers delivered within 48 h of receiving a partial course of ACS and those whose mothers delivered between 48 h and 7 days after a full course of ACS therapy. Participants were the preterm infants of women who received ACS between 28 and 34 weeks of gestation. Neonates exposed to ACS between 48 h and 7 days prior to delivery had significantly lower risks of perinatal mortality and respiratory distress syndrome compared to infants who were delivered <48 h after ACS administration. This finding highlights the importance of optimizing the timing of ACS administration to maximize its potential benefits and minimize risks to preterm neonates. To improve neonatal outcomes, healthcare providers should consider administering ACS to mothers at the appropriate time.

Association between antenatal corticosteroid use and perinatal mortality among preterm births in hospitals in Tanzania.

OBJECTIVES: The primary aims of this study were to investigate if exposure to antenatal corticosteroids (ACS) was associated with lower rates of perinatal mortality (primary outcome) and other adverse perinatal outcomes (i.e., stillbirth, early neonatal mortality, APGAR score of < 7 at 5 mins, neonatal sepsis and respiratory distress syndrome) in preterm infants in hospitals in Tanzania. We also examine factors associated with administration of ACS among women at risk of preterm delivery. METHODS: A hospital-based prospective chart review study was undertaken in four hospitals located in Nyamagana and Sengerema districts, Tanzania. The study population included all stillborn and live born preterm infants delivered between 24 to 34 weeks of gestation between July 2019 to February 2020. A total 1125 preterm infants were delivered by 1008 women (895 singletons, 230 multiple). Sociodemographic and medical data were recorded from participants' medical records. RESULTS: Three hundred and fifty-six (35.3%) women were administered at least one dose of ACS between 24 to 34 weeks' gestation and 385 (34.2%) infants were exposed to ACS. Infants exposed to ACS had a lower rate of perinatal mortality (13.77%) compared to those who were not exposed (28.38%). Multivariate analysis indicated that infants exposed to ACS were less likely to die during perinatal period, aRR 0.34 (95%CI 0.26-0.44). Only one-third of the sample was provided with ACS. Administration of ACS was associated with maternal education, attending antenatal care more than 3 times, method used to assess gestational age, maternal infection, exposure to maternal antibiotics, delivery mode and level of health facility. CONCLUSION: ACS significantly reduced the risk in perinatal mortality among infants born preterm in a limited resource setting. However, only about one-third of eligible women were provided with ACS, indicating low usage of ACS. Numerous factors were associated with low usage of ACS in this setting.

Reducing neonatal mortality and respiratory distress syndrome associated with preterm birth: a scoping review on the impact of antenatal corticosteroids in low- and middle-income countries.

BACKGROUND: The most common cause of death among preterm infants in low- and middle-income countries is respiratory distress syndrome. The purpose of this review was to assess whether antenatal corticosteroids given to women at risk of preterm birth at ≤ 34 weeks of gestation reduce rates of neonatal mortality and respiratory distress syndrome in low- and middle-income countries. METHODS: Two reviewers independently searched four databases including MEDLINE (through PubMed), CINAHL, Embase, and Cochrane Libraries. We did not apply any language or date restrictions. All publications up to April 2020 were included in this search. RESULTS: The search yielded 71 articles, 10 of which were included in this review (3 randomized controlled trials, 7 observational studies, 36,773 neonates). The majority of studies reported associations between exposure to antenatal corticosteroids and lower rates of neonatal mortality and respiratory distress syndrome. However, a few studies reported that antenatal corticosteroids were not associated with improved preterm birth outcomes. CONCLUSIONS: Most of the studies in low- and middle-income countries showed that use of antenatal corticosteroids in hospitals with high levels of neonatal care was associated with lower rates of neonatal mortality and respiratory distress syndrome. However, the findings are inconclusive because some studies in low-resource settings reported that antenatal corticosteroids had no benefit in reducing rates of neonatal mortality or respiratory distress syndrome. Further research on the impact of antenatal corticosteroids in resource-limited settings in low-income countries is a priority.

Prescription patterns and adequacy of blood pressure control among adult hypertensive patients in Kenya; findings and implications.

BACKGROUND: Hypertension is a major cause of global morbidity and mortality, with high prevalence rates in Africa including Kenya. Consequently, it is imperative to understand current treatment approaches and their effectiveness in practice. Currently, there is paucity of such data in Kenya, which is a concern. The aim is to describe prescribing patterns and adequacy of blood pressure (BP) control in adult hypertensive patients to guide future practice. METHOD: Retrospective study of patients attending a sub-county outpatient clinic combined with qualitative interviews. RESULTS: 247 hypertensive patients, predominantly female, mean age 55.8 years on antihypertensive therapy for 1-5 years, were analyzed. ACEIs and thiazide diuretics were the most commonly prescribed drugs, mainly as combination therapy. Treatment typically complied with guidelines, mainly for stage 2 hypertension (75%). BP control was observed in 46% of patients, with a significant reduction in mean systolic (155 to 144 mmHg) and diastolic (91 to 83 mmHg) BP (P < 0.001). Patients on ≥2 antihypertensive drugs were more likely to have uncontrolled BP (OR:1.9, p = 0.021). CONCLUSION: Encouragingly good adherence to guidelines was helped by training. Poor blood pressure control in the majority needs to be addressed. Additional training of prescribers and follow-up of measures to improve BP control will be introduced and followed up.

Patient-related beliefs and adherence toward their medications among the adult hypertensive outpatients in Tanzania.

AIM: Hypertension is a leading global health problem requiring lifelong treatment. However, adherence to antihypertensive medicines is a problem, greater among developing countries. Consequently, there is a need to determine current adherence rates and their associations among developing countries to plan future initiatives. MATERIALS & METHODS: Cross-sectional study among adult outpatients with essential hypertension in Tanzania. Predesigned questionnaires were used to gather information on adherence rates and patient-related beliefs. The main outcome measure was adherence. RESULTS: A total of 180 participants were included, with females making up 65%. High-adherence rates were seen in 54% of the patients. Patients' belief about their medication and its necessity was higher in the high adherent group and concerns about their medicines and their necessity were higher in the low adherent group. Conclusion & recommendations: Adherence rates were low compared with a suggested level ≥80%. Educational initiatives are needed to address knowledge and concerns with hypertension to improve future outcomes.

Outcome of the second Medicines Utilisation Research in Africa Group meeting to promote sustainable and appropriate medicine use in Africa.

The second Medicines Utilization Research in Africa (MURIA) group workshop and symposium again brought researchers together from across Africa to improve their knowledge of drug utilization (DU) methodologies and exchange ideas to further progress DU research in Africa. This built on extensive activities from the first conference including workshops and multiple publications. Anti-infectives were again the principal theme for the 2016 symposium following the workshops. This included presentations regarding strategies to improve antibiotic utilization among African countries, such as point-prevalence studies, as well as potential ways to reduce self-purchasing of antibiotics. There were also presentations on antiretrovirals including renal function and the impact of policy changes. Concerns with adherence in chronic treatments as well as drug-drug interactions and their implications were also discussed. The deliberations resulted in a number of agreed activities including joint publications before the next MURIA conference in Namibia in 2017.

Microbial contamination of traditional liquid herbal medicinal products marketed in Mwanza city: magnitude and risk factors.

INTRODUCTION: The use of the traditional herbal medicinal products (THMPs) has been increasing worldwide due to the readily availability of raw materials and low cost compared to the synthetic industrial preparations. With this trend in mind, the safety and quality of THMPs need to be addressed so as to protect the community. The present study evaluated the magnitude and risk factors associated with microbial contamination of liquid THMPs marketed in Mwanza. METHODS: A cross-sectional study was conducted in Mwanza city involving 59 participants from whom 109 liquid THMPs were collected and processed following the standard operating procedures. The data were analyzed using STATA software version 11. RESULTS: The median age (interquartile range) of participants was 35 (27-43) years, with males accounting for 36 (61%). Of 109 liquid THMPs collected, 89 (81.7%) were found to be contaminated; with predominant fecal coliforms being Klebsiella spp and Enterobacter spp. fortunately, no pathogenic bacteria like Salmonella spp and Shigella spp were isolated. There was a significant association of liquid THMPs contamination with low education level (p< 0.001), lack of formal training on THMPs (p = 0.023), lack of registration with the Ministry of Health (p = 0.001), lack of packaging of products (p < 0.001) and use of unboiled solvents during preparation of THMPs (p < 0.001). CONCLUSION: There is high contamination rate of liquid THMPs in Mwanza City which is attributable to individuals and system-centered factors. Urgent measures to provide education to individuals involved in THMPs as well as setting up policies and regulations to reinforce THMPs safety is needed.

The prevalence of substance use among psychiatric patients: the case study of Bugando Medical centre, Mwanza (northern Tanzania).

World Health Organization (2004) documented that substance use or abuse and mental disorders are important causes of disease burden accounting for 8.8% and 16.6% of the total burden of disease in low income and lower middle-income countries, respectively. Alcohol use/abuse disorders alone contribute to 0.6%-2.6% of the total burden of disease in these countries. This cross-sectional descriptive study recruited 184 psychiatric patients seen at Bugando Medical centre and assessed them for substance involvement using the WHO Alcohol, Smoking and Substance Involvement Screening Test. The most frequently used substances among respondents were alcohol (59.3%), tobacco (38.6%), and cannabis (29.3%), while heroin and cocaine were least used (2.1% and 1.6%, respectively). Statistical significant difference existed between substance use and participants: level of education, formal employment, marital status, gender, family history of mental illness, and family history of substance use. About a third attributed their involvement into substance exclusively to peer pressure, 8.7 to both peer pressure and curiosity while 7.1% exclusively to curiosity. This result represents one of the most important risks to mental health, and is a leading factor that causes high rates of admission or reason to be seen by a psychiatrist, this cannot be ignored when managing psychiatric disorders and therefore calls for routing screening for substance involvement among clients seeking psychiatric treatment. It also calls for appropriate standard operation policy procedures that can be operationlized as a matter of clinical practice by mental health workers in their routine medical practice.

4Beta-hydroxycholesterol is a new endogenous CYP3A marker: relationship to CYP3A5 genotype, quinine 3-hydroxylation and sex in Koreans, Swedes and Tanzanians.

OBJECTIVES: To study the potential endogenous marker of CYP3A activity, 4beta-hydroxycholesterol, and its relation to sex and the CYP3A5 geno/haplotypes and compare with CYP3A4/5 catalyzed 3-hydroxylation of quinine in the three major races. METHODS: The plasma concentration of 4beta-hydroxycholesterol was measured in healthy Tanzanians (n=138), Swedes (n=161) and Koreans (n=149) by gas chromatography-mass spectrometry. The metabolic ratio of quinine/3-hydroxyquinine in plasma 16-h post dose was determined by high performance liquid chromatography, previously reported in Tanzanians and Swedes, and now also in Koreans. The participants were genotyped for relevant alleles of CYP3A5. RESULTS: The mean plasma concentrations of 4beta-hydroxycholesterol in Koreans, Swedes and Tanzanians were 29.3, 26.8 and 21.9 ng/ml, respectively (P<0.01 between all three populations). Within all three populations there were significant differences in 4beta-hydroxycholesterol levels between the CYP3A5 genotypes. Women had higher concentrations than men, but the difference was only significant in Tanzanians (P<0.001) and Koreans (P<0.00001). The quinine/3-hydroxyquinine metabolic ratio was significantly different in all three populations with the highest CYP3A activity in Koreans and the lowest in Tanzanians. Korean women had a lower metabolic ratio than men (P<0.00001). Significant correlations between 4beta-hydroxycholesterol and quinine 3-hydroxylation were found in Tanzanians and Koreans. CONCLUSION: Clear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4beta-hydroxycholesterol and quinine/3-hydroxyquinine metabolic ratio showed a higher CYP3A activity in women than in men. The results give strong evidence that the plasma concentration of 4beta-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4+5).

CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population.

OBJECTIVES: To study the correlation between CYP3A5 genotype and quinine 3-hydroxylation in black Tanzanian and Swedish Caucasians as well as to investigate the interethnic differences in CYP3A activity between the two populations. METHODS: Tanzanian (n=144) and Swedish (n=136) healthy study participants were given a single oral 250 mg dose of quinine hydrochloride and a 16-h post-dose blood sample was collected. The metabolic ratio of quinine/3-hydroxyquinine was determined in plasma by high-performance liquid chromatography. All the participants were genotyped for the known mutations of CYP3A5, which are relevant for the respective population. Correlation between quinine metabolic ratio and CYP3A5 genotype as well as the interethnic difference in CYP3A activity between the two populations was studied. RESULTS: Tanzanians had significantly higher (P<0.0001) mean quinine metabolic ratio (9.5+/-3.5) than Swedes (7.6+/-3.1). As expected, the frequency of high CYP3A5 expression alleles was higher in Tanzanians (51%) than in Swedes (7%). The mean+/-SD quinine metabolic ratio (10.7+/-3.9) in Tanzanians homozygous for low CYP3A5 expression gene was significantly higher than the corresponding mean metabolic ratio in participants heterozygous (9.5+/-3.3; P=0.02) or homozygous (8.1+/-3.1; P=0.002) for high expression CYP3A5 alleles, respectively. A tendency to higher quinine metabolic ratio in Swedes with low expression alleles compared with those with one or two high expression alleles was observed. Tanzanians homozygous for low CYP3A5 expression gene (i.e. only CYP3A4 is expressed) had significantly (P<0.0001) higher quinine metabolic ratio (10.7+/-3.9) than corresponding Swedes (7.7+/-3.1). CONCLUSIONS: Clear interethnic differences were observed in the activity of CYP3A between Tanzanians and Swedes. A significant association is noted between CYP3A5 genotype and quinine 3-hydroxylation in Tanzanians, indicating a significant contribution of CYP3A5 to total 3A activity. The CYP3A4 catalyzed hydroxylation of quinine (two low CYP3A5 expression alleles) was lower in Tanzanians than in Swedes.

Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans.

OBJECTIVE: To investigate the likelihood of artemisinin and thiabendazole causing pharmacokinetic interactions involving cytochrome P450 (CYP1A2) in humans given their potent inhibitory effects on the isoform in vitro. METHODS: Ten healthy volunteers received caffeine (136.5 mg), and after a washout period of 48 h, the volunteers were given a caffeine tablet (136.5 mg) together with thiabendazole (500 mg). After an additional 14 days, the volunteers received caffeine together with artemisinin (500 mg). After each treatment, plasma was obtained up to 24 h post-dose. The plasma concentrations of the drugs were measured by HPLC with UV and MS detection. RESULTS: Using the ratio of paraxanthine to caffeine after 4 h as an indicator of CYP1A2 activity, thiabendazole and artemisinin inhibited 92 and 66%, respectively, of the enzyme activity in vivo. In addition, the pharmacokinetics of caffeine were altered in the presence of the drugs; increases in AUC(0-24) of 1.6-fold (P < 0.01) and 1.3-fold of caffeine in the presence of thiabendazole and artemisinin respectively were measured. The use of in vitro data to predict the effects of thiabendazole on the formation of paraxanthine yielded good results and underestimated the effects of artemisinin when total plasma concentrations were used. Corrections for protein binding resulted in underestimation of inhibitory effects on CYP1A2. CONCLUSIONS: Co-administration of thiabendazole or artemisinin with CYP1A2 substrates could result in clinically significant effects. Our results highlight the validity of in vitro data in predicting in vivo CYP inhibition. The formation of paraxanthine seems to be a better indicator of in vivo CYP1A2 activity than caffeine levels.

Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal livers.

BACKGROUND: The fetal liver cytochrome P450 (CYP) 3A enzymes metabolize potentially toxic and teratogenic substrates and drugs in addition to endogenous hormones and differentiation factors. CYP3A7 is the most abundant CYP in the human liver during fetal stages and the first months of postnatal age and shows a large interindividual variability of unknown molecular basis. METHODS: A new variant gene (CUpsilonP3A7*2), which carries a mutation in exon 11 of CUpsilonP3A7 causing a T409R substitution, was identified by direct sequencing. Genotype analysis was performed by use of polymerase chain reaction followed by restriction enzyme analysis. CYP3A7.2 activity was assessed in heterologous expression systems and human fetal liver microsomes. RESULTS: The frequency of CUpsilonP3A7*2 was 8%, 17%, 28%, and 62% in white, Saudi Arabian, Chinese, and Tanzanian individuals, respectively. By use of human HEK293 cells, no significant differences in expression between CYP3A7.1 and CYP3A7.2 were found and fetal livers homozygous for CUpsilonP3A7*2 had similar or higher CYP3A7 protein contents than CUpsilonP3A7*1 livers. Kinetic studies showed that CYP3A7.2 was a functional enzyme with a significantly higher catalytic constant (kcat) as compared with CYP3A7.1 (P < .05). Interestingly, fetal livers that expressed CYP3A7.2 also expressed CYP3A5 protein, and we found a linkage disequilibrium between the CUpsilonP3A7*2 and CUpsilonP3A5*1 alleles that was subject to interethnic differences. Determination of the alprazolam 1-hydroxylation rate revealed that CYP3A5 plays a significant role in the metabolism of CYP3A substrates in the fetal liver. CONCLUSION: We have identified 2 different CYP3A phenotypes in the fetal liver--one that is the result of a CUpsilonP3A7*1/CUpsilonP3A5*3 haplotype causing CYP3A7.1 but no CYP3A5 expression and another with higher detoxification capacity, inherent in the CUpsilonP3A7*2/CUpsilonP3A5*1 haplotype, where CYP3A5 and a more active form of CYP3A7 are expressed.