The Novelty of Inhalable Medications: Interest, Use, and Impact of Inhalant Medications in Low-Resource Settings.

INTRODUCTION: Postpartum haemorrhage (PPH) claims more than 100,000 maternal lives annually worldwide, most of them in low-resource settings. To address morbidity and mortality from PPH, the global health community is exploring novel drug formulations, such as inhalable medicine, to improve treatment availability and use, especially in community settings with limited access to skilled birth attendants. A major limitation in the ability to prevent or treat PPH in resource-limited settings is that the most effective medications for prevention and treatment are injectables, which require administration by skilled birth attendants. METHODOLOGY: We conducted formative research, including online surveys and in-person interviews, with a range of providers across a variety of health-care settings in Guatemala, Indonesia, Kenya, and Nigeria, to better understand the standard of care for mothers and newborns in low-resource settings, including care practices related to PPH. RESULTS: It is estimated that up to 40% of PPH deaths could be averted if an inhalable prevention and treatment were available. However, survey and interview respondents noted a desire for more intravenous and oral medicinal formulations over inhalable formulations. DISCUSSION/CONCLUSION: Lack of knowledge and use of inhalable medicines among these health workers illuminates key challenges to introducing novel formulations in low-resource settings.

Interventions to reduce neonatal mortality: a mathematical model to evaluate impact of interventions in sub-Saharan Africa.

AIM: To determine which interventions would have the greatest impact on reducing neonatal mortality in sub-Saharan Africa in 2012. METHODS: We used MANDATE, a mathematical model, to evaluate scenarios for the impact of available interventions on neonatal deaths from primary causes, including: (i) for birth asphyxia - obstetric care preventing intrapartum asphyxia, newborn resuscitation and treatment of asphyxiated infants; (ii) for preterm birth - corticosteroids, oxygen, continuous positive air pressure and surfactant; and, (iii) for serious newborn infection - clean delivery, chlorhexidine cord care and antibiotics. RESULTS: Reductions in infection-related mortality have occurred. Between 80 and 90% of deaths currently occurring from infections and asphyxia can be averted from available interventions, as can 58% of mortality from preterm birth. More than 200 000 neonatal deaths can each be averted from asphyxia, preterm birth and infections. Using available interventions, more than 80% of the neonatal deaths occurring today could be prevented in sub-Saharan Africa. CONCLUSION: Reducing neonatal deaths from asphyxia require improvements in infrastructure and obstetric care to manage maternal conditions such as obstructed labour and preeclampsia. Reducing deaths from preterm birth would also necessitate improved infrastructure and training for preterm infant care. Reducing infection-related mortality requires less infrastructure and lower-level providers.

Tranexamic acid to reduce postpartum hemorrhage: A MANDATE systematic review and analyses of impact on maternal mortality.

OBJECTIVE: Postpartum hemorrhage (PPH) is a major cause of maternal mortality, with almost 300,000 cases and ~72,000 PPH deaths annually in sub-Saharan Africa. Novel prevention methods practical in community settings are required. Tranexamic acid, a drug to reduce bleeding during surgical cases including postpartum bleeding, is potentially suitable for community settings. Thus, we sought to determine the impact of tranexamic acid on PPH-related maternal mortality in sub-Saharan Africa. STUDY DESIGN: We created a mathematical model to determine the impact of interventions on PPH-related maternal mortality. The model was populated with baseline birth rates and mortality estimates based on a review of current interventions for PPH in sub-Saharan Africa. Based on a systematic review of literature on tranexamic acid, we assumed 30% efficacy of tranexamic acid to reduce PPH; the model assessed prophylactic and treatment tranexamic acid use, for deliveries at homes, clinics, and hospitals. RESULTS: With tranexamic acid only in the hospitals, less than 2% of the PPH mortality would be reduced. However, if tranexamic acid were available in the home and clinic settings for PPH prophylaxis and treatment, a nearly 30% reduction (nearly 22,000 deaths per year) in PPH mortality is possible. CONCLUSION: These analyses point to the importance of preventive and treatment interventions compatible with home and clinic use, especially for sub-Saharan Africa, where the majority of births occur at home or community health clinics. Given its feasibility to be given in the home, tranexamic acid has potential to save many lives.

Reducing maternal mortality from preeclampsia and eclampsia in low-resource countries--what should work?

OBJECTIVE: Preeclampsia/eclampsia (PE/E) remains a major cause of maternal death in low-income countries. We evaluated interventions to reduce PE/E-related maternal mortality in sub-Saharan Africa. DESIGN: Mathematical model to assess impact of interventions on PE/E-related maternal morbidity and mortality. SETTING: Sub-Saharan Africa countries. POPULATION: Pregnant women in sub-Saharan Africa in 2012. METHODS: A systematic literature review populated a decision-tree mathematical model with interventions to diagnose, prevent, and treat women with PE/E. The impact of increased use of interventions [diagnostics, transfer to a hospital, magnesium sulfate (MgSO4 ) use, cesarean section/labor induction] on PE/E-related maternal mortality was analyzed. MAIN OUTCOME MEASURES: Prevalence of PE/E and PE/E-associated maternal mortality rates in sub-Saharan Africa. RESULTS: Without interventions, an estimated 20 570 PE/E-associated deaths would have occurred in sub-Saharan Africa in 2012. With current low rates of diagnosis, MgSO4 use, transfers and cesarean section/induction rates, about 17 520 maternal deaths were associated with PE/E in 2012. Higher use of MgSO4 would have prevented about 610 deaths. With high diagnostic levels, MgSO4 use, transfer and cesarean section/induction, mortality was reduced to 3750 annual deaths, saving about 13 770 maternal lives. If all MgSO4 use was removed from the model, 4060 maternal deaths would occur, increasing maternal deaths by only 310. CONCLUSIONS: In sub-Saharan Africa, our model suggests that increasing use of PE/E diagnostics, transfer to higher levels of care and increased hospitalization with cesarean section/induction of labor would substantially reduce maternal mortality from PE/E. Increasing use of MgSO4 would have a smaller impact on maternal mortality.

Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects.

This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0-t, AUC(0-∞), and C(max) for midazolam and 1-hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C(max), AUC(0-t), and AUC(0-∞) parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs.

The MANDATE model for evaluating interventions to reduce postpartum hemorrhage.

OBJECTIVE: To create a comprehensive model of the comparative impact of various interventions on maternal, fetal, and neonatal (MFN) mortality. METHODS: The major conditions and sub-conditions contributing to MFN mortality in low-resource areas were identified, and the prevalence and case fatality rates documented. Available interventions were mapped to these conditions, and intervention coverage and efficacy were identified. Finally, a computer model developed by the Maternal and Neonatal Directed Assessment of Technology (MANDATE) initiative estimated the potential of current and new interventions to reduce mortality. RESULTS: For PPH, the sub-causes, prevalence, and MFN case fatality rates were calculated. Available interventions were mapped to these sub-causes. Most available interventions did not prevent or treat the overall condition of PPH, but rather sub-conditions associated with hemorrhage and thus prevented only a fraction of the associated deaths. CONCLUSION: The majority of current interventions address sub-conditions that cause death, rather than the overall condition; thus, the potential number of lives saved is likely to be overestimated. Additionally, the location at which mother and infant receive care affects intervention effectiveness and, therefore, the potential to save lives. A comprehensive view of MFN conditions is needed to understand the impact of any potential intervention.

WITHDRAWN: Maintaining the momentum of antitubercular drug discovery.

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Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (+/-standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/-0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/-0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.

Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects.

PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 microg/ml for drug-sensitive strains and between 0.03 and 0.53 microg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 microg/ml (1,500-mg dose) in the single-dose study and 3.8 microg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.

Assessment of the effects of the nitroimidazo-oxazine PA-824 on renal function in healthy subjects.

The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.