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Real-world studies of pyruvate kinase (PK) deficiency and estimates of mortality are lacking. This retrospective observational study aimed to identify patients with PK deficiency and compare their overall survival (OS) to that of a matched cohort without PK deficiency. Patients with ≥1 diagnosis code related to PK deficiency were selected from the US Veterans Health Administration (VHA) database (01/1995–07/2019); patients with a physician-documented diagnosis were included (PK deficiency cohort; index: date of first diagnosis code related to PK deficiency). Patients in the PK deficiency cohort were matched 1:5 to patients from the general VHA population (non-PK deficiency cohort; index: random visit date during match's index year). OS from index was compared between the two cohorts. Eighteen patients in the PK deficiency cohort were matched to 90 individuals in the non-PK deficiency cohort (both cohorts: mean age 57 years, 94% males; median follow-up 6.0 and 8.0 years, respectively). At follow-up, patients in the non-PK deficiency cohort had significantly longer OS than the PK deficiency cohort (median OS: 17.1 vs. 10.9 years; hazard ratio: 2.3; p = 0.0306). During their first-year post-index, 75% and 40% of the PK deficiency cohort had laboratory-confirmed anemia and iron overload, respectively. Among patients who died, cause of death was highly heterogeneous. These results highlight the increased risk of mortality and substantial clinical burden among patients with PK deficiency. While the intrinsic characteristics of the VHA database may limit the generalizability of the results, this is the first real-world study to characterize mortality in patients with PK deficiency. [ABSTRACT FROM AUTHOR]

Summary: Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow‐up) was common (52.5%), even in never‐transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients. [ABSTRACT FROM AUTHOR]

The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n = 20) or AQ-AS (n = 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (C(max)) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of 113 ng.h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean C(max) of 473 ng/ml and an AUC(0-infinity) of 1,404 ng.h/ml. AR-DHA exhibited a C(max) of 34/119 ng/ml and an AUC(0-infinity) of 168/382 ng.h/ml, respectively. For LR, C(max) and AUC(0-infinity) were 6,757 ng/ml and 210 microg.h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the C(max)s were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC(0-infinity)s were 39.3 ng.h/ml and 148 microg.h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.

Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h(-1), 29.6 liters, and 0.25 h(-1) (once daily) and 2.7 h(-1), 32.1 liters, and 0.15 h(-1) (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).

Introduction: The treatment of tuberculosis (TB) is a mature discipline, with more than 60 years of clinical experience accrued across the globe. The requisite Multi-drug treatment of drug-susceptible TB, however, lasts 6 months and has never been optimized according to current standards. Multi-drug resistant TB and TB in individuals coinfected with HIV present additional treatment challenges., Objective: This article reviews the role that existing drugs and new compounds could have in shortening or improving treatment for TB. The key to treatment shortening seems to be sterilizing activity, or the ability of drugs to kill mycobacteria that persist after the initial days of multi-drug treatment., Results: Among existing anti-TB drugs, the rifamycins hold the greatest potential for shortening treatment and improving outcomes, in both HIV-infected and HIV-uninfected populations, without dramatic increases in toxicity. Clinical studies underway or being planned, are supported by in vitro , animal and human evidence of increased sterilizing activity--without significant increases in toxicity--at elevated daily doses. Fluoroquinolones also seem to have significant sterilizing activity. At present, at least two class members are being evaluated for treatment shortening with different combinations of first-line drugs. However, in light of apparent rapid selection for fluoroquinolone-resistant mutants, relative frequency of serious adverse events and a perceived need to 'reserve' fluoroquinolones for the treatment of drug-resistant TB, their exact role in TB treatment remains to be determined. Other possible improvements may come from inhaled delivery or split dosing (linezolid) of anti-TB drugs for which toxicity (ethionamide) or lack of absorption (aminoglycosides and polypeptides) precludes delivery of maximally effective, oral doses, once daily. New classes of drugs with novel mechanisms of action, nitroimidazopyrans and a diarylquinoline, among others, may soon provide opportunities for improving treatment of drug-resistant TB or shortening treatment of drug-susceptible TB., Conclusion: More potential options for improved TB treatment currently exist than at any other time in the last 30 years. The challenge in TB pharmacotherapy is to devise well-tolerated, efficacious, short-duration regimens that can be used successfully against drug-resistant and drug-resistant TB in a heterogeneous population of patients.