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Small interfering RNA (siRNA) therapeutics represent an emerging class of pharmacotherapy with the potential to address previously hard-to-treat diseases. Currently approved siRNA therapeutics include lipid nanoparticle-encapsulated siRNA and tri-N-acetylated galactosamine-conjugated siRNA. These siRNA therapeutics exhibit distinct pharmacokinetic characteristics and unique absorption, distribution, metabolism, and elimination (ADME) properties. As a new drug modality, limited clinical data are available for siRNA therapeutics in specific populations, including pediatrics, geriatrics, individuals with renal or hepatic impairment, and pregnant women, making dosing challenging. In this Minireview, a mechanistic overview of the ADME properties of the 5 currently approved siRNA therapeutics is presented. A concise overview of the clinical data available for therapeutic siRNAs in special populations, focusing on the potential impact of physiologic changes during pregnancy on siRNA disposition, is provided. The utility of physiologically based pharmacokinetic (PBPK) modeling as a tool to elucidate the characteristics and disposition of siRNA therapeutics in pregnant women is explored. Additionally, opportunities to integrate known physiologic alterations induced by pregnancy into PBPK models that incorporate siRNA ADME mechanisms to predict the effects of pregnancy on siRNA disposition are discussed. Clinical data regarding the use of therapeutic siRNA in special populations remain limited. Data for precise parameterization of maternal-fetal siRNA PBPK models are lacking presently and underscore the need for further research in this area. Addressing this gap in knowledge will not only enhance our understanding of siRNA pharmacokinetics during pregnancy but also advance the possible development of siRNA therapeutics to treat pregnancy-related conditions. SIGNIFICANCE STATEMENT: This Minireview proposes a framework on how small interfering RNA (siRNA) disposition can be predicted in pregnancy based on mechanistic absorption, distribution, metabolism, and elimination (ADME) information using physiologically-based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently Food and Drug Administration-approved siRNA therapeutics are summarized. Additionally, how physiological changes during pregnancy may affect siRNA disposition is reviewed, and the opportunities to use PBPK modeling to predict siRNA disposition in pregnant women is explored., Competing Interests: Conflict of interest Sara Shum is an employee of ReNAgade Therapeutics Management Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are a class of environmental toxicants, and some, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), have been associated with hepatic steatosis in rodents and monkeys. It was hypothesized that perfluorosulfonic acids (C4, 6, 8), perfluorocarboxylic acids (C4-14), perfluoro(2-methyl-3-oxahexanoic) acid (HFPO-DA), 1H, 1H, 2H, 2H-perfluorooctanesulfonic acid (6:2 FTS) along with 3 PFOS precursors could induce expression of lipid metabolism genes and lipid deposition in human hepatocytes. Five-donor pooled cryopreserved human hepatocytes were cultured and treated with 0.1% DMSO vehicle or various PFAS (0.25 to 25 μM) in media. After a 48-h treatment, mRNA transcripts related to lipid transport, metabolism, and synthesis were measured using a Quantigene Plex assay. After 72-h treatments, hepatocytes were stained with Nile Red dye to quantify intracellular lipids. Overall, PFAS were transcriptionally active at 25 μM. In this model, lipid accumulation was not observed with C8-C12 treatments. Shorter chain PFAS (C4-C5), 6:2 FTS, and PFOS precursor, metFOSA, induced significant liver lipid accumulation, and gene activation at lower concentrations than legacy PFAS. In summary short chain PFAS and other alternative PFAS were more potent gene inducers, and potential health effects of replacement PFAS should be critically evaluated in humans., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Successful interventions for substance use disorders (SUDs), though obtainable, are not effectively utilized due to the high cost of treatment. The adoption of any given therapy is often impeded by insufficient evidence of the effectiveness of such treatment., Objective: This study aimed to assess the direct medical cost of treating SUD in two tertiary hospitals in South-West, Nigeria., Methods: A descriptive, cross-sectional survey of patients managed for SUD at the two psychiatric hospitals was carried out between January and June 2020. The inclusion criteria were patients with SUD above 18 years of age, registered and managed at the two hospitals. Data were collected from selected patients' case notes using a standardized data collection tool and analyzed using descriptive and inferential statistics., Results: The average costs of treatment for alcohol use disorder, drug use disorder, and drug and alcohol use disorder were ₦146,425.38 ± 57,388.84, ₦135,282.09 ± 53,190.39, and ₦143,877.33 ± 68,662.04, respectively. This translates to $384.82, $355.53, and $378.12, respectively. The highest contributors to SUD treatment cost are inpatient admissions and the cost of medicines; inpatient admissions include accommodation, feeding, and laundry., Conclusion: Considering that over 60% of the Nigerian population lives below the poverty line, the direct cost of SUD treatment is unaffordable to the patients and the health care system, which is grossly underfunded., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Margaret Ilomuanya et al.)

Background and Objective: The use of herbal medicines is common in Africa, and patients often use a combination of herbs and drugs. Concurrent herbal and pharmaceuticals treatments can cause adverse effects through herb-drug interactions (HDI). This study evaluated the potential risk of HDI for five medicinal plants, Vernonia amygdalina, Ocimum gratissimum, Moringa oleifera, Azadirachta indica, and Picralima nitida, using in vitro assays. Patients with diabetes and some other disease conditions commonly use these medicinal plants in Nigeria, and little is known regarding their potential for drug interaction, despite their enormous use., Methods: Crude extracts of the medicinal plants were evaluated for reversible and time-dependent inhibition (TDI) activity of six cytochrome P450 (CYP) enzymes using pooled human liver microsomes and cocktail probe-based assays. Enzyme activity was determined by quantifying marker metabolites' formation using liquid chromatography-mass spectrometry/mass spectrometry. The drug interaction potential was predicted for each herbal extract using the in vitro half-maximal inhibitory concentration (IC 50 ) values and the percentage yield., Results: O. gratissimum methanol extracts reversibly inhibited CYP 1A2, 2C8, 2C9 and 2C19 enzymes (IC 50 : 6.21 µg/ml, 2.96 µg/ml, 3.33 µg/ml and 1.37 µg/ml, respectively). Additionally, V. amygdalina methanol extract inhibited CYP2C8 activity (IC 50 : 5.71 µg/ml); P. nitida methanol and aqueous extracts inhibited CYP2D6 activity (IC 50 : 1.99 µg/ml and 2.36 µg/ml, respectively) while A. indica methanol extract inhibited CYP 3A4/5, 2C8 and 2C9 activity (IC 50 : 7.31 µg/ml, 9.97 µg/ml and 9.20 µg/ml, respectively). The extracts showed a potential for TDI of the enzymes when incubated at 200 µg/ml; V. amygdalina and A. indica methanol extracts exhibited TDI potential for all the major CYPs., Conclusions: The medicinal plants inhibited CYP activity in vitro, with the potential to cause in vivo HDI. Clinical risk assessment and proactive monitoring are recommended for patients who use these medicinal plants concurrently with drugs that are cleared through CYP metabolism.

Background: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines., Objective: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions., Method: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance., Result: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC 50 : 3.8 and 5.4 μg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 μg/mL, respectively)., Conclusion: Our studies suggested that the medicinal plants' extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)