Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Greening the pharmacy.

New measures and research are needed to limit the ecological impact of pharmaceuticals.

Spectrophotometric Methods for Determination of Dopamine Hydrochloride in Bulk and in Injectable Forms.

Two highly simple, economical, accurate and sensitive spectrophotometric methods for determination of dopamine hydrochloride (DAH) in either pure form and pharmaceutical formulations are described. The first method is based on determination of (DAH) spectrophotometrically at maximum absorbance 280 nm (method A). The second one is based on reduction of alkaline KMnO4 by (DAH) leading to the formation of green manganate species which are measured at 610 nm (method B). Under optimized conditions, the calibration graphs were linear in the range of 3.793 - 45.513, 0.190 - 4.362 µg.mL-1 of (DAH) for methods A and B respectively. The developed methods were successfully applied for the determination of dopamine hydrochloride in pharmaceutical samples.

Evaluation of Excipient Risk in BCS Class I and III Biowaivers.

The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here. Graphical Abstract.

NCATS Inxight Drugs: a comprehensive and curated portal for translational research.

The United States has a complex regulatory scheme for marketing drugs. Understanding drug regulatory status is a daunting task that requires integrating data from many sources from the United States Food and Drug Administration (FDA), US government publications, and other processes related to drug development. At NCATS, we created Inxight Drugs (https://drugs.ncats.io), a web resource that attempts to address this challenge in a systematic manner. NCATS Inxight Drugs incorporates and unifies a wealth of data, including those supplied by the FDA and from independent public sources. The database offers a substantial amount of manually curated literature data unavailable from other sources. Currently, the database contains 125 036 product ingredients, including 2566 US approved drugs, 6242 marketed drugs, and 9684 investigational drugs. All substances are rigorously defined according to the ISO 11238 standard to comply with existing regulatory standards for unique drug substance identification. A special emphasis was placed on capturing manually curated and referenced data on treatment modalities and semantic relationships between substances. A supplementary resource 'Novel FDA Drug Approvals' features regulatory details of newly approved FDA drugs. The database is regularly updated using NCATS Stitcher data integration tool that automates data aggregation and supports full data access through a RESTful API.

Comparative application of biological and ninhydrin- derivatized spectrophotometric assays in the evaluation and validation of amikacin sulfate injection

Abstract Instrumental techniques are preferred over bioassay methods for antibiotic quantification mainly due to speed and ability to quantify metabolites in biological samples; however, the potency and biological activity of these drugs cannot be assessed. Two methods - agar well diffusion (bio-assay) and spectrophotometric methods were used to evaluate amikacin sulfate injection. Agar plates were inoculated with S. aureus inoculum; zones of inhibition from its susceptibility to amikacin were obtained, while spectrophotometric absorption at 650 nm of ninhydrin- derivatized amikacin in phosphate buffer (pH 8) was measured. Methods performance showed linearity from 1 - 16 µgmL-1 (bioassay, r = 0.9994) and 10-50 µgmL-1 (spectrophotometric, r = 0.9998). Molar absorptivity was 2.595 x 104 Lmol-1cm-1. Limits of detection and quantification were 1.07 and 3.24 µgmL-1 respectively for bioassay method, while corresponding values for spectrophotometric method were 0.98 and 2.97 µg mL-1. Relative standard deviations were ≤ 2.0% for both methods, with recoveries from 95.93 - 100.25%. Amikacin in brands ranged from 97.53 ± 2.68 to 100.84 ± 1.82%, student's t-test was ≤ 2.78 (n = 4) with respect to label claim for both methods. Experimental paired t-test (t = 2.07; n = 4) and F-test (F = 3.94; n = 4) values indicated no significant difference between both methods, hence comparable and can jointly be used in quality control assessment of antibiotics

Pharmaceutical evaluation of compounded furosemide capsules and excipient performance

Abstract Compounding pharmacies play an important role not only in compounding personalized formulations, but also preparing drugs at the same concentration and dosage as those from commercial manufacturers. The excipients used in compounding are generally standardized for many drugs, however they do not consider the intrinsic properties, such as the poor water solubility, of each substance. The excipient performance of commercially available compounded furosemide capsules in 7 compounding pharmacies from Manaus was evaluated and compared them to the performance of the reference medicinal product (Lasix® tablets) and 2 batches of capsules made in-house (T2 and T4) with a standardized excipient. All batches were subjected to tests for weight variation, assay, uniformity of dosage units, disintegration and dissolution profile. Of the 7 different compound formulas acquired in the compounding pharmacies, only 2 passed all tests. Most formulas passed the tests for weight determination, disintegration time and assay, however batches from 2 establishments failed in regards to the uniformity of the content and 5 batches failed the dissolution test. The reference medicinal product was approved in all tests, as were the T2 capsules made in-house with drug-excipient ratio 1:2. These results confirm the importance of the excipient composition, especially for poorly soluble drugs.

Evaluation of copaiba oil as enhancer of ibuprofen skin permeation

Abstract The administration of medications on the skin through transcutaneous routes is a practice that has been used by mankind for millennia. Some studies have been reporting the use of terpenes and natural oils rich in terpenes as an enhancer of cutaneous penetration. Copaiba oil, due to its rich content of terpenes, presents itself as a great choice of penetration enhancer for drugs administered on the skin. In this study, we developed two cream formulations containing 5% of ibuprofen (IBU) and copaiba oil: IBCO5 and IBCO10 with 5% and 10% of copaiba oil respectively. Ex vivo cutaneous penetration/permeation studies of IBU were performed using pig ear skin as biological membrane in the Franz-type diffusion cells. The steady-state flux of IBU samples, IBCO5 (35.72 ± 6.35) and IBCO10 (29.78 ± 2.41) were significantly higher when compared with control without copaiba oil (10.32 ±1.52) and with a commercial product (14.44 ± 2.39). In the penetration analysis, the amount of IBU found in the samples IBCO5 and IBCO10 was markedly higher in the dermis than epidermis. Our results showed that copaiba oil possesses attracting properties in promoting skin penetration and permeation of IBU when added into cream formulations.

Innovation in Pharmaceutical Assistance

Abstract Innovation is the driving force that is able to create and transform products, processes, and organization in the health system. Innovation in the field of pharmaceutical assistance covers a wide spectrum of aspects, from drug discovery to pharmaceutical care, contributing to the improvement in treatments through novel drugs or methods. This work will present the major characteristics of innovation with special emphasis on aspects pertaining to pharmaceutical assistance. The types and models of innovation, as well as the interaction between academia and industry, will be presented with examples of successful products and methods. In addition, the challenges and perspectives for innovation in pharmaceutical assistance will be discussed with a focus on drug discovery.

Validation of the Brazilian version of the hepatitis B quality of life evaluation instrument - HBQOL, and its application to patients with chronic hepatitis B in Cascavel - PR

Abstract The objective of this study is to validate the specific questionnaire for Hepatitis B HBQOL (Hepatitis B Quality of Life Instrument, version 1.0) for the Brazilian version, in addition to testing its applicability in patients with hepatitis B under treatment and comparing the quality of life between patients using first-line drugs (tenofovir and entecavir). For the validation, the back-translation technique was used in a sample of 47 patients. Factor analysis was performed between the items in each domain of the questionnaire and the internal consistency was calculated using Cronbach's α coefficient. In assessing the applicability of the validated questionnaire, interviews were carried out with 124 patients. Sociodemographic and treatment data were collected to characterize the sample and perform correlation analyzes. The results demonstrate that the Brazilian version of the questionnaire was successfully validated. In the analysis carried out among the 124 patients, the domains psychological well-being and stigma obtained the highest scores in quality of life and the lowest level of education conferred better results in these two domains. The comparison between tenofovir and entecavir showed no significant difference in patients' quality of life. The use of this validated instrument can make therapeutic decisions more rational

Medicamentos de elaboración o preparación no industrial: una nueva propuesta de clasificación / Non-industrially elaborated or prepared drugs: a new classification proposal

Introducción: Ni el legislador, ni los diferentes estudios previos han establecido una clasificación exhaustiva de los medicamentos de elaboración o preparación no industrial en el territorio regulatorio español. Métodos: Revisión bibliográfica sobre la normativa (nacional y comunitaria) y estudios doctrinales relativos al marco jurídico de los medicamentos de uso humano, y el análisis de la misma. Resultados: En la literatura no se encuentra una clasificación adecuada de los medicamentos de elaboración o preparación no industrial. Conclusiones: Se ha propuesto una clasificación doctrinal de los medicamentos de elaboración o preparación no industrial basada en cuatro categorías principales. (AU)

Introduction: Neither the legislator nor the different previous studies have established an exhaustive classification of non-industrially elaborated or prepared drugs in the Spanish regulatory territory. Method: Bibliographic review on the regulations (national and community) and doctrinal studies related to the legal framework of medicines for human use, and their analysis. Results: There is no adequate classification of non-industrially elaborated or prepared drugs in the literature. Conclusions: A doctrinal classification of non-industrially elaborated or prepared drugs has been proposed based on four main categories

An Insight on RNA Based Therapeutics and Vaccines: Challenges and Opportunities.

In this era, RNA molecules have provided a unique opportunity to researchers all over the world for expanding their range of targets in the development of drugs. Due to the unique pharmacological as well as physicochemical characteristics of different RNA molecules such as aptamers, small interfering RNAs (siRNA), antisense oligonucleotides (ASO) and guide RNAs (gRNA), they have emerged recently as a new class of drugs. They are used for selective action on proteins and genes that were not possible to target by conventional drug molecules. These RNA molecules like guide RNAs are also components of novel gene editing mechanisms which can modify the genome nearly in all cells. Vaccines based on RNA molecules have also provided a promising alternative to conventional live attenuated vaccines. RNA based vaccines have high potency, can be rapidly developed, and have potential for manufacturing at a cheaper rate and safe administration. However, the application of these RNAs has been restricted by the high instability and inefficient in vivo delivery. Technological advancement needs to overcome these issues so that RNA based drugs targeting several diseases can be developed. This article emphasizes the potential of RNA based drugs and the major barriers associated with the development of RNA therapeutics. Additionally, the role of RNA based vaccines and their challenges in advancing this promising vaccine platform for the prevention of infectious diseases have been discussed.

Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis.

Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders. In particular, this review will highlight the current pharmacogenomics knowledge about biologics and small-molecule treatments for psoriasis. To date, studies performed on genes involved in the metabolism of biological drugs (tumor necrosis factor inhibitors and cytokines inhibitors) and small molecules (apremilast, dimethyl fumarate, and tofacitinib) have provided conflicting results, and further investigations are necessary in order to establish a set of biomarkers to be introduced into clinical practice.

FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish.

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs' administration caused HSPCs diminishment and 118 drugs' treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1-/- mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

Prediction of Pregnancy-Induced Changes in Secretory and Total Renal Clearance of Drugs Transported by Organic Anion Transporters.

Pregnancy can significantly change the pharmacokinetics of drugs, including those renally secreted by organic anion transporters (OATs). Quantifying these changes in pregnant women is logistically and ethically challenging. Hence, predicting the in vivo plasma renal secretory clearance (CLsec) and renal CL (CLrenal) of OAT drugs in pregnancy is important to design correct dosing regimens of OAT drugs. Here, we first quantified the fold-change in renal OAT activity in pregnant versus nonpregnant individual using available selective OAT probe drug CLrenal data (training dataset; OAT1: tenofovir, OAT2: acyclovir, OAT3: oseltamivir carboxylate). The fold-change in OAT1 activity during the 2nd and 3rd trimester was 2.9 and 1.0 compared with nonpregnant individual, respectively. OAT2 activity increased 3.1-fold during the 3rd trimester. OAT3 activity increased 2.2, 1.7 and 1.3-fold during the 1st, 2nd, and 3rd trimester, respectively. Based on these data, we predicted the CLsec, CLrenal and total clearance ((CLtotal) of drugs in pregnancy, which are secreted by multiple OATs (verification dataset; amoxicillin, pravastatin, cefazolin and ketorolac, R-ketorolac, S-ketorolac). Then, the predicted clearances (CLs) were compared with the observed values. The predicted/observed CLsec, CLrenal, and CLtotal of drugs in pregnancy of all verification drugs were within 0.80-1.25 fold except for CLsec of amoxicillin in the 3rd trimester (0.76-fold) and cefazolin in the 2nd trimester (1.27-fold). Overall, we successfully predicted the CLsec, CLrenal, and CLtotal of drugs in pregnancy that are renally secreted by multiple OATs. This approach could be used in the future to adjust dosing regimens of renally secreted OAT drugs which are administered to pregnant women. SIGNIFICANCE STATEMENT: To the authors' knowledge, this is the first report to successfully predict renal secretory clearance and renal clearance of multiple OAT substrate drugs during pregnancy. The data presented here could be used in the future to adjust dosing regimens of renally secreted OAT drugs in pregnancy. In addition, the mechanistic approach used here could be extended to drugs transported by other renal transporters.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic ß-blockers with Clinically Relevant Drugs-An Overview.

Adrenergic ß-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the ß-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those ß-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. ß-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, ß-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of ß-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with ß-blockers to prevent possible adverse drug interactions.

Comparative effectiveness of pharmacological interventions to prevent postoperative delirium: a network meta-analysis.

Many pharmacologic agents were investigated for the effect to prevent delirium. We aimed to comprehensively compare the effect of the pharmacological interventions to prevent postoperative delirium. A Bayesian network meta-analysis of randomized trials was performed using random effects model. PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched on 20 January 2021. Randomized trials comparing the effect of a drug to prevent postoperative delirium with another drug or placebo in adult patients undergoing any kind of surgery were included. Primary outcome was the postoperative incidence of delirium. Eighty-six trials with 26,992 participants were included. Dexmedetomidine, haloperidol, and atypical antipsychotics significantly decreased the incidence of delirium than placebo [dexmedetomidine: odds ratio 0.51, 95% credible interval (CrI) 0.40-0.66, moderate quality of evidence (QOE); haloperidol: odds ratio 0.59, 95% CrI 0.37-0.95, moderate QOE; atypical antipsychotics: odds ratio 0.27, 95% CrI 0.14-0.51, moderate QOE]. Dexmedetomidine and atypical antipsychotics had the highest-ranking probabilities to be the best. However, significant heterogeneity regarding diagnostic time window as well as small study effects precludes firm conclusion.

New Drugs Approved in 2020.

In 2020, the US Food and Drug Administration approved 53 novel drugs. Thirty-six of the 53 (68%) drugs were reviewed and approved through an expedited review pathway, and 31 of the 53 (58%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the US Food and Drug Administration in 2020.