The concept of chirality and its association with drug safety: Traditional review

Literatürde biyolojik sistemlerde yer alan objelerin ayna görüntüleriyle örtüşmeme durumları üzerinden ifade edilen kiralite, ilaçların vücutta ortaya çıkardığı etkiler bakımından önemli bir rol oynamaktadır. 1950’li yıllarda sentetik ilaç üretiminde görülen artışla birlikte izomer karışımı formundaki ilaçların piyasada yaygınlaştığı görülmektedir. İlacın yapısında bulunan her bir izomerin, farmakolojik olarak birbirinden farklı etki ve advers ilaç reaksiyonlarına yol açabildiği bilinmektedir. Bu durum, klinikte ilaç etkililiğini olumsuz yönde değişebilmesi riskinin yanı sıra potansiyel güvenlilik sorunlarına da zemin hazırlayabilir. Örneğin farmakovijilans tarihçesinde önemli bir kilometre taşı olan talidomid trajedisinde de farklı klinik sonuçlar alınmasında molekülün farklı izomerlerinin rol oynadığı literatürde gösterilmiştir. Kiralite kavramı ile ilgili söz konusu gelişmeler ışığında uluslararası sağlık otoriteleri, yeni üretilen ilaçların mumku ̈ n oldu ̈ ğunca saf enantiyomer olarak üretilmesi yönünde pek çok tavsiyede bulunmuştur. Farmasötik teknoloji alanında kaydedilen ilerlemelerin de katkısıyla piyasaya giren yeni ilaçlarda saf izomerlerin payı eskiye kıyasla giderek artmıştır. Ayrıca mevcut olan izomer karışımı formundaki ilaçların saflaştırılarak piyasaya sürülmesi prensibine dayanan “kiral dönüşüm” örnekleri de ilaç pazarında görülmeye başlanmıştır. Hâlihazırda ilaçların saf izomer olarak geliştirilmesi gibi bir zorunluluk bulunmamakla birlikte, izomer karışımlar ile ilgili guvenl ̈ ilik endişelerinin gelecekte yeni yaklaşımlara kapı aralamasının mumku ̈ n olab ̈ ileceği düşünülmektedir. Bu derlemede; kiralite kavramı ve söz konusu kavramın ilaçlardaki güvenlilik sorunları ile olası ilişkisi ele alınmıştır.Chirality, which is expressed in terms of non-overlapping of mirror images of objects in biological systems, plays an important role for drugs to exert their effects on the body. With the increase in the manufacture of synthetic drugs in the 1950s, drugs in the form of isomeric mixtures became widespread in the market. Each isomer in the structure of the drug can cause pharmacologically different effects and adverse drug reactions. This situation may adversely affect the clinical efficacy of the drug, as well as lay the groundwork for safety problems. For example, in the thalidomide tragedy, which is an important milestone in the history of pharmacovigilance, different isomers of the molecule have been shown to play a role in obtaining different clinical outcomes. In the light of these developments in chirality concept, health authorities have recommended that new drugs be produced as pure enantiomers as much as possible. With the contribution of the advances in pharmaceutical technology, the share of pure isomers in new drugs entering the market has gradually increased. In addition, examples of “chiral switch” based on the purification of existing isomeric mixture drugs have begun to be introduced. Although there is currently no obligation to develop drugs as pure isomers, it is possible that safety concerns regarding isomeric mixtures will leads to new approaches in the future. In this review, the concept of chirality is discussed from the perspective of its possible relationship with the safety problems in drugs

Investigation of antioxidant and anticonvulsant activity of Hypericum triquetrifolium Turra

Epilepsy is a state characterized by sudden, recurrent epileptic seizures that are not initiated by an identifiable event. There are various studies has been shown that Hypericum species may be used for their anticonvulsant potentials. Besides, the relationship between anticonvulsant activity and antioxidant effect has already been shown in the literature. In the current study, H. triquetrifolium was investigated for the first time for its potential antioxidant and anticonvulsant potential using in vitro and in vivo test models. H. triquetrifolium extracts were tested with DPPH assay, FRAP assay, copper (II) ion reducing antioxidant capacity assay, and acetylcholinesterase inhibitory activity assay to understand their antioxidant potential. Especially, methanolic extract of H. triquetrifolium was shown the highest antioxidant activity. Moreover, a pentylenetetrazole (PTZ, 80 mg/kg, i.p.)-induced seizure model was conducted to analyze the anticonvulsant activities of H. triquetrifolium extracts in mice. In addition, this study revealed that H. triquetrifolium decreased the ratio of severe seizures and increased the mean onsite of mortality and survival rate in a dose-dependent manner. It is thought that the anticonvulsant effect may be either related to the antioxidant potential of H. triquetrifolium or its interference in the GABAergic system

Utilization trend of gastric acid-suppressing agents in relation to analgesics

Background: Controversies exist about excessive use of gastric acid-suppressing agents or lack of adequate indications, especially when co-prescribed with analgesics for gastroprotection. We aimed to analyze the nationwide trend of gastric acid-suppressing agents and analgesics. Methods: We obtained nationwide consumption data of analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, others) and gastric acid-suppressing agents (proton pump inhibitors [PPI] and histamine-2 receptor antagonists [H2RAs]) between years of 2014–2018 from IQVIA Turkey. Drug utilization was measured by defined daily dose (DDD)/1000 inhabitants/day (DID) unit. Drug sales data were further used to test the correlation of PPIs and H2RAs to analgesics. Results: During the study period, analgesic utilization increased from 65.7 to 67.4 DID. NSAIDs constituted 82.7%–84.9% of all analgesic utilization. The consumption of NSAIDs increased by 3.1%, and the most commonly consumed analgesic was diclofenac (18.5 ± 1.5 DID), constituting 25.4%–29.0% of all analgesics. PPI utilization was found to regularly raise from 52.1 DID in 2014 to 72.0 DID in 2018 with an overall increment of 38.2%. Use of H2RAs was found to increase from 11.4 DID in 2014 to 14.0 DID in 2018. The physician visit-adjusted utilization of both antirheumatic NSAIDs and non-antirheumatic analgesics showed significantly moderate-strong positive correlations with PPIs (r: 0.63, 0.48–0.76 and r: 0.63, 0.47–0.75, respectively) and H2RAs (r: 0.61, 0.44–0.73 and r: 0.57, 0.41–0.71, respectively). Conclusion: The utilization trend exhibited a dramatic increase of the gastric acid-suppressing agents -more pronounced for PPIs, with a modest increase in analgesics. Excessive utilization of PPIs does not seem to imply a tendency toward only NSAID-related gastroprotection

The impact of chiral switch on drug labeling in Turkey: Indication, posology, and adverse effects

Objective: Chiral switch, which involves replacing racemic drugs to market them as pure enantiomers, is presumed to improve efficacy and safety. Data on how chiral switch-related changes are represented in summary of product characteristics (SmPC) is scarce. We aimed to compare the indication, posology, and safety expressions in SmPCs of racemates and their pure enantiomers. Materials and Methods: We examined SmPCs of nine drug pairs (racemate/pure enantiomer) that underwent chiral switching among top 100 utilized active substances throughout Turkey. We evaluated the expressions in “indications”, “posology”, and “adverse effects” (AE) subheadings. Daily doses were examined based on “Defined Daily Dose” (DDD) metric. Results: We detected indication differences in four drug pairs, including absence of “peptic ulcer” in dexlansoprazole and “prevention of depression relapses” in escitalopram. DDDs of pure enantiomers decreased in most of the pairs. Recommended daily doses of esomeprazole and dexibuprofen per DDD were lower than their racemates. Cautions about use in renal and/or hepatic insufficiency varied in three pairs. AE expressions differed in seven drug pairs, mainly citalopram/escitalopram. Conclusion: This study demonstrated few indication differences in SmPCs of the drug pairs frequently used in Turkey and underwent chiral switching. However, dose reductions and distinctions in safety expressions were remarkable

HPTLC quantification, assessment of antioxidant potential and in vivo hypoglycemic activity of Scorzonera latifolia (Fisch. & Mey.) DC and its major compounds

Scorzonera L. (Asteraceae) species have long been the topic of many phytochemical, analytical, and biological studies since various species of the Scorzonera genus have been widely used as food and medicinal purposes. Apart from its traditional use to relieve pain, promote wound healing, treat helminth infections or women infertility, Scorzonera latifolia (Fisch. & Mey.) DC is also used for its antidiabetic activity. We aimed to investigate antidiabetic activity of the aerial parts of the title plant and its major secondary metabolites (hyperoside, isoquercitrin, 7-O-methylisoorientin, isoorientin, swertisin, chlorogenic acid, 4,5-O-dicaffeoylquinic acid and hydrangenol-8-O-β-glucoside) isolated from aerial parts in alloxan-induced diabetic mice. Blood glucose levels were measured four times: before the treatment, after 1st, 2nd, and 4th hours of sample treatments (100 mg/kg i.p.). S. latifolia extract displayed notable decline after 4 hours of administration. Among the metabolites; swertisin, 7-O-methyl-isoorientin, and hydrangenol-8-O-β-glucoside were associated with significant reduction on blood glucose level of alloxan-induced diabetic mice. Due to the strong relationship between oxidative stress and diabetes, antioxidant activity of S. latifolia was additionally tested. Furthermore, 4,5-O-dicaffeoylquinic acid, chlorogenic acid, hyperoside, and swertisin contents as major components of the extract were quantified by HPTLC-densitometry, as their biological effects can be attributed to their phenolic contents