De impact van CYP2D6-polymorfisme op een behandeling met aripiprazol bij kinderen en jongeren: een systematische review

Impact of CYP2D6 polymorphism on children and adolescents treated with aripiprazole: a systematic review Psychotropic drugs show a significant individual variability in efficacy and adverse events. To explain these differences, there is a promising focus on studies which examine the genetic variants of the cytochrome P450 enzyme 2D6 (CYP2D6). The CYP2D6 gene has a large genetic variability with over 100 known allelic variants encoding this protein. These variants contain predictive value for the function of the CYP2D6 enzyme. Aripiprazole is metabolized by the CYP2D6 enzyme, thereby CYP2D6 allelic variants potentially affect the pharmacokinetics of the drug. This systematic literature review summarizes research on that potential influence of CYP2D6 polymorphism on the treatment outcomes of aripiprazole in minors, in terms of pharmacokinetic changes, efficacy and adverse events. Relevant articles were selected according to PRISMA guidelines (‘preferred reporting items for systematic reviews and meta-analyses’) using Embase and PubMed. After applying the inclusion and exclusion criteria, 10 relevant research articles were retained. The available research shows a possible link between genetic variants of the CYP2D6 enzyme on the one hand, and efficacy and adverse events such as hyperprolactinemia or weight gain on the other hand, in minors treated with aripiprazole. However, the number and quality of studies are low. Recommendations for future studies are made since this systematic review offers insight into the relevance of CYP2D6 genotyping in children and adolescents treated with aripiprazole.

Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases

For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation. Thus, the emergence of further in-depth research into diverse groups of compounds capable of activating this receptor has prompted reconsideration of its use therapeutically. The aim of this review is to summarize the body of research surrounding AhR and its role in regulating inflammation. Specifically, evidence supporting the potential of targeting this receptor to modulate the immune response in inflammatory and autoimmune diseases will be highlighted. Additionally, the opportunities and challenges of developing AhR-based therapies to suppress inflammation will be discussed.

In Silico Taste, Cytochrome and Toxicity Prediction Study of Major Chamomile Constituents

Chamomile is an ancient herb used for various medications. It contains many bioactive constituents such as volatile oils, terpenoids, flavonoids, lactones, acid esters, glycosides and others. By reviewing many references, a confliction appeared of using Chamomile preparations to treat primary teeth eruption symptoms as a therapy administered by pediatric dentist or pediatrician. In this study, thirteen bioactive constituents (α-bisabolol (B), chamazulene (C), umbelliferone (U), apigenin (A), apigetrin (AT), apiin (AI), luteolin (L), quercetin (Q), quercimertrin (QT), rutin (R), α-cadinene (CD), α-farnesene (F), and matricarin (M) were subject to computational predication through various online websites to predicate their taste, activity towards several CYP450 enzymes and their action as Hepatotoxic, carcinogenic, immunotoxic, mutagenic, and cytotoxic compounds. Our calculations revealed several points such as high value of taste predication indicated that Chamomile constituents under study were with sour taste, did not classify as individual fatal compound Class (GHS) 1 or 2, 44.87% of them showed inhibition character toward specific cytochrome P450 enzyme while 43.59% were non- inhibition character, more than (0.5) probability predication of various cytochrome P450 enzymes gave a positive activity that may affect liver functions. Also, hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity predictions were more than (0.5), unsaturated Chamomile constituent (Farnesene, F) had highest immune – and mutagenic properties whilst the disaccharide flavonoid (Rutin, R) had the highest Carcino- immunogenic response. According to the above notes, our conclusion is to use minimum concentration of Chamomile preparation for less period of time and lowest repeating intake that ensure effective treatment of teething symptoms under supervision of pediatricians with minimum side effect.

A case of complete atrioventricular block with extremely high blood concentration of azelnidipine

Background Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported. Case presentation In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment. Conclusions Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Oteseconazole: an advance in treatment of recurrent vulvovaginal candidiasis

Recurrent vulvovaginal candidiasis (RVVC) has significant disease, financial and quality-of-life burdens, affects women from all strata of society worldwide, and lacks an approved therapeutic solution. Fluconazole emerged in 2004 as an antifungal for RVVC; it provides symptom control and has been accepted worldwide as a first-line treatment. Its limitations include the development of resistance and a high rate of vulvovaginal candidiasis recurrence after therapy cessation. There is now an improved treatment option on the horizon: oteseconazole – a novel, oral, selective fungal cytochrome P450 enzyme 51 inhibitor, designed to avoid off-target toxicities. In clinical studies to date, oteseconazole has demonstrated impressive efficacy, a positive tolerability profile and hope for a superior RVVC treatment option.

A Systematic Review on Anti-tubercular Therapy Induced Hepatotoxicity

Tuberculosis is the leading cause of major morbidities and mortalities around the globe. One in every three persons suffers from tubercular infection in their lifetime. Antitubercular therapy-induced hepatitis occurs due to toxicity from the primary compound, metabolite, or an immunologically mediated response. Risk factors associated with hepatotoxicity are age, sex, low BMI, hypoalbuminemia, alcohol consumption, HIV, hepatitis B, and C. There are 6 major pathways by which anti-TB drugs are involved in hepatotoxicity including hampering of intracellular calcium homeostasis, derangement of actin fibril assembly that occurs next to the canaliculus, the drug binds to the heme-containing cytochrome p-450 and forms enzyme-drug adduct and produces an immune response, The enzyme- drug addict when gets incorporated to vesicle acts as antigen for the production antibodies, some drugs also inhibit the ? oxidation and respiration and hence reduction in ATP production hence damaging cell and mitochondrial DNA, and some directly leads to apoptosis. Isoniazid is being metabolized to acetyl-isoniazid followed by hydrolysis to acetyl hydrazine via cytochrome P450 enzyme which produces toxic metabolites responsible for hepatotoxicity. Rifampicin activates the cytochrome enzyme and hence stimulates the production of harmful toxic materials leading to ATT-induced hepatotoxicity. It is the duty of the he pharmacist / medical staff has to provide the patient with adequate education about diseases and to inform them about their therapy regarding possible side effects and side effects. Pharmacists / medical staff must also train patients to comply with medication.

Conversion of viridicatic acid to crustosic acid by cytochrome P450 enzyme-catalysed hydroxylation and spontaneous cyclisation

Cytochrome P450 monooxygenases (P450s) are considered nature’s most versatile catalysts and play a crucial role in regio- and stereoselective oxidation reactions on a broad range of organic molecules. The oxyfunctionalisation of unactivated carbon-hydrogen (C-H) bonds, in particular, represents a key step in the biosynthesis of many natural products as it provides substrates with increased reactivity for tailoring reactions. In this study, we investigated the function of the P450 enzyme TraB in the terrestric acid biosynthetic pathway. We firstly deleted the gene coding for the DNA repair subunit protein Ku70 by using split marker-based deletion plasmids for convenient recycling of the selection marker to improve gene targeting in Penicillium crustosum. Hereby, we reduced ectopic DNA integration and facilitated genetic manipulation in P. crustosum. Afterward, gene deletion in the Δku70 mutant of the native producer P. crustosum and heterologous expression in Aspergillus nidulans with precursor feeding proved the involvement of TraB in the formation of crustosic acid by catalysing the essential hydroxylation reaction of viridicatic acid. Key points •Deletion of Ku70 by using split marker approach for selection marker recycling. •Functional identification of the cytochrome P450 enzyme TraB. •Fulfilling the reaction steps in the terrestric acid biosynthesis.