Harnessing Intranasal Delivery Systems of Sumatriptan for the Treatment of Migraine

Sumatriptan (ST) is a commonly prescribed drug for treating migraine. The efficiency of several routes of ST administration has been investigated. Recently, the intranasal route with different delivery systems has gained interest owing to its fast-acting and effectiveness. The present study is aimed at reviewing the available studies on novel delivery systems for intranasal ST administration. The oral route of ST administration is common but complicated with some problems. Gastroparesis in patients with migraine may reduce the absorption and effectiveness of ST upon oral use. Furthermore, the gastrointestinal (GI) system and hepatic metabolism can alter the pharmacokinetics and clinical effects of ST. The bioavailability of conventional nasal liquids is low due to the deposition of a large fraction of the delivered dose of a drug in the nasal cavity. Several delivery systems have been utilized in a wide range of preclinical and clinical studies to enhance the bioavailability of ST. The beneficial effects of the dry nasal powder of ST (AVP-825) have been proven in clinical studies. Moreover, other delivery systems based on microemulsions, microspheres, and nanoparticles have been introduced, and their higher bioavailability and efficacy were demonstrated in preclinical studies. Based on the extant findings, harnessing novel delivery systems can improve the bioavailability of ST and enhance its effectiveness against migraine attacks. However, further clinical studies are needed to approve the safety and efficacy of employing such systems in humans.

Comparative Pharmacokinetic Studies of Marketed and Microsponges Gel Loaded with Diclofenac Diethylamine in Rabbits

Oral administration of the non-steroidal anti-inflammatory drug, Diclofenac Diethylamine (DDEA) is often associated with gastrointestinal ulcers, bleeding and extensive first-pass hepatic metabolism. As an alternative to oral administration, formulated microsponges-based gel of DDEA was developed for topical administration, to quantify diclofenac diethylamine in plasma of rabbits for this a sensitive Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) method was developed using carbamazepine as Internal standard (IS) and DDEA (pure drug) was provoked on Hypersil RP C18 column (250mm × 4.6mm 5µm) using a mobile phase mixture of potassium dihydrogen buffer pH 2.5 and acetonitrile in the ratio of 30:70 v/v at an isocratic flow rate of 1mL/min. The drug peak area was detection and found at 276nm. The retention time of DDEA was found to be 5.3 min. The calibration curve was linear over the concentration range of 50-750ng/ml of DDEA. This method was accurate for quantitative estimation of the drug from the marketed gel and optimized microsponge gel. The main of investigation is to compare pharmacokinetic profile of diclofenac diethylamine in pharmaceutical dosage forms (marketed gel and microsponges gel) using WinNonlin software version 8.1.

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

Azelaic acid and its esters, the azelates, occur naturally in organisms ranging from plants to humans. We have shown that diethyl azelate (DEA) exhibits a broad range of immunomodulatory activities in vitro and in vivo, and mitigates insulin resistance. To further investigate the therapeutic utility of DEA, we evaluated its mutagenicity in Salmonella typhimurium strains, examined metabolism of DEA in rat, dog, monkey and human primary hepatocytes and in human saliva, determined pharmacokinetics of DEA after an oral dose in rats, and queried its physicochemical properties for drug-like characteristics. DEA was not mutagenic in bacterial strains ± rat liver metabolic activation system S-9. It was chemically unstable in hepatocyte culture medium with a half-life of <1 h and was depleted by the hepatocytes in <5 min, suggesting rapid hepatic metabolism. DEA was also quickly degraded by human saliva in vitro. After an oral administration of DEA to rats, the di- and monoester were undetectable in plasma while the levels of azelaic acid increased over time, reached maximum at <2 h, and declined rapidly thereafter. The observed pharmacological properties of DEA suggest that it has value both as a drug or a nutritional supplement.

Machine learning analysis of volatolomic profiles in breath can identify non-invasive biomarkers of liver disease: A pilot study

Disease-related effects on hepatic metabolism can alter the composition of chemicals in the circulation and subsequently in breath. The presence of disease related alterations in exhaled volatile organic compounds could therefore provide a basis for non-invasive biomarkers of hepatic disease. This study examined the feasibility of using global volatolomic profiles from breath analysis in combination with supervised machine learning to develop signature pattern-based biomarkers for cirrhosis. Breath samples were analyzed using thermal desorption-gas chromatography-field asymmetric ion mobility spectroscopy to generate breathomic profiles. A standardized collection protocol and analysis pipeline was used to collect samples from 35 persons with cirrhosis, 4 with non-cirrhotic portal hypertension, and 11 healthy participants. Molecular features of interest were identified to determine their ability to classify cirrhosis or portal hypertension. A molecular feature score was derived that increased with the stage of cirrhosis and had an AUC of 0.78 for detection. Chromatographic breath profiles were utilized to generate machine learning-based classifiers. Algorithmic models could discriminate presence or stage of cirrhosis with a sensitivity of 88–92% and specificity of 75%. These results demonstrate the feasibility of volatolomic profiling to classify clinical phenotypes using global breath output. These studies will pave the way for the development of non-invasive biomarkers of liver disease based on volatolomic signatures found in breath.

Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier

Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.

The Effect of Rivaroxaban on CYP4F2 and Transcription Factors’ Activity in HUVECs

Interindividual variabilities between patients taking the anticoagulant rivaroxaban are a result of hepatic metabolism by CYP 450 enzymes. The objective of this study was to evaluate the impact of rivaroxaban on CYP4F2 and transcription factors’ activity in HUVECs. Rivaroxaban and its metabolites were detected by UPLC-ESI-MS and UPLC-QTOF-MS. CYP4F2, HNF4α, PXR and CAR expressions were determined in HUVECs by qPCR; CYP4F2 protein concentration was determined by ELISA. Rivaroxaban metabolites (M-1, M-2, M-5, M-8, M-10, M-11 and M-18) were detected in endothelial cells’ culture medium. Increasing concentrations of rivaroxaban determined lower 13-docosenamide concentrations. Rivaroxaban and dexamethasone reduced the expression of CYP4F2 when hsa-miR-24-3p—both CYP4F2 expression and CYP4F2 protein levels in HUVECs. The expression of the transcription factors HNF4α, PXR and CAR was not detected in HUVECs.

Possibilities and limitations of antidepressant use to correct depressive and negative symptoms in schizophrenia

The purpose of this review is to analyze approaches to the treatment of depressive and negative disorders in schizophrenia in terms of their level of efficacy and safety. Materials and Methods: A search was conducted for full-text articles published over the last 10 years in PubMed, Springer, Wiley Online Library, Taylor & Francis Online, APA PsycInfo, CORE, Science Direct, and eLIBRARY.RU databases. Several articles published previously to this period were also included into the review due to their high scientific value. Results: Our review suggests that antidepressants (ADs) are effective medications and they can be prescribed to correct depressive disorders and negative symptoms in patients with schizophrenia when used in combination with antipsychotics (АPs). However, when administering ADs and АPs combinations, it is important to consider the safety profile of these combinations as well as their tolerance. Negative symptoms of schizophrenia, including those induced by a number of АP, are less amenable to correction by АDs monotherapy, which requires a long period of АPs (on average - 8 weeks), which can be limited in the real life of the patient outside the hospital. Current approaches to the therapy of depressive disorders in patients suffering from schizophrenia vary from country to country. However, most of АDs used in clinical psychiatric practice are widely used in the comorbid state under consideration. Conclusion: The efficacy and safety of АDs of the different classes considered in this review depends on their mechanisms of action, duration of admission, type of АPs taken, and specific clinical situation (acute depressive disorder, major depressive episode, or chronic depressive episode). Most promising in clinical practice are serotonin–norepinephrine reuptake inhibitors (SNRIs) and dual ADs. The use of tricyclic antidepressants (TCAs) is limited due to a higher risk of adverse drug reactions (ADRs). The use of most selective serotonin reuptake inhibitors (SSRIs) is limited due to the risk of aggravation of hallucinations (this risk being higher for patients with visual hallucinations, and lower for those with auditory hallucinations) and\or iatrogenic psychosis. These ADRs may probably occur in patients suffering from schizophrenia due to their ideal "poor metabolizer" pharmacogenetic profile, since most of the drugs considered in this review have hepatic metabolism.

Mucosal Fixed Drug Eruption to Levetiracetam with Early Positive Patch Test on Non-Lesional Skin

Levetiracetam (LEV) is a second-generation antiepileptic drug (AED) that is well tolerated, has a broad spectrum of action, low protein binding, and minimal hepatic metabolism. The incidence of hypersensitivity to LEV in children and adults is 0.6%. This is the first reported fixed drug eruption (FDE) identified using a patch test in a pediatric case associated with LEV

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.