A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

Neuroacting drugs and its pharmacological response in relation to different stress status: A review

This article intended to review many methods and types of stressors in the previous works of literaturethat describe the role of these stressors to induce modifications and alterations in the pharmacological response of the drugs acting on the nervous system (neuroacting drugs) in human and animal models. The current review focus on the different methods for inducing stress status which categorized as chemical, physical and miscellaneous stressors that affect on the well-known pharmacological response of the neuroacting drugs and by which mechanism can the stressor induce a modification in the drug target response with mentioning the findings related to changes in the pharmcologiacal response of the neuroacting drugs in previous literature. In conclusion, most studies suggest an alteration of the pharmacological response of neuroacting drugs, commonly by potentiating their efficacy and subsequent toxicity, due to different stressful methods, which may be obligated to the direct and indirect receptor modification (pharmacodynamic interaction) in addition to the direct pharmacokinetic influence on the essential parameters of absorption, distribution, metabolism, and excretion of the neuroacting drugs.

Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose–response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods and results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1–3 clinical studies. Dose–response models were developed for bempedoic acid monotherapy and bempedoic acid–statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose–response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

Assessment of Prevalence, Drug Utilization Pattern and Potential Drug-Drug Interactions Among Hepatic Impairment Patients

The majority of drugs are metabolised in liver and are known to be hepatotoxic. So, the Drug Utilization Evaluation (DUE) studies become potential tool in hepatic impairment patient to ensure drugs are used appropriately, safely and effectively in order to improve overall health of patient. Drug-Drug Interactions are major cause of concern among hepatic impairment patients due to co-morbidity conditions and wide class of drugs they receive. The clinical result of DDI may manifest as synergism, antagonism or idiosyncratic. This study is aimed to generate data on drug utilization pattern and to assess the prevalence of potential drug-drug interactions (pDDIs) among hospitalised hepatic impairment patients. A prospective observational study was carried out for six months among inpatients of the medicine department of Chigateri District Hospital, Karnataka, India. Potential drug-drug interactions (pDDIs) were analysed using Lexicomp, Medscape drug interaction checker, Stockley’s drug interaction checker. Overall 135 patients were enrolled the study. In this study, 80.68% patients were male. The most common affected age group was 40-59 years. Alcoholic liver disease (46.66%) and chronic liver disease (27.40%) were the most prevalent hepatic condition. Anemia and portal hypertension were the most likely associated comorbidities. Out of 1097 drugs, 569 drugs were used specifically for hepatic impairment. Diuretics (23.02%) were the most frequently prescribed drugs followed by gallstone dissolution agents (18.27%). Total of 264 pDDIs, were identified, of which 76(28.78%) were minor, 180(68.18%) were moderate and 8(3.03%) were major. Potential DDIs were significantly higher in patients taking ?9 medicines (63.63%), hospitalization ?7 days (67.64%) and with one co-morbidity conditions (43.18%). Pharmacodynamic interaction 197 (74.62%) was observed more than that of pharmacokinetic interactions 67(25.37%). The prevalence of alcoholic liver disease in this study was reported th

Current perspectives in herbal and conventional drug interactions based on clinical manifestations

Background Herbs are an important source of pharmaceuticals. Herbs are traditionally used by millions of peoples for medicine, food and drink in developed and developing nations considering that they are safe. But, interaction of herbs with other medicines may cause serious adverse effects or reduces their efficacy. The demand for “alternative” medicines has been increased significantly, which include medicine derived from plant or herbal origin. The objective of this review article mainly focuses on drug interactions of commonly used herbs along with possible mechanisms. The method adopted for this review is searching of herb-drug interactions in online database. Main text Herb-drug interaction leads to pharmacological modification. The drug use along with herbs may show pharmacodynamic and pharmacokinetic interactions. Pharmacokinetic interaction causes alteration in absorption, distribution, metabolism and elimination. Similarly, pharmacodynamic interaction causes additive or synergistic or antagonist effect on the drugs or vice versa. Researchers had demonstrated that herbs show the toxicities and drug interactions like other pharmacologically active compounds. There is lack of knowledge amongst physician, pharmacist and consumers related to pharmacological action and mechanism of herb-drug interaction. This review article focuses on the herb-drug interaction of danshen (Salvia miltiorrhiza), Echinacea (Echinacea purpurea), garlic (Allium sativum), ginkgo (Ginkgo biloba), goldenseal (Hydrastis canadensis), green tea (Camellia sinensis), kava (Piper methysticum), liquorice (Glycyrrhiza glabra), milk thistle (Silybum marianum) and St. John’s wort (Hypericum perforatum) along with probable mechanisms and clinical manifestation based on case studies reported in literature. Conclusion Herb-drug interactions may lead to serious side effects. Physician, pharmacist and patients must be more cautious while prescribing and or consuming these herbs.

Synergistic Interaction between 5-FU and an Analog of Sulforaphane—2-Oxohexyl Isothiocyanate—In an In Vitro Colon Cancer Model

Combination therapy is based on the beneficial effects of pharmacodynamic interaction (synergistic or additive) between combined drugs or substances. A considerable group of candidates for combined treatments are natural compounds (e.g., isothiocyanates) and their analogs, which are tested in combination with anticancer drugs. We tested the anticancer effect of the combined treatment of isothiocyanate 2-oxohexyl isothiocyanate and 5-fluorouracil in colon and prostate cancer cell lines. The type of interaction was described using the Chou-Talalay method. The cytostatic and cytotoxic activities of the most promising combined treatments were investigated. In conclusion, we showed that combined treatment with 5-fluorouracil and 2-oxohexyl isothiocyanate acted synergistically in colon cancer. This activity is dependent on the cytostatic properties of the tested compounds and leads to the intensification of their individual cytotoxic activity. The apoptotic process is considered to be the main mechanism of cytotoxicity in this combined treatment.

PHARMACODYNAMIC INTERACTION OF TINOSPORA CORDIFOLIA WITH ATENOLOL AND PROPRANOLOL IN ISOPROTERENOL INDUCED CARDIAC NECROSIS IN RATS

Objective: The present study was carried out to evaluate the combined cardioprotective effect of standardized extract of Tinospora cordifolia extract (TCE) with atenolol (AT) and propranolol (PP) in isoproterenol (ISO) induced cardiac necrosis in rats. Methods: Myocardial infarction (MI) or cardiac necrosis was induced by subcutaneous administration of ISO for two days consecutively at an interval of 24 h. Rats were pre-administered with test drugs for 21 d followed by ISO was administration on 20 and 21st day. 24 h after final ISO administration, mean arterial blood pressure (MAB), Heart rate (HR), electrocardiogram (ECG), heart bio-marker enzyme, and histopathological study of cardiac tissue were evaluated from control and experimental groups and analyzed statistically by one-way ANOVA followed by Tukeys’s test. Results: Rats administered with ISO showed significant (p<0.001) changes in ECG, HR, MAB, heart bio-marker enzyme, antioxidant parameters, and histopathology of the heart. The activities of biomarkers have reduced in serum and there is a significant (p<0.001) increase in antioxidants in the heart tissue of animals treated with drug combination. Similarly, ECG, MAB, and HR were restored to normalcy in drug-treated animals. Conclusion: It may be concluded that the herb-drug combinations i. e TCE (500 mg/kg)+AT (10 mg/kg) and TCE (500 mg/kg)+PP (10 mg/kg) has shown increased cardioprotective activity than they were used alone.

Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response

OBJECTIVES Neonatal seizures are common complications. Phenobarbital is the agent of choice but leads to adverse neurologic outcomes. There has been increased use of newer agents like levetiracetam. The objective of this study was determining the rate of seizure resolution in neonates treated with phenobarbital or levetiracetam. METHODS This was a retrospective, single-center, cohort study from June 1, 2012–June 1, 2018 evaluating seizure resolution in neonates following first-line treatment with phenobarbital versus levetiracetam. Data were collected via review of the patient's charts in the electronic medical record. The primary outcome was seizure resolution without addition of a second antiepileptic agent. Logistic regression was used to assess the impact of pertinent variables. RESULTS Each group included 73 patients. The mean gestational age was 36.01 and 37.91 weeks for the phenobarbital and levetiracetam groups, respectively (p = 0.011). The phenobarbital group had higher rates of intraventricular hemorrhage at baseline. The median birth weight was 2750 and 3002 grams in the phenobarbital and levetiracetam groups, respectively (p = 0.10). Forty-five neonates (61.6%) achieved seizure resolution with phenobarbital compared with 30 neonates (41.1%) with levetiracetam (p = 0.01). In neonates who did not receive a benzodiazepine, seizure resolution was similar between groups (51–52%). In neonates who received a benzodiazepine, seizure resolution rate was 94.1% (16/17 neonates) for phenobarbital and 18.2% (4/22 neonates) for levetiracetam. CONCLUSIONS These findings suggest seizure resolution with levetiracetam, and phenobarbital may be impacted by benzodiazepine administration. If no benzodiazepine is used, these agents demonstrated similar efficacy. Further research into the pharmacodynamic interaction with benzodiazepines is necessary.

POTENSI INTERAKSI OBAT AMLODIPIN PADA PASIEN HIPERTENSI DISALAH SATU PUSKESMAS KABUPATEN SUMEDANG

Hypertension is still a main health problem in indonesia, the purpose of this research is to know the profile of the antihypertensive agent and the interaction potency of the drugs and the relation between the amount of the drugs towards the interaction occurrence in public health centre of sukasari in district of sumedang by the period of July-December 2019. This was observational research with descriptive method. The data collection was performed using drug interaction checker software. There are data of 112 patients. The analysis was performed quantitatively and qualitatively. the result shows the interaction occurrence are happened to woman with percentage of 90% in age group of 65-74 years (30%). Hypertension stage 2 is the most occurred (69%), also there are 82 (73%) patients with potentially might have interaction, meanwhile from all medicines, there are 116 occurrence of interatction might happen. The most interaction occurred happen to amlodipin and hycrochlorothiazide (41%), with pharmacodynamic interaction of 62% and minor severity of 62%.