Factors Affecting the Binding of Diltiazem to Rainbow Trout Plasma: Implications for the Risk Assessment of Pharmaceuticals in Aquatic Systems.

The accumulation of organic toxicants in fish plasma, and how they partition between the bound and unbound fraction once absorbed, are important metrics in models that seek to predict the risk of such contaminants in aquatic settings. Rapid equilibrium dialysis of diltiazem, an ionizable weak base and important human pharmaceutical contaminant of freshwaters, was conducted with rainbow trout (Oncorhynchus mykiss) plasma. The effect of fed state, fish sex, fish strain/size, and dialysis buffer pH on the binding of radiolabeled diltiazem (9 ng ml-1 ) was assessed. In fed fish, 24.6%-29.5% of diltiazem was free, unbound to plasma proteins. Although starvation of fish resulted in a decrease in plasma protein, the bound fraction of diltiazem remained relatively constant. Consequently, the protein-bound concentration of diltiazem increased with length of starvation. In general, rainbow trout strain was a significant factor affecting plasma binding, although the two strains tested also differed markedly in size. Dialysis buffer pH significantly influenced plasma binding, with a higher unbound diltiazem fraction at pH 6.8 than pH 8.0. These data indicate that empirical measures of plasma binding in fish are important for accurate risk assessment and that the physiological status of a fish is likely to impact its sensitivity to toxicants such as diltiazem. Environ Toxicol Chem 2022;41:3125-3133. © 2022 SETAC.

Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins.

WHAT IS KNOWN AND OBJECTIVES: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin). METHODS: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay. RESULTS: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/- 79.59 ng/ml vs. control 104.09 +/- 44.56 ng/ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/- 157.53 ng/ml vs control 207.6 +/- 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/- 95.93 ng/ml vs control 112.32 +/- 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co-administered apixaban and diltiazem were statistically significant compared with the aggregated non-CYP3A4 control groups (no statin and rosuvastatin). WHAT IS NEW AND CONCLUSION: Herein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P-gp and CYP3A4 inhibitors (amiodarone or diltiazem) co-administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events in high-risk patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non-3A4 statin.

[Assessment of Efficiency of Medicamentous Therapy in Correction of Structurally Functional Changes of The Cardiac Muscle at Patients With Arterial Hypertension in Combination With Bronchial Asthma].

BACKGROUND: Bronchial asthma (BA) is a serious problem. It was found that the frequency of arterial hypertension (AH) detection in patients with asthma is about 30 %. At patients practically all types of violations of a warm rhythm meet a bronkhoobstruktivny syndrome. Emergence of rather new preparations - If-blockers, opens new opportunities in correction of heart rate (HR) and a cardioprotection at a combination of AH and BA. AIM: To assess therapy diltiazem-retard and ivabradine on structurally functional changes of a cardiac muscle and HR at patients with AH in combination with BA. MATERIAL AND METHODS: Patients (n=91) with BA with AH 1, 2. All patients were outpatients and taken therapy on BA with inhaled corticosteroids. The patients used a 2-agonists. All patients were performed the echocardioscopy on Acuson 128XP/ 10c (USA). Holter monitor ECG (HM-EKG) was found myocardium ischemia - 18 patients, research was continued by 73 persons. The patients were divided into 2 groups. In the first group made n=37, age 53+/-7,64, received diltiazem-retard. The second group included n=36, age 51,2+/-7,13 years - ivabradine. Duration of observation is 12 weeks. RESULTS AND CONCLUSION: Therapy ivabradine and diltiazem at patients BA according to HM-EKG reliable decrease in frequency of registration of ventricular extrasistoliya in days and heart rate (HR) (<0,05), the quantity of supraventricular extrasistoliya per day doubtfully decreased. Diltiazem wasn't more effective concerning decrease in HR, ventricular and supraventricular extrasistoliya, when comparing with ivabradine (>0,05). The result of 12 week therapy ivabradine at patients with a combination of AH and BA more significant was observed in comparison with diltiazem, regression a hypertrophy of the left ventricle, improvement of diastolic function and almost full regression of warm ektopiya. The tendency was to decrease and stabilization arterial pressure and decrease in HR to purpose level.