Complimentary Mechanisms Of Action Research Articles

Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug-drug interaction study.

Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile. A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%. The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported. A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.

SY4-1 Combination immunotherapy using anti-PD-1/PD-L1 plus anti-CTLA-4 antibodies

The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, two immune checkpoint inhibitors with distinct but complimentary mechanisms of action has shown clinical efficacy across different solid tumors. This concept also has been investigated in a number of randomized trials in patients with advanced NSCLC. In the Mystic trial patients with a PD-L1 expression =/> 25% were randomized to Durvalumab, Durvalumab plus Tremelimumab or platinum based chemotherapy. While clinical efficacy was observed for Durvalumab and the immunotherapy combination no significant improvement for one of the three primary endpoints was reported. In a retrospective analysis a correlation between blood based TMB and efficacy was shown favoring those patients with a high bTMB level. The BR.34 trial compared the combination of Durvalumab/Tremelimumab and chemotherapy with the immunotherapy combination in untreated advanced NSCLC and reported an improvement in PFS but no difference in OS. A prospective evaluation of the combination Nivolumab/Ipilimumab against chemotherapy in two cohorts of untreated patients with PD-L1 expressing or negative tumors was performed in the Checkmate 227 trial. Besides a significant prolongation of PFS in patients with high tissue based TMB also an improvement in the second coprimary endpoint (OS in patients with PD-L1 expressing tumors) was observed. Interestingly the activity of the immunotherapy combination was independent from the PD-L1 expression. In an approach to improve the early tumor control 2 cycles of chemotherapy were added to the combination of Nivolumab/Ipilimumab and were compared to chemotherapy in the Checkmate 9LA trial. OS as the primary endpoint as well as RR and PFS were significantly improved in favor of this combination independent from histology and PD-L1 expression level. The combination of Nivolumab and Ipilimumab with or without chemotherapy represents an active novel first-line treatment opportunity for NSCLC.

Pharmacokinetics and drug-drug interaction between enalapril, enalaprilat and felodipine extended release (ER) in healthy subjects.

Since angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists have complimentary mechanisms of action, enalapril, an ACE inhibitor, is used in combination with felodipine, a vascular selective dihydropyridine calcium antagonist, for the treatment of hypertension. The present study was designed to investigate the possible drug-drug interaction between these two agents in Chinese healthy subjects. A randomized, open-label, multiple-dose, 3-treatment, 3-period, 6-sequence cross-over study enrolling 12 healthy subjects (six male and six female subjects) was performed. Plasma pharmacokinetic studies were performed after 5 mg of enalapril and 5 mg of felodipine were administered alone or concomitantly twice per day for six days, and once in the morning of day seven. All 12 healthy subjects (mean [SD] age, 24.3 [2.8] years; body weight, 57.3 [5.7] kg; height, 163.2 [5.2] cm) completed all scheduled pharmacokinetic studies. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for enalapril administered concomitantly with felodipine vs. enalapril administered alone were 1.025 (0.80-1.25) and 1.065 (0.70-1.43), respectively. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for felodipine administered concomitantly with enalapril vs. felodipine administered alone were 1.14 (0.97-1.31) and 0.80 (0.65-0.95), respectively. There were no severe or serious drug-related adverse events observed during the study. Our results revealed that the co-administration of enalapril and felodipine affected the pharmacokinetics of felodipine, but not that of enalapril. Although the difference in PK parameters was statistically significant, its clinical significance may be limited, considering safety profile observed in the present study.

The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II)

To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific castration-resistant prostate cancer (CRPC) treatments. The Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for metastatic CRPC based on available data and clinical experience. A consensus was developed to address important questions on management of patients with metastatic CRPC. In the absence of large-scale clinical trials, the Working Group recommends that patients may best be managed with a layered approach of approved therapies with unique or complimentary mechanisms of action.

Topical antibiotics for acne treatment

Urgency. Acne is a prevalent polymorphous multifactorial inflammatory disease with various clinical forms ranging from the mildest ones (comedonal) to the most severe forms such as phlegmonous, indurative and cystic acne. According to epidemiology studies, the acne incidence rate in general population varies from 85% to 93%; moreover, there is a trend towards the growth in the incidence rate of postpubertal and persistent acne in adults. Acne treatment methods depend on the adequate clinical assessment of the disease severity, character of eruptions, skin type, any concomitant pathologies and patient’s age. Topical therapy is administered to all patients regardless of the disease severity and forms a mandatory part of the therapeutic complex treatment of acne patients. Despite the range of available drugs and treatment methods, researchers keep searching for new drugs and treatment methods for treating acne. Combination acne therapies enjoy keen interest in the world for reasons such as stable treatment results and improved compliance. It is essential that the administration of a combination therapy came along with drugs having a complimentary mechanism of action. Drug combinations have an effect on a large number of pathogenetic factors resulting in acne (excessive follicular hyperkeratosis, propagation of P. аспвв, inflammation). Goal. The goal of this article is a review of literature sources on current aspects of acne topical therapy and examining results of studies of a combination therapy, azelaic acid and clindamycin. Study materials and methods. The project was carried out at the GBOU VPO Kursk State Medical University, Ministry of Health of the Russian Federation. Major results. Both Russian and foreign authors use combination therapies with topical administration of azelaic acid and clindamycin on a broad scale. According to a study conducted in Russia, azelaic acid is a good combination substance for administration with both topical antibiotics (the antibiotic is to be applied to pustules once a day) and adapalene. According to the clinical study results, 15% azelaic acid (Azelic gel) as a part of a combination topical therapy reduces adverse effects observed in the course of a monotherapy with topical retinoids and improves the therapeutic efficacy when combined with antibacterial drugs. Conclusion. The practical experience and different variants of a combination therapy with 15% azelaic acid (Azelic gel) and 1% clindamycin gel (Clindovit) provide dermatologists with an opportunity to treat acne in different groups of patients on an everyday basis with increased efficacy achieving a longer remission of the inflammatory process.

Oncovex MGM-CSF –mediated regression of contralateral (non-injected) tumors in the A20 murine lymphoma model does not involve direct viral oncolysis

Meeting abstracts Talimogene laherparepvec (T-VEC) is an injectable modified oncolytic herpes simplex virus type-1 (HSV-1) hypothesized to be efficacious by at least two complimentary mechanisms of action: a) direct oncolysis of the injected tumor and b) elicitation of a systemic anti-tumor immune

The impact of three combinations vildagliptin/metformin, vildagliptin/pioglitazone, and metformin/pioglitazone on glycemic control and atherogenic dyslipidemia in patients with Type 2 diabetes mellitus

Background: There are limitations of currently recommended stepwise treatment for Type 2 diabetes, especially failure with monotherapies to achieve the strict glycemic control. This has prompted the intensification of therapy with such combinations which have additive efficacy and complimentary mechanisms of action. Vildagliptin is one such agent with the above potential which does not increase the risk of hypoglycemia and does not promote weight gain. Methods: It was a prospective, open-label, randomized, and parallel group study involving 90 patients, divided into three Groups A, B, and C. Group A given vildagliptin/metformin (50/500 mg), Group B vildagliptin/pioglitazone (50/15 mg)and Group C metformin/pioglitazone (500/15 mg) combinations twice daily for 12 weeks. Fasting blood glucose (FBG) was estimated biweekly while hemoglobin A1c (HbA1c), lipid profile, insulin, and C-peptide levels at 0 and 12 th week. Statistical analysis was done using ANOVA and Student’s t-test. Results: At the end, mean percentage of age fall in HbA1c and FBG from baseline was maximum in Group B, which was found out to be more efficacious than Group A and C (p&lt;0.001) on glycemic parameters. Mean percentage of age decrease in triglyceride from baseline was maximum in Group C, which was found out to be more efficacious than Group A and B (p&lt;0.001) on lipid parameters. The adverse effects were low in all the groups. However, the incidence of peripheral edema and weight gain was more with the use of Group C while nausea, vomiting, and nasopharyngitis was more with the use of Group A. Conclusion: Vildagliptin/pioglitazone combination is of choice in patients with uncontrolled hyperglycemia but normal lipid profile while metformin/pioglitazone combination in diabetic patients with dyslipidemia.

Comparative evaluation of moderate dose inhalational corticosteroid (ICS) fluticasone with the combination of low dose fluticasone and montelukast in moderate persistent bronchial asthma

Background: Use of inhaled corticosteroids (ICS) are recommended in all grades of persistent asthma and once the symptoms are stabilized, “stepping down of steroids is recommended to minimize their unwanted effects with the addition of a second medication with a complimentary mechanism of action. Aims & Objective: In our study a comparison of moderate dose ICS Fluticasone in “stepping down” strategy with combination of low dose Fluticasone with once-daily montelukast were assessed. Materials and Methods: 50 patients with moderate persistent asthma were randomly assigned in study. Initially stabilized on fluticasone propionate (FP) 250 µg twice daily, for four weeks, there after patients were given the medication as per the protocol Group-I (n=25)- fluticasone 250μg BD; Group-II (n=25)- fluticasone125 μg BD + Montelukast 10 mg in night. Patients were then followed up for 12 weeks. The primary efficacy variables were changes in FEV1%, PEFR%, ACS (asthma control symptom) score and asthma quality of life (QOL) score. Results: Changes in lung function at the end of study in Group-I and Group-II respectively as compared to 0 week (baseline) values, FEV1% value (p <0.05, p <0.05), PEFR% value (p <0.01, p <0.05), ACS score (p <0.01, p <0.05), AQOL score (p <0.05, p <0.05). ICS fluticasone 250 µg BD and low dose fluticasone 125 μg BD + Montelukast 10 mg in night are equally efficacious in improving lung functions, asthma symptoms and QOL. Montelukast group was more expensive with fewer adverse events. Conclusion: Moderate dose fluticasone did not show any benefit over combination of low dose fluticasone and Montelukast 10mg in night. Montelukast 10 mg in combination with low dose fluticasone can be an alternative in moderate persistent asthma.

Bioequivalence of Canagliflozin/Metformin Immediate Release Fixed- Dose Combination Tablets Compared with Concomitant Administration of Single Components of Canagliflozin and Metformin in Healthy Fed Participants

Background: A fixed-dose combination (FDC) tablet formulation of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2 (SGLT2), and metformin can potentially provide complimentary mechanism of action to improve glycemic control in adults with type 2 diabetes mellitus. Objectives: To assess the bioequivalence of immediate release (IR) FDC tablets containing canagliflozin and metformin relative to co-administration of individual tablets of IR canagliflozin and metformin in healthy fed participants. Methods: The six studies were randomized, open-label, single-center, single-dose, 2-treatment, 2-period crossovertrials conducted in healthy male and female participants under fed conditions. Pharmacokinetics of canagliflozin and metformin were investigated following administration of 2 canagliflozin/metformin IR FDC tablets (test) at 50 mg/500 mg, 50 mg/850 mg, 50 mg/1,000 mg, 150 mg/500 mg, 150 mg/850 mg, or 150 mg/1,000 mg compared with co-administration of equivalent doses of single-component IR tablets (reference). Results: Across the six studies, a total of 64 to 83 participants were randomized to each treatment sequence and 57 to 68 were analyzed. The median tmax, mean t1/2, and mean plasma canagliflozin and metformin concentrationtime profiles were similar after administration of IR FDC and individual components.Bioequivalence criteria for the FDC with respect to AUC∞, AUClast, andCmaxof both canagliflozin and metformin met the 90% CI for the test-toreference geometric mean ratios of these parameters and were contained within the bioequivalence limits of 80% to 125%.Both treatments were well-tolerated with similar adverse events and the most common were gastrointestinal events generally attributed to metformin. Conclusions: When administered as IR FDC tablets or individual component IR tablets, the pharmacokinetics of canagliflozin and metformin across six dose levels were bioequivalent and were well-tolerated.

Triple-drug, fixed-dose combinations for the treatment of hypertension: Focus on olmesartan/amlodipine/hydrochlorothiazide combination

Hypertension is a major risk factor for cardiovascular, renal and stroke complications. Its incidence continues to rise worldwide, and it is projected that by the year 2025, 1 billion people will be hypertensive. Despite the enormity of the high blood pressure burden, its control to < 140/90 mmHg for uncomplicated hypertensives and < 130/80 mmHg for patients with diabetes mellitus, chronic kidney disease or coronary artery disease remains poor and currently stands at approximately 50%. Reasons for this poor control include physician inertia and poor patient compliance and adherence due mostly to complicated drug regimens. Since hypertension is a multifactorial condition, its control will require the administration of multiple drugs with complimentary mechanisms of action. Several studies have shown that the patient's compliance and adherence to treatment is inversely related with the number of drugs administered. It is, therefore, important to combine different drugs with complimentary mechanisms of action into a single pill. Recent studies have shown that triple-drug combinations are very effective, safe and well tolerated by the patients. Three different triple-drug, fixed-dose combinations have recently been approved by the FDA for the treatment of hypertension, including, olmesartan medoxomil/amlodipine besylate/hydrochlorothiazide. These studies with collateral literature will be discussed in this concise review.

Renin inhibition with aliskiren in hypertension: focus on aliskiren/hydrochlorothiazide combination therapy

Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.

Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet.

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.