Fixed-dose Combination Research Articles

Efficacy and Safety of a Fixed-Dose Combination Gel with Adapalene 0.1% and Clindamycin 1% for the Treatment of Acne Vulgaris (CACTUS): A Randomized, Controlled, Assessor-Blind, PhaseIII Clinical Trial.

Combination therapy is required for the treatment of moderate acne vulgaris. However, patient compliance in applying multiple topical formulations is poor. To assess the efficacy and safety of a fixed-dose combination gel with adapalene 0.1% and clindamycin 1% (adapalene-clindamycin) relative to adapalene 0.1% monotherapy and clindamycin 1% monotherapy in patients with moderate facial acne vulgaris. This was a randomized, controlled, assessor-blind, phaseIII study conducted in patients with moderate facial acne vulgaris. A total of 1617 patients were enrolled. At week12, patients in the adapalene-clindamycin gel treatment group showed a significant reduction in the percentage change from baseline in total lesion count (- 66.85%), compared with adapalene alone (- 50.82%) or clindamycin gel alone (- 57.61%). The difference in the least square means of the adapalene-clindamycin gel group and adapalene group, or clindamycin gel group was - 16.08% (95%CI - 19.95% to - 12.21%) and - 9.38% (95%CI - 13.25% to - 5.51%;), respectively. At week12, 19.28% of participants who received adapalene-clindamycin gel achieved at least 2-grade improvement in IGA, versus 7.74% with adapalene gel (OR 3.05, 95%CI 1.93, 4.80) and 14.77% with clindamycin gel (OR 1.42, 95%CI 0.97, 2.07). The study also achieved all its secondary endpoints. Adverse event rates were mostly mild to moderate and comparable across the three treatment groups. Adapalene 0.1%-clindamycin 1% combination gel is well tolerated and demonstrated superior efficacy over 0.1% adapalene gel monotherapy and 1% clindamycin gel monotherapy for the treatment of moderate acne vulgaris. ClinicalTrials.gov identifier NCT03615768.

Paracetamol and ibuprofen fixed-dose combination for the management of acute mild-to-moderate pain in children: strengthening and enhancing of result of Nominal Group Technique through Delphi consensus

BackgroundParacetamol and ibuprofen are the most commonly used drugs for pain treatment in children and their combination has shown improved analgesic effect compared to treatment with either drug alone. Current literature lacks specific guidelines regarding the settings in which this combination should be adopted.MethodsThe survey, conducted with Delphi methodology, involved 75 hospital and outpatient pediatricians with clinical experience in the management of pain in children. Pediatricians involved were asked to validate or not the results of the previous NominalGroup Tecnique (NGT) consensus and thus specify the optimal clinical settings in which the paracetamol/ibuprofen fixed-dose combination could be adopted.ResultsThe results confirm the importance of the fixed-dose paracetamol and ibuprofen combination for the control of mild-to-moderate acute pain in children. Particularly, this association seems to be appropriate in case of headache, earache, odontalgia and musculoskeletal pain, and in specific settings such as post-operative and post-procedural pain. The broadening of the panel brought to slight variations in clinical management practices between hospital and outpatient specialists. Nonetheless, overall consensus supports the notion that the fixed dose combination is more efficacious than monotherapies and it is well tolerated. Moreover, experts unanimously agree on the usefulness of the combination for caregivers, leading to improved adherence and effectiveness.ConclusionsBoth the NGT consensus and the broader Delphi consensus confirm the usefulness of the paracetamol-ibuprofen fixed-dose combination in pediatric pain. This is attributed to its superior effectiveness compared to monotherapies, a good tolerability profile, and improved compliance and ease of use. Some pain settings related to chronic, inflammatory and rheumatological pathologies remain to be investigated to evaluate the use of this combination.

Prevention of mechanical valve thrombosis with a combination of the factor Xa inhibitor edoxaban plus aspirin in swine: intermediate results from the EdoValves project

Abstract Background Patients with an implanted mechanical heart valve (MHV) currently have a contraindication to the use of non-vitamin K antagonist oral anticoagulants (NOACs) based on the unfavorable results of the RE-ALIGN trial with dabigatran. We hypothesized that the combination of a Factor Xa inhibitor, acting upstream of thrombin generation, plus aspirin, may effectively prevent valve thrombosis, providing a much more friendly and viable alternative to vitamin K antagonists for such patients. We tested this in a swine model with a recently implanted mechanical valve prosthesis in the mitral position, combining the most unfavorable conditions promoting mechanical valve thrombosis, based on (a) the implanting position; (b) recent surgery; (c) the high thrombogenicity of the animal model. The study was approved by the Animal Ethics Committee of the University of Pisa and the Italian Ministry of Health and conducted according to Good Clinical Practices for Animal Experiments. Methods 17 farm male pigs, weighing ≈30 kg at the beginning, underwent cardiac surgery under general anesthesia and with extracorporeal circulation to receive a 25 mm or 27 mm bileaflet Corcym Bicarbon mechanical heart valve replacement in the mitral position. Pigs were given 1 mg/kg enoxaparin immediately after surgery and started with the oral daily administration of edoxaban 1 mg/kg (30 mg, then escalated to 60 mg with the animal growth) + aspirin 100 mg, both given as crushed tablets with a food pellet since the animal awakening from anesthesia. An initially planned warfarin control group was quickly abandoned because of the extreme difficulty of controlling warfarin activity. Animals were submitted to blood sampling and transthoracic echocardiography at least twice in the follow-up when uneventful for up to three months or in case of health deterioration. The autopsy was performed by a certified pathologist after each spontaneous death or procured sacrifice. Results (Figure 1): Excluding 5 peri-operative deaths, 12 animals survived surgery. Of those, 6 died within the second month: pulmonary edema occurred in 3 cases, due to prosthesis-mismatch in the growing animals; pulmonary infection occurred in 1 subject; heart failure due to valve thrombosis occurred in 2 cases. Six swine were full-term survivors in good health status up to the 3-month planned observational time. No hemorrhagic events were ever documented. Conclusion The combination of edoxaban + aspirin effectively avoided valve thrombosis events in 10 out of 12 (83%) analyzable animals and was safe from bleeding complications. The study is ongoing up to a predicted sample size of ≥20 animals. If further confirmed, these data may open the possibility of an alternative to vitamin K antagonists in humans with the fixed-dose drug combination here used, without the need for continuous anticoagulation monitoring and with expected greater safety.Figure 1

Concurrent Estimation of Pregabalin and Etoricoxib by New Stability-Indicating RP-UPLC Approach - Application in Assay of Commercial Tablets

Background: The study emphasizes establishing a stability-indicating RP-UPLC method for concurrent estimation of pregabalin and etoricoxib in combined pharmaceutical formulations, confirming effective separation, sensitivity, and repeatability, validated according to ICH guidelines. Objective: The present research study aims to establish a new stability-indicating RP-UPLC method for concurrently estimating pregabalin and etoricoxib in blended powder and their combined tablet formulation with less run time, high sensitivity, and specificity. Methods: The effective separation of pregabalin and etoricoxib was achieved with HSS column C18 (150x2.1mm,1.8μm), 0.1% orthophosphoric acid:acetonitrile (65:35 v/v) at a flow rate of 0.3mL/min, and isocratic elution at 228nm. The elution of PRB and ETB was noticed at 1.56 and 2.01 minutes, with good resolution and system suitability with the developed approach. Results: Pregabalin and etoricoxib have shown linear responses from 18.75 to 112.5μg/mL and 15 to 90μg/mL, respectively. The range of the % RSD for intraday and inter-day precision was 0.33 to 0.81. The LOD and LOQ of pregabalin and etoricoxib were computed to be 0.07 μg/mL and 0.21 μg/mL, and 0.01μg/mL and 0.04 μg/mL, respectively, by standard deviation method. The validation method was carried out using ICH standards. The stability-indicating feature of the method was confirmed by the forced degradation studies where degradants generated by stress testing were clearly distinguished from the peaks of analytes. Conclusion: The shorter elution period and superior sensitivity of both analytes with this method have been found to be appropriate for regular analysis of pregabalin and etoricoxib.

LDL-C target attainment and statin use in patients with ASCVD, familial hypercholesterolaemia, and those otherwise at moderate/high-risk of ASCVD in australian general practice (SCOPE-GP)

Abstract Background The proportion of Australian general practice patients not attaining low-density lipoprotein cholesterol (LDL-C) goals is not well described. The SCOPE-GP study evaluated duration of LDL-C exceeding treatment goals, statin use and discontinuation rates in patients with atherosclerotic cardiovascular disease (ASCVD), without ASCVD events but at moderate/high-risk, and familial hypercholesterolemia (FH). Methods This population-based retrospective cohort study used de-identified medical records of adult patients captured in the IQVIA GP-EMR database. Patients were indexed at the earliest date of ASCVD, FH, or hyperlipidemia diagnosis from January 1, 2010 to June 30, 2022, with a variable follow-up period from index to June 30, 2022. Ascertainment of study cohort was based on the 2021 ESC/EAS guidelines and Framingham Risk Equation. LDL-C test result levels were extracted per patient, summarised and analysed. Patients were stratified based on their test results at latest results/closest to censor date. Average time above target levels is the proportion of number of days above LDL-C target levels over total number of follow-up days for each patient. A Poisson distribution was fitted to estimate 95% confidence interval. Lipid lowering therapies (LLT) were stratified by (ASCVD, FH and moderate/high risk of CVD) at last visit/censor date. Combination of LLT were defined as prescriptions for fixed dose combinations or ≥2 separate scripts of LLT from different classes within 180 days from last visit/censor date (look back period). Discontinuation is defined as no statins were prescribed again after the last script for 270 days or more, limited to the first occurrence. Results The average time with LDL-C levels above target was 1077.5 days in ASCVD patients (n=2,688), 938.6 days in moderate-risk ASCVD (n=37,003), 980.9 days in high-risk ASCVD (n=85,199), and 900.8 days in FH (n=279). The proportion of days above target level for all four cohorts is described in Figure 1. Among 107,552 patients with recorded LDL-C levels ≥1.8mmol/L at their last visit/censor date, 30.9% were on statin monotherapy and 1.0% were on statin+ezetimibe. Statin use was highest in ASCVD patients (65.4%), followed by FH (49.5%), high risk (40.0%) and moderate risk subjects (29.5%) (Table 1). Statin discontinuation rates were 60.3%, 76.3, 66.1%, and 65.8% in these groups, respectively. The predominant reason for statin discontinuation was non-specific adverse drug reactions (12.2% ASCVD, 11.7% moderate-risk, 13.2% high-risk and 17.9% FH). The proportion of subjects contraindicated to statins was highest in moderate risk subjects (0.05%). Conclusions Prolonged periods of elevated LDL-C and high statin discontinuation rates were prevalent among at-risk individuals in Australian primary care. This underscores a significant ASCVD burden that could be prevented with more active lipid management.

Combination therapy with GalNAc-siRNA drugs targeting both PCSK9 and APOC3 resulted in enhanced lipid lowering in mice

Abstract Introduction Aggressive lowering of both atherogenic low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) could reduce residual atherosclerotic cardiovascular disease (ASCVD) risk. Drugs targeting PCSK9 or APOC3 have shown good lipid-lowering effects in clinic. Here, we have developed GalNAc-conjugated siRNAs, RBD7022 targeting PCSK9 and RBD5044 targeting APOC3, as novel therapeutic agents to lower LDL-C and triglyceride (TG) plasma levels respectively. Each drug shows potent and durable effect in silencing its own target. However, it is unknown whether the combined therapy with siRNA drugs targeting both PCSK9 and APOC3 will generate enhanced effects in lipid lowering. Purpose To investigate the effects of fixed-dose combination of RBD7022 and RBD5044 on LDL-C, TG and total cholesterol (TC). Methods RBD7022 and RBD5044 completely match the human PCSK9 and APOC3 transcripts respectively. RBD7022 has 2 nucleotide mismatches with mouse pcsk9, but still shows silencing activity in mice, while RBD5044 has no activity due to 5 mismatches with mouse apoc3. Therefore, humanized APOC3 transgenic mice were used in this study, which had serious hypertriglyceridemia with relatively high cholesterol and TG levels. They were randomized into 8 groups with treatment of RBD7022 (1 mg/kg or 3 mg/kg), RBD5044 (3 mg/kg or 6 mg/kg), or 3 different dose combinations of RBD7022 and RBD5044, as well as PBS control. All animals were administrated once on Day 1. Plasma was collected to quantify lipid biomarkers. Results RBD7022 showed a robust effect on LDL-C reduction, with inhibition rates of 45% in 3 mg/kg and 43% in 6 mg/kg, indicating 3 mg/kg was a saturated dose for RBD7022 in LDL-C lowering. RBD5044 showed a dose-dependent effect on LDL-C reduction, with inhibition rate of 52% at 1 mg/kg and 59% at 3 mg/kg. Interestingly, significantly enhanced LDL-C reduction was observed in the combination groups, with 67% reduction in LDL-C at RBD5044 1 mg/kg plus RBD7022 3 mg/kg, 73% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 3 mg/kg and 78% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 6 mg/kg, showing dose-dependent effects (Figure 1A). Enhanced TC reduction was also found in combination at RBD5044 3 mg/kg plus RBD7022 6 mg/kg compared with RBD5044 or RBD7022 alone. RBD5044 showed a dose dependent effect on TG reduction with inhibition rates of 56% at 1 mg/kg and 83% at 3 mg/kg. RBD7022 treatment alone did not show significant effect on TG reduction. No added effects of RBD7022 on TG levels was found in the combination with RBD5044, indicating the TG lowering was induced by RBD5044. Conclusions The combination of RBD7022 targeting PCSK9 and RBD5044 targeting APOC3 simultaneously reduce LDL-C and TC levels. The combination of RBD7022 and RBD5044 could be a better therapeutic option to further reduce LDL-C, particularly for mixed hyperlipidemia patients and other high-risk individuals with both high LDL-C and high TG levels.Figure 1

A survey of availability and affordability of polypills for primary and secondary prevention of cardiovascular diseases in selected countries

Abstract Background/Introduction The recent inclusion of polypills—fixed-dose combinations of two or more antihypertensive drugs and statin with or without aspirin—in the World Health Organization’s Essential Medicines List (EML) reiterates the potential of this approach to improve global treatment coverage for primary or secondary prevention of cardiovascular diseases (CVDs). Although there exists extensive evidence on efficacy, safety, and acceptability of polypills, there is no research to-date assessing the "real world" availability and affordability of polypills globally. Purpose We conducted a cross-sectional survey of public and private sector facilities in 13 countries from around the world to evaluate the availability and affordability of polypills. Methods In the surveyed countries, we first ascertained whether any polypill was authorized for marketing and/or included in the national EMLs and clinical guidelines. The facility survey employed a modified WHO/Health Action International methodology. In each country, we collected retail and price data for polypills from at least one public sector facility and three private pharmacies using convenience sampling. Polypills were considered unaffordable in a given country if the lowest paid worker spends more than a days’ wage to purchase monthly supply. Results Polypills were approved for marketing in four of the 13 surveyed countries: Spain, India, Mauritius, and Argentina. None of these countries included polypills in national guidelines, formularies, or EMLs. Further, none of the surveyed public pharmacies in any of the four countries stocked any polypills. Among the surveyed private sector facilities, availability ranged from 0% in India (out-of-stock on the survey day but listed for sale) to 100% in Argentina and Spain. In the private sector, we identified seven unique polypill combinations, marketed by eight different companies. Although not in stock, India had a wider range of various combinations (n=5). Many combinations (63%) found in this survey were affordable in the local context, but these were limited to India and Spain. A lowest paid government worker would spend between 0.2 (India)–2.8 (Mauritius) days’ wages to pay the price for one month’s supply of the polypills. Polypills were likely to be affordable in countries that locally manufactured them. Further, two-pill combinations (one antihypertensive and a statin) were stocked by private pharmacies in Argentina, Bangladesh, Cameroon, India, Nepal, and Spain, with affordability ranging from 0.2 (India)–7.1 (Cameroon) days’ wages. Conclusion Low availability and affordability of polypills in both public and private sectors suggest that the implementation and overall uptake of polypills remains poor globally. Context-specific multi-disciplinary health system research is required to understand factors affecting polypill implementation and to design and evaluate appropriate implementation strategies.

Efficacy and Safety of Fixed-Dose Combinations for Pain in Older Adults.

Pain is common in older adults and managing pain in this population can be challenging owing to altered pharmacokinetics, multimorbidity, polypharmacy, cognitive impairment, and physical frailty. A fixed-dose combination (FDC) analgesic contains two or more pharmaceutical ingredients in a single pill and may offer more benefits when compared with loose-dose formulations. The benefits include reduced pill burden and better adherence, a broader analgesic spectrum well-suited to multimechanistic pain conditions and more predictable pharmacokinetic and pharmacodynamic properties. These advantages may outweigh disadvantages such as reduced flexibility in dose adjustment. Most of the commonly used FDC analgesics are made up of a combination of paracetamol, muscle relaxant, nonsteroidal anti-inflammatory drug or opioid. They have been shown to have better efficacy and similar safety profiles compared with individual drugs. Adverse effects from the use of FDC analgesics in older patients were comparable with that observed in younger populations. With proper patient selection and continuous surveillance, FDC analgesics will likely benefit older adults by simplifying dosing regimen and improving compliance.

Metformin: Diverse molecular mechanisms, gastrointestinal effects and overcoming intolerance in type 2 Diabetes Mellitus: A review.

Metformin, the first line treatment for patients with type 2 diabetes mellitus, has alternative novel roles, including cancer and diabetes prevention. This narrative review aims to explore its diverse mechanisms, effects and intolerance, using sources obtained by searching Scopus, PubMed and Web of Science databases, and following Scale for the Assessment of Narrative Review Articles reporting guidelines. Metformin exerts it actions through duration influenced, and organ specific, diverse mechanisms. Its use is associated with inhibition of hepatic gluconeogenesis targeted by mitochondria and lysosomes, reduction of cholesterol levels involving brown adipose tissue, weight reduction influenced by growth differentiation factor 15 and novel commensal bacteria, in addition to counteraction of meta-inflammation alongside immuno-modulation. Interactions with the gastrointestinal tract include alteration of gut microbiota, enhancement of glucose uptake and glucagon like peptide 1 and reduction of bile acid absorption. Though beneficial, they may be linked to intolerance. Metformin related gastrointestinal adverse effects are associated with dose escalation, immediate release formulations, gut microbiota alteration, epigenetic predisposition, inhibition of organic cation transporters in addition to interactions with serotonin, histamine and the enterohepatic circulation. Potentially effective measures to overcome intolerance encompasses carefully objective targeted dose escalation, prescription of fixed dose combination, microbiome modulators and prebiotics, in addition to use of extended release formulations.

An analysis of drug approvals in India over past 5 years

Background: Drug development is a tedious process and takes a long time for approval by regulatory authorities. With time, Indian authorities have revised rules and regulations for conducting clinical trials as well as for the marketing of drugs, impacting the number of drugs being approved. Method: The information about drug approvals from 2019–2023 was obtained from the CDSCO website. The single drug products were classified into 14 main anatomical therapeutic chemical (ATC) groups, while Fixed Dose Combinations (FDCs) were classified based on the system they act upon. Descriptive statistical analysis was done. The findings of our observational study were expressed as absolute numbers and percentages. Results: Total 362 drugs were approved. Out of these, 135 were single drug products, and the rest were FDCs. The highest & lowest number of drugs were approved in the year 2022 and 2019 respectively. Maximum single drug product approvals were seen in Category L-antineoplastic and immunomodulating agents, while maximum FDC approvals were for drugs acting on the endocrine system. Conclusion: There is a rising trend of approval for FDCs. The pattern of single drug products approval flattened over the years, coinciding with the implementation of new rules and regulations.

Piperacillin-tazobactam fixed dose combination induced skin reaction in a patient with split thickness skin grafting: a case report

Piperacillin is a semi-synthetic ureido-penicillin. It has a broad spectrum against gram negative bacilli particularly P. aeruginosa. It is one of the most broadly active of the currently available penicillin with regard to other bacterial species like proteus, klebsiella, H. influenzae and gonococci. Tazobactam is β-lactamase inhibitor and combined with piperacillin to increase spectrum of the drug. Patient was 25 years old female, admitted in orthopaedic department for treatment of traumatic leg injury of left limb. Leg was amputated in the accident, so after 1-month split thickness skin grafting was done at plastic surgery department. For prophylaxis piperacillin-tazobactam IV 4.5 gm 8 hourly given, on 2nd post operative day patient reported rashes on neck, trunk, both upper and lower extremities, sparing the mucous membrane. Patient was prescribed anti pruritic and anti-allergic medication for ADR management. It is necessary to use such kind of drugs cautiously in patients whose health is deteriorated by this medication.

Optimising Paediatric HIV Treatment: Recent Developments and Future Directions.

Treatment options for children living with HIV have historically been less effective, less practical and more difficult to implement compared with those for adults, as the research and development of new drugs for children has lagged behind. Significant progress has been achieved in response to the paediatric HIV epidemic over the last decade. Several optimised paediatric antiretroviral formulations are currently available or in development, including fixed-dose combination tablets containing a complete World Health Organization-recommended regimen. Despite these advancements, virological suppression rates in children are generally lower than in adults. Even when oral fixed-dose combinations with the optimal target profiles are developed, for some children virological suppression is not achievable for reasons such as adherence challenges, intolerance, toxicity and genotypic resistance. New safe, effective, well-tolerated antiretroviral agents from existing and novel classes, as well as innovative administration strategies are essential. To achieve the UNAIDS target of virological suppression in 95% of children receiving antiretroviral therapy, concerted efforts are required. This includes identifying priority drugs in line with latest developments, focusing drug development studies on these priorities, ensuring a timely technical knowledge transfer between originator and generic companies, accelerating regulatory approvals and facilitating procurement and implementation in countries. Success in these efforts depends on collaboration among all stakeholders, including communities, researchers, pharmaceutical companies, guideline and policymakers, governments, funders, regulators and healthcare providers. This review outlines which paediatric antiretroviral therapies are currently available, those which are under development and the future directions of paediatric HIV treatment.

Glyceroniosomes for enhanced intestinal absorption of hydrochlorothiazide and lisinopril in their fixed dose combination.

The objective was to investigate the effect of co-administration of hydrochlorothiazide and lisinopril as fixed dose combination on their intestinal absorption. The scope was extended to enhance intestinal absorption of both drugs. In situ rabbit intestinal absorption through the duodenum and jejuno-ileum was used to monitor membrane permeability of both drugs when perfused alone or in combination. Niosomes containing glycerols (glyceroniosomes) were loaded with both drugs. Glyceroniosomes comprised Span 60 or Tween 40 in combination with cholesterol and glycerol were prepared by bath sonication. Glyceroniosomes were characterized with respect to vesicle size, drug entrapment efficiency and were examined using transmission electron microscope (TEM). The prepared vesicles were nanosized spherical vesicles with average size of 202.4nm and 108.8nm for span free and span containing glyceroniosomes, respectively. The recorded Zeta potential values suggested good stability of the prepared formulations. Intestinal absorption studies reflected incomplete absorption of hydrocholothiazide and lisinopril correlating with their categorization as class IV and III drugs, respectively. Co-perfusion of both drugs reduced the intestinal absorption of lisinopril. Simultaneous encapsulation in glyceroniosomes enhanced the intestinal absorption of both drugs. Tween based systems were more efficient. The study introduced glyceroniosomes as carriers of simultaneous delivery of hydrochlorothiazide and lisinopril.

The efficacy of essential oil components with ivermectin against Rhipicephalus annulatus: An in-vitro study

Ivermectin (Iv) is widely used to control Rhipicephalus annulatus infestations in cattle in Egypt. However, increasing resistance to ivermectin necessitates alternative approaches. This study aimed to address this resistance by investigating the interactions between ivermectin and essential oil components (EOCs)—carvacrol, cinnamaldehyde, D-limonene, trans-anethole, and thymol—against four R. annulatus tick isolates collected from Beni-Suef, El-Minia, and El-Fayoum. The larval immersion test was conducted using various ivermectin concentrations (3, 1.5, 0.75, 0.38, 0.19, 0.09, 0.045, 0.025, and 0.0125 mg/mL) prepared in EthTX1 %. Additionally, EOCs were tested at different concentrations (20, 10, 5, and 2.5 mg/mL) prepared by dilution in 5 % ethyl alcohol and EthTX 1 %. Ivermectin and each EOC were tested individually against the isolates. Subsequently, the LC50 of ivermectin was combined with the LC50 of each EOC in a 1:1 ratio to evaluate potential synergistic effects. All EOCs demonstrated significant toxicity against the isolates. The combination of carvacrol and thymol with ivermectin increased mortality, but the combination index (CI) exceeded one for all isolates, indicating no synergism. Similarly, while D-limonene, cinnamaldehyde, and trans-anethole also resulted in high mortality rates, including up to 100 %, no synergism was observed (CI > 1). However, these three EOCs exhibited CIs close to 1, suggesting an additive effect when combined with ivermectin. In conclusion, combining ivermectin with certain EOCs, particularly D-limonene, cinnamaldehyde, and trans-anethole, may offer an effective tool for controlling cattle ticks. Developing topical or pour-on formulations of ivermectin-EOC combinations could be an integral part of integrated management strategies to combat resistance to macrocyclic lactones like ivermectin. Further studies, including tests on adult ticks and field trials, are needed to evaluate the efficacy of these combinations.

In Vitro Analysis of Aerodynamic Properties and Co-Deposition of a Fixed-Dose Combination of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol Trifenatate.

Effective airway delivery of a fixed-dose combination of triple-aerosolized inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) is likely to positively affect therapeutic responses predicted in patients with asthma and chronic obstructive pulmonary disease. This study aimed to conduct in vitro fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide depositions in a Next Generation Impactor. The aerodynamic properties of these inhaled medications influence the spatial distribution and drug abundance, particularly in the smaller airways, to reverse or alleviate disease pathology. The Next Generation Impactor was used to demonstrate the aerodynamic particle size distributions of fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide delivered from a dry powder inhaler at different flow rates across all stages of the impactors. This in vitro study analyzed the distribution pattern of individual drug components to simulate mono-component deposition and co-deposition in the official model in the United States Pharmacopeia. An Andersen cascade impactor together with scanning electron microscope-energy-dispersive X-ray was employed to observe the drug deposition on each stage of the impactor. We found that the distribution pattern of each component at the same cascade level was comparable, and the aerosol particles of the three drugs reached the in vitro representation of the lower airway compartment. The specified flow rates generated the desired fine particle fraction, fine particle dose, and mass median aerodynamic diameter. Our results also demonstrated visualized deposition patterns of the delivered drugs from different stages of the cascade impactor that may predict deposition as it occurs in vivo. Spatial distribution and abundance of ICS/LABA/LAMA in the same cascade levels were closely comparable, and the aerosol particles were able to reach the small aerosol-sized cascades at the lower levels to some extent.

Efficacy of Alogliptin/Metformin Fixed-Dose Combination Tablets and Vildagliptin/Metformin Fixed-Dose Combination Tablets on Glycemic Control in Real-World Clinical Practice for the Patients with Type 2 Diabetes: A Multicenter, Open-Label, Randomized, Parallel Group, Comparative Trial.

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5%-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (-0.3% and -0.4%, P = 0.309) or the FPG level (-9.0 and -15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Real-world usage pattern, effectiveness and safety of oral tramadol/dexketoprofen trometamol fixed-dose combination in moderate-to-severe acute pain in Asia: a prospective, multicentre, observational study

ObjectivesThis study aims to determine the usage pattern, effectiveness and safety of oral tramadol 75 mg and dexketoprofen trometamol 25 mg fixed-dose combination (TRAM/DKP FDC) in the short-term treatment of...

Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO)

BackgroundDual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups.MethodsThe TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed.ResultsData from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study.ConclusionsThe three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

AQbD-guided stability indicating HPLC method for azelnidipine and chlorthalidone fixed-dose combination tablet: a green approach

This study developed a stability-indicating RP-HPLC method for quantifying azelnidipine and chlorthalidone in fixed-dose formulations using Analytical Quality by Design (AQbD) principles. A Plackett-Burman design was used for factor screening, followed by risk assessment and optimization using a central composite design to evaluate the effects of the organic phase percentage, flow rate, and modifier concentration. Acetonitrile percentage was identified as the most critical factor. The optimized method employed a Reliant™ C18 Waters column with a mobile phase of 0.1% formic acid and acetonitrile (62:38% v/v), with chlorthalidone and azelnidipine eluting at 4.1 and 13.7 minutes, respectively. Validation showed the method's robustness, accuracy, and precision. Forced degradation studies confirmed its reliability for tablet formulation analysis, and an Analytical Greenness score of 0.55 highlighted its environmental sustainability. This method is efficient, simple, and well-suited for routine quality control in the pharmaceutical industry.

Severe Combined Kidney Injury in an Hiv-Infected Patient Receiving Antiretroviral Therapy (Clinical Observation)

Kidney injury in patients infected with the human immunodeficiency virus (HIV) has a diverse spectrum. Some antiretroviral therapy (ART) drugs have nephrotoxic effects. We present a clinical case of severe combined kidney injury — chronic kidney disease (CKD) and acute kidney disease (AKD) — in a patient with HIV infection. She was on long-term treatment with a fixed-dose combination of rilpivirine, tenofovir, and emtricitabine and had normal pre-treatment renal function (estimated glomerular filtration rate 69 mL/min/1.73m2 ). There was gradual increase in blood creatinine, but the patient did not visit a nephrologist and the ART was not changed. The patient was admitted to the nephrology department two years later because she had arterial hypertension and hyperazotemia (blood creatinine 718 μmol/l). Diagnosis: chronic tubulointerstitial nephritis, CKD G5 taking into account the gradual increase in blood creatinine during long-term ART. The patient was treated with peritoneal dialysis. There was persistent decrease and stabilization of blood creatinine (210-190 μmol/l was) which indicated in AKD. The presented observation demonstrates that ART in an HIVinfected patient can lead to the development of severe combined chronic and acute kidney injury. HIV-infected patients receiving ART require regular monitoring of renal function and follow-up by a nephrologist.