A promising choice in hypertension treatment:Fixed-dose combinations

Obtaining the target blood pressure level by monotherapy can be challenging currently,especially for the patients who are suffering from other diseases meanwhile.It is demonstrated that a majority of hypertensive patients need two or more antihypertensive drugs to lower their blood pressure effectively.Consequently,fixed-dose which can be defined as that several active agents were combined in single pharmaceutical formulations appears to be a novel and underlying power in overcoming the cardiovascular disease.Based on the analysis of some literature and relative data from FDA,the advantages of fixed-dose combination are elucidated and formulations of common dual,triple-combinations were summarized.Clinical practices proved that fixed-dose combinations had many benefits comparing with single drug and separate agents in terms of effects,convenience,compliance,and costs to a certain extent.From the patients’perspective,the fixed-dose combination therapy will be increasingly utilized in blood pressure control in the future.

Hematologic toxicity of gemcitabine: a comparison between fixed-dose rate infusion and thirty-minute infusion in the treatment of malignancy

Objective： The aim of the study was to compare the hematologic toxicity of gemcitabine between fixed-dose rate （FDR） infusion and 30-minute standard infusion in the treatment of malignancy. Methods： The 25 malignancy patients confirmed by histopathology or cytology received single-agent gemcitabine or gemcitabine in combination with other chemo- therapeutic agents. These patients were randomly divided into gemcitabine 1000 mg/m2 on dl, d8 at a rate of 10 mg/m2/min arm （FDR arm） or 30 rain arm （standard arm）, every 21 days one cycle. Hematologic toxicity was evaluated at the end of each cycle. Results： The 13 of 25 patients received gemcitabine FDR therapy, a total of 28 cycles was completed, and 32 cycles in the others （12 of 25 patients） with the standard arm. All patients were evaluable for hematologic toxicity. The result showed that the grades 3-4 leucopenia was significantly different between the two arms （14.3% vs 0, P 〈 0.05）, and no significant differences of neutropenia, thrombocytopenia and hemoglobin suppression of grades 3-4 （14.3% vs 3.1%, 10.7% vs 3.1%, 3.6% vs 9.4%, P 〉 0.05, respectively） were observed between the two arms, no grade 4 of hemoglobin suppression was observed. Conclusion： Hematologic toxicity of gemcitabine therapy at a fixed-dose rate for malignancy is tolerable.

Gaps and feasibility of fixed-dose combination strategy in the development of modern Chinese medicine

isTraditional Chinese medicine(TCM)is a highly complex chemical substance system,which not only reflected in the complexity of the chemical components and their interrelationships,but also in the intricacy of the prescription’s connection with the human body.Component compatibility strategy has been proposed for developing modern TCM since 2005 and established comprehensive relevant technologies and research approaches.Moreover,to meet the safety and efficacy of current pharmaceuticals,research on fixed-dose combination drugs is directed by modern scientific theories,conforms to TCM compatibility principles and clarifies material basis and pharmacological mechanisms and component-effect correlations.This review summarized gaps and feasibility of fixed-dose combination strategy in the development of modern TCM research and assessed their advantages and disadvantages in light of contemporary drug combination research practices.

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Background：Decreases in the bioavailability of rifampicin （RFP） can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination （FDC; formulation A） and three two-drug FDCs （formulations B,C,and D） used in China,compared with RFP in free combinations of these drugs （reference）,in healthy volunteers.Methods：Eighteen and twenty healthy Chinese male volunteers participated in two open-label,randomized two-period crossover （formulations A and C） or one three-period crossover （formulations B and D） study,respectively.The washout period between treatments was 7 days.Bioequivalence was assessed based on 90％ confidence intervals,according to two one-sided t-tests.All analyses were done with DAS 3.1.5 （Mathematical Pharmacology Professional Committee of China,Shanghai,China）.Results：Mean pharmacokinetic parameter values of RFP obtained for formulations A,B,C,and D products were 11.42 ± 3.41 μg/ml,7.86 ± 5.78 μg/ml,13.05 ± 6.80 μg/ml,and 16.18 ± 3.87 μg/ml,respectively,for peak plasma concentration （Cmax）,91.43± 30.82 μg·h-1 ·ml-1,55.49 ± 37.58 μg·h-1·ml-1,96.50 ± 47.24 μg·h-1·ml-1,101.47 ± 33.07 μg·h-1·ml-1,respectively,for area under the concentration-time curve （AUC0-2,4 h）.Conclusions：Although the concentrations of RFP for formulations A,C,and D were within the reported acceptable therapeutic range,only formulation A was bioequivalent to the reference product.The three two-drug FDCs （formulations B,C and D） displayed inferior RFP bioavailability compared with the reference （Chinese Clinical Trials registration number：ChiCTR-TTRCC-12002451）.

Fabrication of Electrospun Levodopa-Carbidopa Fixed-Dose Combinations

Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2].Non-adherence is a serious problem linked to worsening symptoms and increased motor fluc-tuations[3-5].Levodopa(LD)remains the most effective treatment for PD[6].However,a single dosing treatment is only effective in the early phase of the disease.In the severe phase,4-5 years after diagnosis,the therapeutic window of dopamine becomes narrow,and due to its short half-life of between 0.7 and 1.4 h dosing of LD will be required every 2 h[7-9].One way to ameliorate this issue is to co-admin-ister LD with carbidopa(CD),which can increase LD’s oral bioavailability to 40-70%[10].

Fixed Dose Rate versus Standard Dose Rate Infusion of Gemcitabine and Cisplatin in Advanced Stage Non-Small Cell Lung Cancer

Background: Comparing the efficacy and safety of gemcitabine at a fixed-dose rate (FDR) infusion (10 mg/m2/min) with the standard dose rate infusion in patients with locally advanced and metastatic non-small squamous cell carcinoma (NSCLC). Methods: The study randomized 60 patients with confirmed diagnosis of NSCLC to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 given as a 30-min infusion (Arm A) or at a rate of 10 mg/m2/min (Arm B). Cisplatin 75 mg/m2 was administered intravenously on day 2 in both arms. Results: No difference in overall response rate (46.6% versus 43.3%). Median time to progression for Arm A was 7 months (95% CI, 6.207 - 7.793 months), versus 6 months for Arm B (95% CI, 4.990 - 7.010 months). Median survival time was comparable [12 months (95% CI, 8.588 - 15.412 months) versus 11 months (95% CI, 9.066 - 12.934 months)] respectively. Two-year survival (18% versus 11%, p = 0.38) was detected. No treatment related deaths occurred. Main hematological toxicities were grade I and II neutropenia, in 36.7% and 53.3% respectively (p = 0.044). Grade III anemia was observed in 10% and 6.7% in both arms respectively (p = 0.024). Grade I and II nausea and vomiting was observed in 50% and 46.7%. Conclusions: FDR gemcitabine in combination with cisplatin had equivalent efficacy and more severe hematologic toxicities compared to the standard 30-min gemcitabine infusion with cisplatin in patients with advanced NSCLC.

Desimplification to multi-tablet antiretroviral regimens in human immunodeficiency virus-type 1 infected adults: A cohort study

BACKGROUND Highly active antiretroviral therapy (HAART) is provided free of charge to all human immunodeficiency virus (HIV) positive residents in Italy. As fixed dose coformulations (FDCs) are often more expensive in comparison to the same drugs administered separately in a multi-tablet regimen (MTR), we considered a costeffective strategy involving patients in the switch from their FDCs to corresponding MTRs including generic antiretrovirals. AIM To verify if this would affect the virological and immunological response in comparison to maintaining the FDC regimens. METHODS From January 2012 to December 2013, we assessed the eligibility of all the HIV-1 positive adults on stable HAART being treated at our hospital-based outpatient clinic in Treviso, Italy. Participants who accepted to switch from their FDC regimen to the corresponding MTR joined the MTR group, while those who maintained a FDC regimen joined the FDC group. Clinical data, including changes in HAART regimens, respective reasons why and adverse effects, were recorded at baseline and at follow-up visits occurring at weeks 24, 48 and 96. All participants were assessed for virological and immunological responses at baseline and at weeks 24, 48 and 96. RESULTS Two hundred and forty-three eligible HIV-1 adults on HAART were enrolled: 163 (67%) accepted to switch to a MTR, joining the MTR group, while 80 (33%) maintained their FDCs, joining the FDC group. In a parallel analysis, there were no significant differences in linear trend of distribution of HIV-RNA levels between the two groups and there were no significant odds in favour of a higher level of HIV-RNA in either group at any follow-up and on the overall three strata analysis. In a before-after analysis, both FDC and MTR groups presented no significant differences in distribution of HIV-RNA levels at either weeks 48 vs 24 and weeks 96 vs 24 cross tabulations. A steady increase of mean CD4 count was observed in the MTR group only, while in the FDC group we observed a slight decrease (-23 cells per mmc) between weeks 24 and 48. CONCLUSION Involving patients in the switch from their FDC regimens to the corresponding MTRs for economic reasons did not affect the effectiveness of antiretroviral therapy in terms of virological response and immunological recovery.

Evaluation of the Influence of Hyoscine Butylbromide on the Oral Bioavailability of Lansoprazole in Healthy Adult Volunteers

The gastroesophageal reflux and/or peptic ulcer diseases are clinical conditions that occur usually accompanied of symptomatic pain. Lansoprazole, a proton pump inhibitor class drug is widely used in clinical practice for treatment of these diseases. However, its efficacy can be improved by combining with spasmolytic and/or visceral analgesic such as hyoscine butylbromide. Since hyoscine butylbromide is barely absorbed and exerts some local effects at gastrointestinal tract which may modify the absorption of lansoprazole, it is important to establish if there is a pharmacokinetic interaction after the oral concomitant administration of both drugs. For this objective, twenty-five subjects received under a crossover design an oral administration of lansoprazole (15 mg) plus placebo or a fixed-dose combination with hyoscine butiylbromide (15 mg + 10 mg, respectively). Plasma samples were obtained at different times during 10 hours. Lansoprazole plasma concentrations were determined by a high performance liquid chromatography method coupled to tandem mass spectrometry. Fixed-dose combination was well tolerated. Lansoprazole pharmacokinetic parameters were: Cmax 621.81 ± 212.79 and 450.38 ± 192.14 ng/mL;AUC0-t 1941.36 ± 845.57 and 1454.66 ± 757.28 ng·h/mL;tmax 2.83 ± 0.99 and 3.40 ± 1.82h;t1/2 1.35 ± 0.39 and 1.45 ± 0.51 h, for alone and combined fixed-dose formulation, respectively. Pharmacokinetic parameters were compared by analysis of variance and ratios of AUC0-t, Cmax and 90% confidence intervals obtained. Since confidence intervals exceed the 80% - 125% limits for these parameters, we conclude that there is a significantly pharmacokinetic interaction of lansoprazole when it is administered concomitantly with hyoscine butylbromide.

Observational Study of a Multi-Active Ingredient Over-the-Counter Cold Remedy Following Active Pharmacist Recommendation

Real-world user satisfaction with a fixed dose combination over-the-counter cold remedy (Vicks Symptomed Complete Cytrynowy hot drink;VSCC) was evaluated in a prospective, non-comparative, observational study involving 176 pharmacies in Poland from February to April 2015. 1391 participants completed a questionnaire in the pharmacy and several paper questionnaires at home following use of the product at their own discretion. Participants returned their completed questionnaires to the pharmacy. 1356 participants were included in the intent-to-treat analysis. Participants highly valued the advice from their pharmacist (97%, P < 0.0001, important vs. not important) and thought the quality of that advice was good (93%, P < 0.0001, good/very good vs. very bad-fair). 96% of participants found VSCC to be effective in some way against their cold symptoms (P < 0.0001, effective vs. not effective) and 68% of them stated that it was better than any other cold therapy they had used before (P < 0.0001, better/best vs. same/worse). Adverse event reporting was very low.

Assessment of the availability and rationality of unregistered fixed dose drug combinations in Nepal:a multicenter crosssectional study

Background:The medications that are registered and available in a country are meant for the prevention and treatment of ailments and diseases.However,a lack of effective regulatory bodies and operative control mechanisms,especially in developing countries,promotes irrational and inappropriate use of medicines.This study aims to evaluate the availability and rationality of unregistered fixed-dose drug combinations(FDCs)in Nepal.Methods:A snowball sampling method with visits to 20 retail pharmacies in each of five major cities in Nepal was used to assess the availability of unregistered FDCs.To justify the rationality of the FDCs obtained from these five cities,the toolkit developed by Health Action International Asia-Pacific(HAI-AP)was used.Results:Altogether,41 unregistered FDCs were obtained from the five cities.Among the total 41 FDCs,a majority were anti-inflammatory/analgesic/antipyretics.A maximum of eight drugs and a minimum of two drugs per combination were present among the total 41 FDCs,with a majority in the form of tablets followed by suspensions.The cost ranges from a minimum of 3.7 Nepalese Rupees(NRs)(=USD 0.05)to a maximum of 240 NRs(=USD 3.15).None of the FDCs fulfilled all the fundamental requirements as stated in the toolkit;thus,they were categorized as‘irrational’.Conclusions:Unregistered FDCs are available in the Nepalese pharmaceutical market.All the unregistered FDCs found in our study were‘irrational’as per the HAI-AP toolkit.Regulatory authorities should initiate strict monitoring and appropriate regulatory mechanisms to prohibit the use of unregistered and irrational FDCs.