Raltegravir 1200 mg once daily as maintenance therapy in virologically suppressed HIV-1 infected adults: QDISS open-label trial

Background Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. Methods The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm. Results Of 100 participants 91% maintained viral suppression (95% CI: 83.6–95.8) at week 24 and 89% (81.2–94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3–4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007). Conclusion RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes. Trial registration: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.

Cyclodextrins-in-Liposomes: A Promising Delivery System for Lippia sidoides and Syzygium aromaticum Essential Oils

Biological activity of essential oils (EOs) has been extensively reported; however, their low aqueous solubility, high photosensitivity, and volatility compromise a broad industrial use of these compounds. To overcome these limitations, we proposed a nanoencapsulation approach to protect EOs, that aims to increase their stability and modulate their release profile. In this study, drug-in-cyclodextrin-in-liposomes encapsulating two essential oils (Lippia sidoides and Syzygium aromaticum) and their respective major compounds (thymol and eugenol) were produced by ethanol injection and freeze-dried to form proliposomes and further physicochemically characterized. Liposomes showed high physical stability over one month of storage at 4 °C, with slight changes in the mean size, polydispersity index (PDI), and zeta potential. Reconstituted proliposomes showed a mean size between 350 and 3300 nm, PDI from 0.29 to 0.41, and zeta potential between −22 and −26 mV. Differential scanning calorimetry and X-ray diffraction of proliposomes revealed a less-ordered crystalline structure, leading to high retention of the major bioactive compounds (between 73% and 93% for eugenol, and 74% and 84% for thymol). This work highlights the advantages of using drug-in-cyclodextrin-in-liposomes as delivery systems to retain volatile compounds, increasing their physicochemical stability and their promising potential to be utilized as carriers in products in the pharmaceutical, food, and cosmetic industries.

Antipyretic, Analgesic and Anti-inflammatory Activity of Qurs Afsanteen Saghir (A Polyherbal Unani Tablet) in Experimental Animals

Qurs Afsanteen Saghir is a polyherbal Unani formulation in the form of tablet. This formulation consists of multiple medicinal plants like Afsanteen (Artemisia absinthium L.), Badam Talkh (Prunus dulcis (Mill.) D.A.Webb), Asaroon (Asarum europaeum L.), Anisoon (Pimpinella anisum L.) and Tukhm-e-Karafs (Apium graveolens L.). The clinical adult dose of study drug is 3.5 –7 g per day as mentioned in Unani literature. The present study evaluated the antipyretic, analgesic and anti-inflammatory potential of Qurs Afsanteen Saghir using different animal models. Antipyretic activity was measured using yeast-induced pyrexia model in rats at 360 and 720 mg/kg bw dose of test drug and paracetamol (70 mg/kg bw p.o.) as standard control. Analgesic effect was evaluated using acetic acid-induced writhing test in mice using test drug at dose 720 and 1440 mg/kg bw and diclofenac sodium (15 mg/kg bw p.o.) as standard control. Eddy’s hot plate test was conducted in rats using test drug at the dose of 360 and 720 mg/kg bw and buprenorphine (0.10 mg/kg s.q.) as standard control. Anti-inflammatory activity was assessed by carrageenan-induced paw edema model in rats with the dose of 360 and 720 mg/kg of test drug and Indomethacin (10 mg/kg p.o.) as standard control. The study drug significantly reduced the temperature and pain at both dose levels in a time-dependent manner as compared to normal control. However, the reduction of inflammation was observed at low dose (360 mg/kg bw) only after 3 hours of carrageenan administration. These findings indicated that tested drug showed potential activity as antipyretic and analgesic; whereas the drug may not be considered quite effective as an anti-inflammatory agents.

Frequency and Antimicrobial Susceptibility Pattern of Gram-Negative Bacilli Isolated From Urine Specimens at a Tertiary Care Setting

OBJECTIVES: To find out the frequency and pattern of conventional antibiotic susceptibility of gram-negative bacilli cultured from urine specimens of patients at a tertiary care setting. METHODOLOGY: This study was conducted at the Microbiology Department of Combined Military Hospital Multan from June 2016 to May 2017. The data in this retrospective descriptive study was collected from urine culture records of the Microbiology Department, CMH Multan. Only those urine specimens who revealed positive gram-negative bacilli cultures were included in the study. Drug susceptibility patterns of these isolates were recorded against routinely used antibiotics (e.g. Nitrofurantoin, Imipenem, Sulbactum-cefoperazone, Gentamicin and Ciprofloxacin) and evaluated accordingly. RESULTS: A total of 1703 urine specimens were submitted for culture and antibiotics susceptibility testing during the period of study. A total of 128 specimens showed growth of gram-negative rods. Imipenem (95% sensitivity), Sulbactam- Cefoperazone (88% sensitivity) and Nitrofurantoin (87% sensitivity) were highly effective antibiotics against the cultured gram-negative bacilli in the study. CONCLUSION: This study showed that E. coli is the commonest cause of urinary tract infection (UTIs), followed by Klebsiella and Enterobacter species among gram-negative bacilli in our set up. In-vitro efficacy of Imipenem, Sulbactam- Cefoperazone and Nitrofurantoin was found to be the highest against these gram-negative bacilli as compared to other antimicrobials. On the contrary, in-vitro efficacy of ciprofloxacin and gentamycin was found to be extremely low.

A Prospective Study of Azilsartan Medoxomil in the Treatment of Patients with Essential Hypertension and Type 2 Diabetes in Asia

This phase 4 study evaluated the efficacy and safety of azilsartan medoxomil (AZL-M) in patients with essential hypertension and type 2 diabetes mellitus (T2DM) in Hong Kong, Taiwan, and Thailand. This was a prospective, multicenter, single-arm, open-label study with patients aged 18–75 years with T2DM and essential hypertension and on stable treatment for T2DM. Patients with uncontrolled hypertension were treated with AZL-M 40 mg daily, with the option to uptitrate to 80 mg at 6 weeks. In all, 380 of the 478 patients screened in Hong Kong, Taiwan, and Thailand were enrolled. At week 6, 97 patients (25.5%) were titrated up to AZL-M 80 mg based on BP readings. At 12 weeks, 54.8% of patients reached the blood pressure (BP) goal of <140/85 mm Hg by trough sitting clinic BP (primary endpoint), and 62.8% and 27.0% achieved a BP of <140/90 mm Hg and <130/80 mm Hg, respectively. The efficacy of AZL-M over 12 weeks was also seen in different age and body mass index groups. The incidence of treatment emergent adverse events (TEAEs) was 12.9% before 6 weeks and 16.1% after 6 weeks, and they were mostly mild in severity. The most frequent TEAE was dizziness (4.7%). The incidence of TEAEs leading to study drug discontinuation (4.5%) and drug-related TEAEs (5.0% before 6 weeks; 3.9% after 6 weeks) was low. In patients with essential hypertension and T2DM in Asia, treatment with AZL-M indicated a favorable efficacy and safety profile in achieving target BP.

EFFECT OF COMBINATION OF FRUIT OF BADARA [Ziziphus jujuba (L). Lam] AND PALM JAGGERY IN DYSFUNCTIONAL UTERINE BLEEDING

Dysfunctional uterine bleeding (DUB) is a state of abnormal uterine bleeding. It is a diagnosis of excluding any clinically detectable organic, systemic and iatrogenic cause. Current treatments available have many side effects, including hormonal imbalance. So there exists a lacuna for a safe and effective treatment without side effects for this condition. The present study is an effort to evaluate the combined effect of fruit of Badara [Ziziphus jujuba(L). Lam] with Palm jaggery in Dysfunctional uterine bleeding. The study design is interventional with a sample size of 15 subjects within the age group of 16-50 years. The study drug was administered in 6gm in the morning and the evening before food for 90 days. The following 30 days was follow up period without medication. The effect was assessed on subjective and objective parameters before treatment and on the 31st, 61st, 91st and 121st days. The results were statistically analyzed using Paired t-test and Wilcoxon Signed Rank test. The study drug showed the statistically significant result in DUB as reducing the amount and duration of bleeding, an interval of menstruation, number of clots, pain, fatigue, and increasing the Haemoglobin percentage.

Safety assessment of a new anti-tuberculosis drug in silico and with the participation of healthy volunteers

Relevance. In connection with the increase in the number of cases of multidrug-resistant tuberculosis (MDR-TB), the search for new anti-tuberculosis drugs (ATD) is necessary. The assessment of its effect on the human body outside the aspect of the therapeutic effect is one of the main directions in the development of anti-TB drugs.Aim. Evaluation of the possible toxicity of thiosonide, a new domestic anti-TB drug, combining a consistent study of this side of the drug using a bioinformatics approach and an analysis of the results of a clinical safety study.Methods. The bioinformatic assessment was carried out using web services and models to predict the toxicity of thiosonide. The safety assessment in relation to healthy volunteers was carried out as part of a clinical study according to the protocol: «An open-label study of the pharmacokinetics, safety and tolerability of the drug thiozonide, capsule 100 mg with a single dose of increasing doses by various groups of healthy volunteers.» (2013, Permit No. 187 to conduct a clinical trial dated March 22, 2013, issued by the Ministry of Health of the Russian Federation).Results. Potential unwanted targets were identified, the predicted activity value for which was greater than 7. The results obtained indicate the likelihood of the effect of thiosonide on these protein targets and, possibly, the ability of the latter to cause side effects associated with changes in the activity of these molecules. The cytotoxic and carcinogenic effect of thiosonide is not predicted. During a clinical study, the drug thiosonide showed good tolerance and safety, since the identified adverse events did not show a definite or reliable relationship with the study drug. The resolution of all adverse events was complete, and dose escalation did not affect the number, severity of AEs and association with the study drug.Conclusion. The safety analysis of thiosonide demonstrated its good tolerability both during in silico assessment and in a study with the participation of healthy volunteers.

Three-step matching algorithm to enhance between-group comparability and minimize confounding in comparative effectiveness studies

We developed a three-step matching algorithm to enhance the between-group comparability for comparative drug effect studies involving prevalent new-users of the newer study drug versus older comparator drug(s). The three-step matching scheme is to match on: (1) index date of initiating the newer study drug to align the cohort entry time between study groups, (2) medication possession ratio measures that consider prior exposure to all older comparator drugs, and (3) propensity scores estimated from potential confounders. Our approach is illustrated with a comparative cardiovascular safety study of glucagon-like peptide-1 receptor agonist (GLP-1ra) versus sulfonylurea (SU) in type 2 diabetes patients using Taiwan’s National Health Insurance Research Database 2003–2015. 66% of 3195 GLP-1ra users had previously exposed to SU. The between-group comparability was well-achieved after implementing the matching algorithm (i.e., standardized mean difference < 0.2 for all baseline patient characteristics). Compared to SU, the use of GLP-1ra yielded a significantly reduced risk of the primary composite cardiovascular events (hazard ratio [95% confidence interval]: 0.71 [0.54–0.95], p = 0.022). Our matching scheme can enhance the between-group comparability in prevalent new-user cohort designs to minimize time-related bias, improve confounder adjustment, and ensure the reliability and validity of study findings.

Heparin, Enoxaparin, and Mechanical Prophylaxis Utilization Evaluation in DVT Prophylaxis in a Major Teaching Hospital in West of Iran

Background: Considering the high prevalence and risk of Deep Vein Thrombosis (DVT) and pulmonary thromboembolism (PTE) in hospitalized patients and the existence of different prophylaxis methods in these patients, the necessity of evaluating the rational administration of heparin or enoxaparin and mechanical prophylaxis is one of the important priorities. The present study aimed to evaluate the consistency of the Heparin/Enoxaparin administration in comparison to guidelines in patients admitted to Imam Reza Hospital. Methods: In this prospective study drug use evaluation (DUE), 300 hospitalized patients receiving venous thrombosis prophylaxis were enrolled, of which 150 patients were selected from surgical wards and 150 patients from internal wards. The demographic and clinical data of patients were collected using clinical records of them. We used the checklists based on the Geneva System for patients admitted to internal wards and the Caprini Questionnaire for patients in surgical wards to evaluate whether patients had received heparin/enoxaparin prophylaxis and mechanical DVT prevention according to guidelines. Results: In the surgical ward, prophylactic treatment for venous thrombosis was administered in 85 (56.6%) patients admitted to surgical wards in accordance with the clinical guideline and in the internal ward, in 42 (28%) patients, with a significant difference between two sections (P: 0.0001). Mechanical prophylaxis, including compressive socks, was performed in 99 (66%) patients in the surgical ward and in the internal ward only in 56 (37.4%) patients, according to the guideline. Drug prophylaxis was administered in surgical wards in 116 (77.3%) patients and in internal wards, in 79 (52.6%) patients according to the guideline. Conclusion: Intravenous thrombosis prophylaxis, according to the guidelines, is more common in patients admitted to surgical wards than in internal wards. But in both sectors, statistics are far from international standards.

The pharmacokinetic and safety profile of single-dose deferiprone in subjects with sickle cell disease

Patients with sickle cell disease (SCD) who undergo repeated blood transfusions often develop iron overload. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of transfusional iron overload due to thalassemia syndromes and has been recently approved as a treatment for iron overload in adult and pediatric patients with SCD and other anemias. The present study aims to characterize the pharmacokinetic (PK) profile of deferiprone (DFP) in adult subjects with SCD. In this phase I, open-label study, subjects with SCD were administered a single 1500 mg dose of DFP. Blood and urine samples were collected for PK assessments of DFP and its main metabolite, deferiprone 3-O-glucuronide (DFP-G). Eight subjects were enrolled and completed the study. Following drug administration, serum levels of DFP and DFP-G rose to maximum concentrations at 1.0 and 2.8 h post-dose, respectively. The half-lives of DFP and DFP-G were 1.5 and 1.6 h, respectively. The majority of administered drug was metabolized and excreted as DFP-G, with less than 4% excreted unchanged in urine up to 10 h post-dose. Subjects received a safety assessment 7 (± 3) days post-dose. Two subjects reported mild adverse events unrelated to the study drug, and no other safety concerns were reported. The PK profile of DFP in SCD subjects is consistent with previous reports in healthy adult volunteers, suggesting no special dosing adjustments are indicated for this population. These findings provide valuable insight for treating iron overload in patients with SCD, who have limited chelation therapy treatment options (trial registration number: NCT01835496, date of registration: April 19, 2013).