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.

Effects of Dose Titration on Dipyridamole-Induced Headache: A Randomized, Double-Blind Clinical Trial

<b><i>Purpose:</i></b> The aim of this study is to investigate the effect of gradual dipyridamole titration and the incidence of dipyridamole-induced headache in patients with ischemic stroke or transient ischemic attack (TIA). <b><i>Methods:</i></b> A randomized, double-blind, double-placebo, parallel group, phase 4 clinical trial (KCT0005457) was conducted between July 1, 2019, and February 25, 2020, at 15 medical centers in South Korea. The study included patients aged &#x3e;19 years diagnosed with a noncardioembolic ischemic stroke or TIA within the previous 3 weeks. The participants were randomized 1:1:1 to receive Adinox® (aspirin 25 mg/dipyridamole 200 mg) and aspirin (100 mg) once daily for the first 2 weeks followed by Adinox® twice daily for 2 weeks (titration group), Adinox® twice daily for 4 weeks (standard group), and aspirin 100 mg once daily for 4 weeks (control group). The primary endpoint was incidence of headache over 4 weeks. The key secondary endpoint was mean cumulative headache. <b><i>Results:</i></b> Ninety-six patients were randomized into the titration (<i>n</i> = 31), standard (<i>n</i> = 32), and control (<i>n</i> = 33) groups. The titration and standard groups (74.1% vs. 74.2%, respectively) showed no difference in the primary endpoint. However, the mean cumulated headache was significantly lower in the titration group than in the standard group (0.31 ± 0.46 vs. 0.58 ± 0.51, <i>p</i> = 0.023). Further, adverse drug reactions were more common in the standard group than in the titration group (28.1% vs. 9.7%, respectively, <i>p</i> = 0.054), although not significantly different. <b><i>Conclusion:</i></b> The titration strategy was effective in lowering the incidence of cumulative dipyridamole-induced headache.

Anticoagulants after Discharge in Patients with COVID-19: What we Know at the End of 2021

This review discusses reasons for prolonged use of anticoagulants after discharge of patients with COVID-19 without additional indication for anticoagulation. Data regarding rate of thrombotic and thromboembolic complications in patients with COVID-19 after discharge from the hospital are presented. Large randomized controlled trials EXCLAIM, ADOPT, MAGELLAN, APEX and MARINER with prolonged use of anticoagulants in patients hospitalized with acute nonsurgical diseases before pandemia of COVID-19 are discussed. The first prospective randomized controlled trial MICHELLE with direct oral anticoagulant rivaroxaban in a dose 10 mg once daily after discharge of patients with COVID-19 with high risk at least venous thromboembolism are analyzed. It seems that the most relevant approach for the determination of indications for prolonged use of anticoagulants in doses dedicated for primary prevention of venous thromboembolism after discharge of patients with COVID-19 without apparent indication for anticoagulation is a modified IMPROVE VTE risk score with the addition of elevated in-hospital D-dimer level. And the most well-studied approach for anticoagulation in these patients is a direct peroral anticoagulant rivaroxaban 10 mg once daily for 35 (and possibly up to 45) days after discharge.

Case report: Medical cannabis—warfarin drug-drug interaction

Aim A case of an 85-year-old patient with concurrent use of warfarin and medical cannabis containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is described. Warfarin continues to be a cornerstone of anticoagulation treatment despite the recent addition of FDA-approved anticoagulant agents. It is well known that warfarin has numerous drug interactions; however, much remains unknown about its interaction with THC and CBD. A literature review was conducted to identify documented cases of possible interactions between cannabis and warfarin. The case reports we identified noted that cannabis may potentially increase warfarin’s effect. Therefore, we aimed to determine why an effect was not seen on our patient’s warfarin dose despite daily use of medical cannabis. Case This case report describes an 85-year-old patient who despite starting an oromucosal medical cannabis regimen of THC and CBD (which provided 0.3 mg of THC and 5.3 mg CBD once daily and an additional 0.625 mg of THC and 0.625 mg CBD once daily as needed) had minimal INR fluctuations from October 2018 to September 2019. Conclusion Despite the introduction and use of medical cannabis therapy, with both THC and CBD components, an elderly patient with concurrent warfarin use did not see major INR fluctuations, in contrast to published literature. The potential for warfarin and THC/CBD interactions may be dependent on route of administration and dose of the cannabis product.

Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration NCT03276858, registered September 8, 2017, retrospectively registered.

A Comparison between Type-2 Diabetics and Non-Diabetics in Terms of Papillary Bleeding Index (PBI)

OBJECTIVES: The purpose of this study was to compare the Type 2 diabetes mellitus patients and non-diabetics in terms of Papillary bleeding index (PBI) of periodontal disease. METHODOLOGY: This comparative cross-sectional study was conducted during the period of November 2020 to February 2021 in three (3) tertiary care hospitals of Peshawar. The sampling technique was purposive sampling. The sample comprised 105 individuals, 56 participants in Type–2 diabetes group and 49 in non-diabetes group. Male and females, having age between 40-65 years were recruited. Each diabetic and non-diabetic were clinically examined for periodontitis. Age and sex-matched participants suffering from periodontitis without a history of diabetes as well as with good glycemic control (HbA1c) were considered as controls subjects. Glycated hemoglobulin (HbA1c) was carried out for all the participants free of cost by using Human Gmbh-Max-Planck-Ring 21-65205 Wiesbaden-Germany kit. The study was approved by the ethical committee of the Peshawar Medical College. Data was analyzed using software package SPSS version 20. RESULTS: Out of 56 diabetics, 24 subjects brushed once daily, 15 brushed twice daily, 11 brushed occasionally and 6 didn’t brush whereas in 49 non diabetics, 20 subjects brushed once daily, 13 brushed twice daily, 11 brushed occasionally and 5 didn’t brush. The clinical parameter mean (PBI) was recorded in our study. Score was 2.09 (±0.82) in diabetics and 1.02 (±0.47) in non-diabetics. P-value measured by the chi square test was significant. Spearman correlation test was performed to explore the association between the type 2 diabetes and Papillary bleeding index (PBI). CONCLUSION: We concluded that a significant difference exists between the mean PBI scores of Type 2 diabetics and non-diabetics.

Phase Ib Study of the Histone Deacetylase 6 Inhibitor Citarinostat in Combination With Paclitaxel in Patients With Advanced Solid Tumors

BackgroundCitarinostat (CC-96241; previously ACY-241), an oral inhibitor of histone deacetylases (HDACs) with selectivity for HDAC6, has demonstrated synergistic anticancer activity with paclitaxel in multiple solid tumor models. Combination therapy using citarinostat with paclitaxel was evaluated in this phase Ib 3 + 3 dose-escalation study in patients with advanced solid tumors.MethodsPatients with previously treated advanced solid tumors received citarinostat 180, 360, or 480 mg once daily on days 1 to 21 plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was determination of the maximum tolerated dose (MTD). Secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics.ResultsTwenty patients were enrolled and received study treatment; 15 had received prior taxane therapy. No dose-limiting toxicities were reported at any dose; therefore, the MTD was not identified. Citarinostat 360 vs 480 mg was associated with reduced incidence and severity of neutropenia. Three patients experienced a confirmed partial response and 13 achieved stable disease. Pharmacokinetic parameters were linear up to citarinostat 360 mg, the dose at which the highest levels of histone and tubulin acetylation were observed in peripheral blood mononuclear cells.ConclusionsThe combination of citarinostat plus paclitaxel showed an acceptable safety profile, with no unexpected or dose-limiting toxicities and potential evidence of antitumor activity in patients with heavily pretreated advanced solid tumors. Citarinostat 360 mg once daily is considered the recommended phase II dose for use in combination with paclitaxel 80 mg/m2 every 3 of 4 weeks. This trial is registered on ClinicalTrials.gov (NCT02551185).

Radiation and Systemic Therapy for Limited-Stage Small-Cell Lung Cancer

Progress in the overall treatment of small-cell lung cancer (SCLC) has moved at a slower pace than non–small-cell lung cancer. In fact, the standard treatment regimen for limited stage SCLC has not appreciably shifted in more than 20 years, consisting of four to six cycles of cisplatin and etoposide chemotherapy concurrent with thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI) for responsive disease. Nevertheless, long-term outcomes have improved with median survival approaching 25-30 months, and approximately one third of patients now survive 5 years. This is likely attributable in part to improvements in staging, including use of brain magnetic resonance imaging and fluorodeoxyglucose–positron emission tomography imaging, advances in radiation treatment planning, and supportive care. The CONVERT and CALGB 30610 phase III trials failed to demonstrate a survival advantage for high-dose, once-daily TRT compared with standard 45 Gy twice-daily TRT, although high-dose, once-daily TRT remains common in practice. A phase III comparison of high-dose 60 Gy twice-daily TRT versus 45 Gy twice-daily TRT aims to confirm the provocative outcomes reported with 60 Gy twice daily in the phase II setting. Efforts over time have shifted from intensifying PCI, to attempting to reduce treatment-related neurotoxicity, to more recently questioning whether careful magnetic resonance imaging surveillance may obviate the routine need for PCI. The addition of immunotherapy has resulted in mixed success in extensive-stage SCLC with modest benefit observed with programmed death-ligand 1 inhibitors, and several ongoing trials assess programmed death-ligand 1 inhibition concurrent or adjuvant to chemoradiotherapy in limited-stage SCLC. Major advances in future treatment will likely depend on a better understanding and exploiting of molecular characteristics of SCLC with increasing personalization of therapy.