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Displaying publications 301 - 307 of 307 in total

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Alpha-tomatine synergises with paclitaxel to enhance apoptosis of androgen-independent human prostate cancer PC-3 cells in vitro and in vivo

Lee ST, Wong PF, Hooper JD, Mustafa MR

Phytomedicine, 2013 Nov 15;20(14):1297-305.
PMID: 23920276 DOI: 10.1016/j.phymed.2013.07.002

Alpha (α)-tomatine, a major saponin found in tomato has been shown to inhibit the growth of androgen-independent prostate cancer PC-3 cells. The effects of α-tomatine in combination with the chemotherapeutic agent paclitaxel against PC-3 cells were investigated in the present study. Combined treatment with a sub-toxic dose of α-tomatine and paclitaxel significantly decreased cell viability with concomitant increase in the percentage of apoptotic PC-3 cells. The combined treatment, however, had no cytotoxic effect on the non-neoplastic prostate RWPE-1 cells. Apoptosis of PC-3 cells was accompanied by the inhibition of PI3K/Akt pro-survival signaling, an increase in the expression of the pro-apoptotic protein BAD but a decrease in the expressions of anti-apoptotic proteins, Bcl-2 and Bcl-xL. Results from a mouse xenograft model showed the combined treatment completely suppressed subcutaneous tumor growth without significant side effects. Consistent with its in vitro anti-cancer effects, tumor materials from mice showed increased apoptosis of tumor cells with reduced protein expression of activated PI3K/Akt. These results suggest that the synergistic anti-cancer effects of paclitaxel and α-tomatine may be beneficial for refractory prostate cancer treatment.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Boceprevir early-access for advanced-fibrosis/cirrhosis in Asia-Pacific hepatitis C virus genotype 1 non-responders/relapsers

Sukeepaisarnjaroen W, Pham T, Tanwandee T, Nazareth S, Galhenage S, Mollison L, et al.

World J Gastroenterol, 2015 Jul 28;21(28):8660-9.
PMID: 26229408 DOI: 10.3748/wjg.v21.i28.8660

To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia.

Matched MeSH terms: Drug Therapy, Combination
Body composition and metabolic outcomes after 96 weeks of treatment with ritonavir-boosted lopinavir plus either nucleoside or nucleotide reverse transcriptase inhibitors or raltegravir in patients with HIV with virological failure of a standard first-line antiretroviral therapy regimen: a substudy of the randomised, open-label, non-inferiority SECOND-LINE study

Boyd MA, Amin J, Mallon PW, Kumarasamy N, Lombaard J, Wood R, et al.

Lancet HIV, 2017 01;4(1):e13-e20.
PMID: 27815068 DOI: 10.1016/S2352-3018(16)30189-8

BACKGROUND: Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir.
METHODS: Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122.
FINDINGS: Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10).
INTERPRETATION: Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen.
FUNDING: The Kirby Institute and the Australian National Health and Medical Research Council.

Matched MeSH terms: Drug Therapy, Combination
A molecular approach in drug development for Alzheimer's disease

Agatonovic-Kustrin S, Kettle C, Morton DW

Biomed Pharmacother, 2018 Oct;106:553-565.
PMID: 29990843 DOI: 10.1016/j.biopha.2018.06.147

An increase in dementia numbers and global trends in population aging across the world prompts the need for new medications to treat the complex biological dysfunctions, such as neurodegeneration associated with dementia. Alzheimer's disease (AD) is the most common form of dementia. Cholinergic signaling, which is important in cognition, is slowly lost in AD, so the first line therapy is to treat symptoms with acetylcholinesterase inhibitors to increase levels of acetylcholine. Out of five available FDA-approved AD medications, donepezil, galantamine and rivastigmine are cholinesterase inhibitors while memantine, a N-methyl d-aspartate (NMDA) receptor antagonist, blocks the effects of high glutamate levels. The fifth medication consists of a combination of donepezil and memantine. Although these medications can reduce and temporarily slow down the symptoms of AD, they cannot stop the damage to the brain from progressing. For a superior therapeutic effect, multi-target drugs are required. Thus, a Multi-Target-Directed Ligand (MTDL) strategy has received more attention by scientists who are attempting to develop hybrid molecules that simultaneously modulate multiple biological targets. This review highlights recent examples of the MTDL approach and fragment based strategy in the rational design of new potential AD medications.

Matched MeSH terms: Drug Therapy, Combination
Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial

Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, et al.

Lancet, 2018 01 20;391(10117):205-218.
PMID: 29132879 DOI: 10.1016/S0140-6736(17)32458-3

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.

METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.

FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).

INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.

FUNDING: Bayer AG.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial

Andrieux-Meyer I, Tan SS, Thanprasertsuk S, Salvadori N, Menétrey C, Simon F, et al.

Lancet Gastroenterol Hepatol, 2021 Jun;6(6):448-458.
PMID: 33865507 DOI: 10.1016/S2468-1253(21)00031-5

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV.
METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183.
FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment.
INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality.
FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Matched MeSH terms: Drug Therapy, Combination
Fulltext Rationale, Design, and Baseline Characteristics of the EPICOR Asia Study (Long-tErm follow-uP of antithrombotic management patterns In Acute CORonary Syndrome patients in Asia)

Huo Y, Lee SW, Sawhney JP, Kim HS, Krittayaphong R, Nhan VT, et al.

Clin Cardiol, 2015 Sep;38(9):511-9.
PMID: 26206158 DOI: 10.1002/clc.22431

BACKGROUND: In-hospital and postdischarge mortality for acute coronary syndromes (ACS) vary across Asia and remain generally poorer than globally. The relationship between real-life antithrombotic management patterns (AMPs) and ACS-related outcomes in Asia is unclear.
METHODS: EPICOR Asia (Long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients in Asia) (NCT01361386) is a prospective, multinational, observational study of patients discharged after hospitalization for an ACS, with 2-year follow-up. The aim is to describe short- and long-term (up to 2 years post-index event) AMPs in patients hospitalized for ACS and to record clinical outcomes, healthcare resource use, and self-reported health status. Pre- and in-hospital management, AMPs, and associated outcomes, with particular focus on ischemic and bleeding events, will be recorded during the 2-year follow up.
RESULTS: Between June 2011 and May 2012, 13 005 patients were enrolled. From these, 12 922 patients surviving an ACS (6616 with STEMI, 2570 with NSTEMI, and 3736 with UA) were eligible for inclusion from 219 hospitals across 8 countries and regions in Asia: China (n = 8214), Hong Kong (n = 177), India (n = 2468), Malaysia (n = 100), Singapore (n = 93), South Korea (n = 705), Thailand (n = 957), and Vietnam (n = 208).
CONCLUSIONS: EPICOR Asia will provide information regarding clinical management and AMPs for ACS patients in Asia. Impact of AMPs on clinical outcomes, healthcare resource use, and self-reported health status both during hospitalization and up to 2 years after discharge will also be described.

Matched MeSH terms: Drug Therapy, Combination