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Utilizing Zebrafish to Identify Anti-(Lymph)Angiogenic Compounds for Cancer Treatment: Promise and Future Challenges

Okuda KS, Lee HM, Velaithan V, Ng MF, Patel V

Microcirculation, 2016 08;23(6):389-405.
PMID: 27177346 DOI: 10.1111/micc.12289

Cancer metastasis which predominantly occurs through blood and lymphatic vessels, is the leading cause of death in cancer patients. Consequently, several anti-angiogenic agents have been approved as therapeutic agents for human cancers such as metastatic renal cell carcinoma. Also, anti-lymphangiogenic drugs such as monoclonal antibodies VGX-100 and IMC-3C5 have undergone phase I clinical trials for advanced and metastatic solid tumors. Although anti-tumor-associated angiogenesis has proven to be a promising therapeutic strategy for human cancers, this approach is fraught with toxicities and development of drug resistance. This emphasizes the need for alternative anti-(lymph)angiogenic drugs. The use of zebrafish has become accepted as an established model for high-throughput screening, vascular biology, and cancer research. Importantly, various zebrafish transgenic lines have now been generated that can readily discriminate different vascular compartments. This now enables detailed in vivo studies that are relevant to both human physiological and tumor (lymph)angiogenesis to be conducted in zebrafish. This review highlights recent advancements in the zebrafish anti-vascular screening platform and showcases promising new anti-(lymph)angiogenic compounds that have been derived from this model. In addition, this review discusses the promises and challenges of the zebrafish model in the context of anti-(lymph)angiogenic compound discovery for cancer treatment.

Matched MeSH terms: Neovascularization, Pathologic/drug therapy
Lipophilic Statin Versus Rosuvastatin (Hydrophilic) Treatment for Heart Failure: a Meta-Analysis and Adjusted Indirect Comparison of Randomised Trials

Bonsu KO, Reidpath DD, Kadirvelu A

Cardiovasc Drugs Ther, 2016 Apr;30(2):177-88.
PMID: 26780905 DOI: 10.1007/s10557-015-6636-z

OBJECTIVES: This study aims to compare lipophilic and hydrophilic statin therapy on clinical outcomes of heart failure (HF) using a systematic review and an adjusted indirect comparison meta-analysis. Outcomes were all-cause mortality, cardiovascular mortality, cardiovascular hospitalization and hospitalization for worsening HF.
METHODS: We conducted a search of PubMed, EMBASE and Cochrane databases until 31st December 2014 for randomized control trials (RCTs) in HF evaluating statins versus placebo. Identified RCTs and their respective abstracted information were grouped according to statin type evaluated and analyzed separately. Outcomes were initially pooled with the Peto's one-step method, producing odd ratios (OR) and 95 % confidence intervals (CI) for each statin type. Using these pooled estimates, we performed adjusted indirect comparisons of lipophilic versus hydrophilic statin for each outcome.
RESULTS: Thirteen studies involving 10,966 patients were identified and analyzed. Lipophilic statins were superior to hydrophilic rosuvastatin regarding all-cause mortality (OR 0 · 50; 95 % CI, 0 · 11-0 · 89; p = 0 · 01), cardiovascular mortality (OR 0 · 61; 0 · 25-0 · 97; p = 0 · 009), and hospitalization for worsening HF (OR 0 · 52; 0 · 21-0 · 83; p = 0 · 0005). However, both statins were comparable with regards to cardiovascular hospitalization [OR 0 · 80 (0 · 31, 1 · 28); p = 0 · 36].
CONCLUSIONS: Lipophilic statin treatment shows significant decreases in all-cause mortality, cardiovascular mortality and hospitalization for worsening HF compared with rosuvastatin treatment. This meta-analysis provides preliminary evidence that lipophilic statins offer better clinical outcomes in HF till data from head to head comparisons are available.

Matched MeSH terms: Heart Failure/drug therapy*
Effects of 1α-Calcidol (Alfacalcidol) on Microvascular Endothelial Function, Arterial Stiffness, and Blood Pressure in Type II Diabetic Nephropathy Patients

Munisamy S, Daud KM, Mokhtar SS, Rasool AH

Microcirculation, 2016 Jan;23(1):53-61.
PMID: 26749451 DOI: 10.1111/micc.12256

To determine the effects of six months alfacalcidol on microvascular endothelial function, arterial stiffness, and BP in DN patients.

Matched MeSH terms: Vitamin D Deficiency/drug therapy
Deactivation of Telomerase Enzyme and Telomere Destabilization by Natural Products: a Potential Target for Cancer Green Therapy

Sasidharan S, Jothy SL, Kavitha N, Chen Y, Kanwar JR

Asian Pac J Cancer Prev, 2015;16(18):8671.
PMID: 26745135
Matched MeSH terms: Neoplasms/drug therapy*
Pre-hospital delays in ischemic stroke patients in a Malaysian tertiary hospital

Al-Dubai SA, Sempeho J, Yadav H, Sahathevan R, Law ZK, Manaf MR

Int J Stroke, 2016 07;11(5):NP58-9.
PMID: 26865155 DOI: 10.1177/1747493016632252
Matched MeSH terms: Stroke/drug therapy*
On-Demand Guided Bone Regeneration with Microbial Protection of Ornamented SPU Scaffold with Bismuth-Doped Single Crystalline Hydroxyapatite: Augmentation and Cartilage Formation

Selvakumar M, Srivastava P, Pawar HS, Francis NK, Das B, Sathishkumar G, et al.

ACS Appl Mater Interfaces, 2016 Feb 17;8(6):4086-100.
PMID: 26799576 DOI: 10.1021/acsami.5b11723

Guided bone regeneration (GBR) scaffolds are futile in many clinical applications due to infection problems. In this work, we fabricated GBR with an anti-infective scaffold by ornamenting 2D single crystalline bismuth-doped nanohydroxyapatite (Bi-nHA) rods onto segmented polyurethane (SPU). Bi-nHA with high aspect ratio was prepared without any templates. Subsequently, it was introduced into an unprecedented synthesized SPU matrix based on dual soft segments (PCL-b-PDMS) of poly(ε-caprolactone) (PCL) and poly(dimethylsiloxane) (PDMS), by an in situ technique followed by electrospinning to fabricate scaffolds. For comparison, undoped pristine nHA rods were also ornamented into it. The enzymatic ring-opening polymerization technique was adapted to synthesize soft segments of PCL-b-PDMS copolymers of SPU. Structure elucidation of the synthesized polymers is done by nuclear magnetic resonance spectroscopy. Sparingly, Bi-nHA ornamented scaffolds exhibit tremendous improvement (155%) in the mechanical properties with excellent antimicrobial activity against various human pathogens. After confirmation of high osteoconductivity, improved biodegradation, and excellent biocompatibility against osteoblast cells (in vitro), the scaffolds were implanted in rabbits by subcutaneous and intraosseous (tibial) sites. Various histological sections reveal the signatures of early cartilage formation, endochondral ossification, and rapid bone healing at 4 weeks of the critical defects filled with ornamented scaffold compared to SPU scaffold. This implies osteogenic potential and ability to provide an adequate biomimetic microenvironment for mineralization for GBR of the scaffolds. Organ toxicity studies further confirm that no tissue architecture abnormalities were observed in hepatic, cardiac, and renal tissue sections. This finding manifests the feasibility of fabricating a mechanically adequate nanofibrous SPU scaffold by a biomimetic strategy and the advantages of Bi-nHA ornamentation in promoting osteoblast phenotype progression with microbial protection (on-demand) for GBR applications.

Matched MeSH terms: Bacterial Infections/drug therapy*
A Comprehensive Review on the Chemotherapeutic Potential of Piceatannol for Cancer Treatment, with Mechanistic Insights

Seyed MA, Jantan I, Bukhari SN, Vijayaraghavan K

J Agric Food Chem, 2016 Feb 3;64(4):725-37.
PMID: 26758628 DOI: 10.1021/acs.jafc.5b05993

Cancer is a diverse class of diseases characterized by uncontrolled cell growth that constitutes the greatest cause of mortality and morbidity worldwide. Despite steady progress, the treatment modalities of cancer are still insufficient. Several new concepts have emerged for therapeutic intervention in malignant diseases with the goal of identifying specific targets and overcoming resistance against current cytotoxic therapies. Many studies have reported the remarkable and significant properties of dietary plant polyphenols such as curcumin, resveratrol, flavopiridol, indirubin, magnolol, piceatannol, parthenolide, epigallocatechin gallate, and cucurbitacin as anticancer agents known for their pleiotropic effects on cancer, immune cells, and inflammation. Piceatannol, an analogue and metabolite of resveratrol, is a natural stilbene commonly found in grape skins and wine. Compared to resveratrol, this molecule exhibits superior bioactivities as an inhibitor of COX-1/2 and the CSN-associated kinase. Piceatannol is thought to be a potent natural compound with many therapeutic effects, such as the prevention of hypercholesterolemia, arrhythmia, atherosclerosis, angiogenesis, and cardiovascular diseases. It also demonstrates vasorelaxation, antioxidant, and anticancer activities. This comprehensive review summarizes the current data regarding the mechanisms of action of piceatannol, its chemopreventive properties, and its possible therapeutic potential against various types of human cancer.

Matched MeSH terms: Neoplasms/drug therapy*
Optimal Antibiotic Dosage for Chronic Kidney Disease Patient: A Pharmacological Manual for Oral Clinicians

Chidambaram R

Recent Pat Antiinfect Drug Discov, 2015;10(2):113-23.
PMID: 26220069

Chronic kidney disease, (CKD) a gradual and inevitable deterioration in renal function, is the disease with the most associations in dentistry. Dosage adjustment is one amongst the vital elements to be familiar with during their oral care. CKD patients take extended duration to filter out medications, therefore dosage must always be tailored under the supervision of nephrologist. The relished benefits from antibiotic could transform as anti-microbial resistance on their abuse and nephrotoxic when contraindicated drugs are encouraged. New patented drug belonging to oxazoliodine group has driven the researchers to handle the emerging AMR. The present communication discusses the pharmacological factors influencing in prescribing the antibiotics for CKD patient from the dentist's point of view. The formulas destined for calculating the optimal dosage of antibiotics have been documented to aid oral physicians.

Matched MeSH terms: Renal Insufficiency, Chronic/drug therapy*
Fulltext Effects of tumour necrosis factor antagonists on insulin sensitivity/resistance in rheumatoid arthritis: a systematic review and meta-analysis

Burska AN, Sakthiswary R, Sattar N

PLoS One, 2015;10(6):e0128889.
PMID: 26110878 DOI: 10.1371/journal.pone.0128889

OBJECTIVE: Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS.
METHODS: We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model.
RESULTS: A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi.
CONCLUSION: There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy.

Matched MeSH terms: Arthritis, Rheumatoid/drug therapy*
Antithrombotic treatment for stroke prevention in atrial fibrillation: The Asian agenda

Chen CH, Chen MC, Gibbs H, Kwon SU, Lo S, On YK, et al.

Int J Cardiol, 2015 Jul 15;191:244-53.
PMID: 25978611 DOI: 10.1016/j.ijcard.2015.03.369

Atrial fibrillation (AF) is the most common heart arrhythmia. Untreated AF incurs a considerable burden of stroke and associated healthcare costs. Asians have AF risk factors similar to Caucasians and a similarly increased risk of AF-related stroke; however, with a vast and rapidly ageing population, Asia bears a disproportionately large disease burden. Urgent action is warranted to avert this potential health crisis. Antithrombotic therapy with oral anticoagulants is the most effective means of preventing stroke in AF and is a particular priority in Asia given the increasing disease burden. However, AF in Asia remains undertreated. Conventional oral anticoagulation with warfarin is problematic in Asia due to suboptimal control and a propensity among Asians to warfarin-induced intracranial haemorrhage. Partly due to concerns about intracranial haemorrhage, there are considerable gaps between AF treatment guidelines and clinical practice in Asia, in particular overuse of antiplatelet agents and underuse of anticoagulants. Compared with warfarin, new direct thrombin inhibitors and Factor Xa inhibitors are non-inferior in preventing stroke and significantly reduce the risk of life-threatening bleeding, particularly intracranial bleeding. These agents may therefore provide an appropriate alternative to warfarin in Asian patients. There is considerable scope to improve stroke prevention in AF in Asia. Key priorities include: early detection of AF and identification of asymptomatic patients; assessment of stroke and bleeding risk for all AF patients; evidence-based pharmacotherapy with direct-acting oral anticoagulant agents or vitamin K antagonists for AF patients at risk of stroke; controlling hypertension; and awareness-raising, education and outreach among both physicians and patients.

Matched MeSH terms: Atrial Fibrillation/drug therapy*
Fulltext Major pathophysiological correlations of rosacea: a complete clinical appraisal

Vemuri RC, Gundamaraju R, Sekaran SD, Manikam R

Int J Med Sci, 2015;12(5):387-96.
PMID: 26005373 DOI: 10.7150/ijms.10608

Rosacea is a characteristic cutaneous disorder with a diverse clinical manifestations ranging from facial vascular hyper-reactivity to sebaceous gland hyperplasia. Many theories on pathophysiology of rosacea were proposed over the past decade, however the pathogenicity is poorly understood.

Matched MeSH terms: Rosacea/drug therapy*
Fulltext Rapamycin and its analogues (rapalogs) for Tuberous Sclerosis Complex-associated tumors: a systematic review on non-randomized studies using meta-analysis

Sasongko TH, Ismail NF, Nik Abdul Malik NM, Zabidi-Hussin ZA

Orphanet J Rare Dis, 2015;10:95.
PMID: 26259610 DOI: 10.1186/s13023-015-0317-7

Rapamycin has gained significant attention for its potential activity in reducing the size of TSC-associated tumors, thus providing alternative to surgery. This study aimed at determining the efficacy of rapamycin and rapalogs for reducing the size of TSC-associated solid tumors in patients with Tuberous Sclerosis Complex (TSC).

Matched MeSH terms: Neoplasms/drug therapy*
Fulltext Identification of putative drug targets for human sperm-egg interaction defect using protein network approach

Sabetian S, Shamsir MS

BMC Syst Biol, 2015;9:37.
PMID: 26187737 DOI: 10.1186/s12918-015-0186-7

Sperm-egg interaction defect is a significant cause of in-vitro fertilization failure for infertile cases. Numerous molecular interactions in the form of protein-protein interactions mediate the sperm-egg membrane interaction process. Recent studies have demonstrated that in addition to experimental techniques, computational methods, namely protein interaction network approach, can address protein-protein interactions between human sperm and egg. Up to now, no drugs have been detected to treat sperm-egg interaction disorder, and the initial step in drug discovery research is finding out essential proteins or drug targets for a biological process. The main purpose of this study is to identify putative drug targets for human sperm-egg interaction deficiency and consider if the detected essential proteins are targets for any known drugs using protein-protein interaction network and ingenuity pathway analysis.

Matched MeSH terms: Infertility/drug therapy*
Fulltext Applications of calixarenes in cancer chemotherapy: facts and perspectives

Yousaf A, Hamid SA, Bunnori NM, Ishola AA

Drug Des Devel Ther, 2015;9:2831-8.
PMID: 26082613 DOI: 10.2147/DDDT.S83213

Research on the therapeutic applications of calixarene derivatives is an emerging area of interest. The anticancer activity of various functionalized calixarenes has been reported by several research groups. Due to their superior geometric shape, calixarenes can accommodate drug molecules by forming inclusion complexes. Controlled release of anticancer drugs by calixarenes might help in targeted chemotherapy. This review summarizes the anticancer potential of the calixarenes and their drug loading properties. The potential use of calixarenes in chemoradiotherapy is also highlighted in brief.

Matched MeSH terms: Neoplasms/drug therapy*
Fulltext Cesarean scar pregnancy: What can we offer?

Ng BK, Lim PS, Ahmad S, Kampan NC, Abdul Karim AK, Omar MH

Taiwan J Obstet Gynecol, 2015 Apr;54(2):208-10.
PMID: 25951734 DOI: 10.1016/j.tjog.2014.11.022
Matched MeSH terms: Pregnancy, Ectopic/drug therapy
Cerebroprotective effects of RAS inhibitors: Beyond their cardio-renal actions

Kalra J, Prakash A, Kumar P, Majeed AB

J Renin Angiotensin Aldosterone Syst, 2015 Sep;16(3):459-68.
PMID: 25944853 DOI: 10.1177/1470320315583582

Work on the brain renin-angiotensin system has been explored by various researchers and has led to elucidation of its basic physiologies and behavior, including its role in reabsorption and uptake of body fluid, blood pressure maintenance with angiotensin II being its prominent effector. Currently, this system has been implicated for its newly established effects, which are far beyond its cardio-renal effects accounting for maintenance of cerebral blood flow and cerebroprotection, seizure, in the etiology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and bipolar disorder. In this review, we have discussed the distribution of angiotensin receptor subtypes in the central nervous system (CNS) together with enzymatic pathways leading to active angiotensin ligands and its interaction with angiotensin receptor 2 (AT2) and Mas receptors. Secondly, the use of angiotensin analogues (angiotensin converting enzyme inhibitors and AT1 and/or AT2 receptor blockers) in the treatment and management of the CNS disorders mentioned above has been discussed.

Matched MeSH terms: Nervous System Diseases/drug therapy
A note on (+)-catechin

Wiart C

Nutr Res, 2015 Jun;35(6):545.
PMID: 25957969 DOI: 10.1016/j.nutres.2015.04.014
Matched MeSH terms: Diabetes Mellitus, Experimental/drug therapy*
Complementary and alternative medicine use in patients with hematological cancers in Malaysia

Gan GG, Leong YC, Bee PC, Chin E, Teh AK

Support Care Cancer, 2015 Aug;23(8):2399-406.
PMID: 25876158 DOI: 10.1007/s00520-015-2614-z

BACKGROUND: Complementary and alternative medicine (CAM) is often used by cancer patients, but not many studies had been published on the prevalence of CAM use in patients with hematological cancers. This study aims to determine the prevalence of CAM and type of CAM used in this group of patients in a multiracial and multicultural country.
PATIENTS AND METHODS: This is a cross-sectional survey carried out in two hospitals in Malaysia. Patients with underlying hematological cancers were asked to complete the questionnaires on CAM and the Hospital Anxiety and Depression Scale.
RESULTS: A total of 245 patients participated. The prevalence of CAM use was 70.2 %. The most common types of CAM used are biological-based therapies (90.2 %) and mind-body interventions (42 %). Vitamin and diet supplements (68.6 %) and folk/herb remedies (58 %) are the most common biological-based therapies used. There is no significant association of CAM use with age, gender, education level, and household income. Female patients are more likely to use more than one CAM therapies. The most common reason reported for CAM use was to boost immunity (57 %) and cure (24 %). Majority of patients (65 %) felt CAM was effective, and 60 % did not inform their physicians regarding CAM usage.
CONCLUSION: In view of the high prevalence of CAM use in patients with hematological cancers, it is important that the physicians play an active role in seeking information from patients and to monitor possible drug-vitamin-herbal interactions.

Matched MeSH terms: Hematologic Neoplasms/drug therapy*
Fulltext Formulation and evaluation of galantamine gel as drug reservoir in transdermal patch delivery system

Fong Yen W, Basri M, Ahmad M, Ismail M

ScientificWorldJournal, 2015;2015:495271.
PMID: 25853145 DOI: 10.1155/2015/495271

Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer's disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.

Matched MeSH terms: Alzheimer Disease/drug therapy*
Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand

Permsuwan U, Chaiyakunapruk N, Nathisuwan S, Sukonthasarn A

Heart Lung Circ, 2015 Sep;24(9):860-8.
PMID: 25837019 DOI: 10.1016/j.hlc.2015.02.018

Non-ST elevation acute coronary syndrome (NSTE-ACS) imposes a significant health and economic burden on a society. Anticoagulants are recommended as standard therapy by various clinical practice guidelines. Fondaparinux was introduced and evaluated in a number of large randomised, controlled trials. This study therefore aimed to determine the cost-effectiveness of fondaparinux versus enoxaparin in the treatment of NSTE-ACS in Thailand.

Matched MeSH terms: Acute Coronary Syndrome/drug therapy*

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