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Clinical Pharmacology: Advances and Applications

Virendra Rambiritch, Poobalan Naidoo, Goonaseelan Pillai
AIM: To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients. PATIENTS AND METHODS: A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis...
2016: Clinical Pharmacology: Advances and Applications
Béla Z Schmidt, Jérémy B Haaf, Teresinha Leal, Sabrina Noel
Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients...
2016: Clinical Pharmacology: Advances and Applications
Yan Li, Leonidas N Carayannopoulos, Michael Thomas, Maria Palmisano, Simon Zhou
CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals...
2016: Clinical Pharmacology: Advances and Applications
Sagar Munjal, Anirudh Gautam, Alan M Rapoport, Dennis M Fisher
OBJECTIVE/BACKGROUND: Factors such as body size (weight and body mass index [BMI]), age, sex, and race might influence the clinical response to sumatriptan. We evaluated the impact of these covariates on the plasma concentration (Cp) profile of sumatriptan administered subcutaneously. METHODS: We conducted three pharmacokinetic studies of subcutaneous sumatriptan in 98 healthy adults. Sumatriptan was administered subcutaneously (236 administrations) as either DFN-11 3 mg, a novel 0...
2016: Clinical Pharmacology: Advances and Applications
Amy Tawfik, Joanna M Bielecki, Murray Krahn, Paul Dorian, Jeffrey S Hoch, Heather Boon, Don Husereau, Petros Pechlivanoglou
BACKGROUND: In the last 4 years, four novel oral anticoagulants have been developed as alternatives to warfarin and antiplatelet agents for stroke prevention in atrial fibrillation (AF) patients. The objective of this review was to estimate the comparative effectiveness of all antithrombotic treatments for AF patients. MATERIALS AND METHODS: Data sources were Medline Ovid (1946 to October 2015), Embase Ovid (1980 to October 2015), and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 9, 2015)...
2016: Clinical Pharmacology: Advances and Applications
Virendra Rambiritch, Poobalan Naidoo, Breminand Maharaj, Goonaseelan Pillai
AIM: The aim of this study was to describe the pharmacokinetics (PK) of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods. METHODS: A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d) of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling) and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling) on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2...
2016: Clinical Pharmacology: Advances and Applications
Melanie Davies, Sudesna Chatterjee, Kamlesh Khunti
Worldwide, an estimated 200 million people have chronic kidney disease (CKD), the most common causes of which include hypertension, arteriosclerosis, and diabetes. Importantly, ~40% of patients with diabetes develop CKD, yet evidence from major multicenter randomized controlled trials shows that intensive blood glucose control through pharmacological intervention can reduce the incidence and progression of CKD. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin...
2016: Clinical Pharmacology: Advances and Applications
Pingali Usharani, Chandrasekhar Nutalapati, Venkata Kishan Pokuri, Chiranjeevi Uday Kumar, Gangadhar Taduri
OBJECTIVES: To evaluate the efficacy and tolerability of standardized aqueous extracts of Terminalia chebula and Terminalia bellerica versus febuxostat and placebo on reduction in serum uric acid levels in subjects with hyperuricemia. MATERIALS AND METHODS: A total of 110 eligible subjects with hyperuricemia were enrolled and randomized to either of the five treatment groups - T. chebula 500 mg twice a day (BID), T. bellerica 250 mg BID, T. bellerica 500 mg BID, placebo BID, and febuxostat 40 mg once daily plus an identical placebo - for a duration of 24 weeks...
2016: Clinical Pharmacology: Advances and Applications
Rolf P Kreutz, Jeffrey A Breall, Anjan Sinha, Elisabeth von der Lohe, Richard J Kovacs, David A Flockhart
BACKGROUND: Reloading with high-dose atorvastatin shortly before percutaneous coronary interventions (PCIs) has been proposed as a strategy to reduce periprocedural myonecrosis. There has been a concern that statins that are metabolized by cytochrome P450 3A4 may interfere with clopidogrel metabolism at high doses. The impact of simultaneous administration of high doses of atorvastatin and clopidogrel on the efficacy of platelet inhibition has not been established. METHODS: Subjects (n=60) were randomized to receive atorvastatin 80 mg together with clopidogrel 600 mg loading dose (n=28) versus clopidogrel 600 mg alone (n=32) at the time of PCI...
2016: Clinical Pharmacology: Advances and Applications
Nidhi Tandon, Vijay Ramakrishnan, Shaji K Kumar
The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM...
2016: Clinical Pharmacology: Advances and Applications
Kashif M Munir, Stephen N Davis
With rates of obesity and diabetes rising across the world, effective therapies to treat hyperglycemia and its associated comorbidities continue to be in demand. Empagliflozin is a highly selective sodium glucose transporter-2 inhibitor that improves serum glucose levels by inducing glucosuria. Taken orally, it is rapidly absorbed with linear pharmacokinetics consistent in Asian and Caucasian populations. Empagliflozin treatment demonstrates consistent reductions in hemoglobin A1c, fasting plasma glucose, body weight, and blood pressure in individuals with type 2 diabetes...
2016: Clinical Pharmacology: Advances and Applications
Kazuaki Matsumoto, Erika Watanabe, Naoko Kanazawa, Tomohide Fukamizu, Akari Shigemi, Yuta Yokoyama, Kazuro Ikawa, Norifumi Morikawa, Yasuo Takeda
BACKGROUND: Teicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration-time curve (AUC)/minimum inhibitory concentration (MIC) was identified as a pharmacokinetic-pharmacodynamic (PK-PD) parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK-PD are needed, a PK-PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) infections has not yet been performed...
2016: Clinical Pharmacology: Advances and Applications
Jonathan Q Tran, Ahmed A Othman, Alvydas Mikulskis, Paul Wolstencroft, Jacob Elkins
BACKGROUND: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials. OBJECTIVE: To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS)...
2016: Clinical Pharmacology: Advances and Applications
Nathan P Wiederhold
Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various pathogenic fungi, including yeast and moulds. Clinical studies have demonstrated that this agent is efficacious as prophylaxis against invasive fungal infections in patients at high risk, and may also be useful as salvage therapy against invasive aspergillosis and mucormycosis. However, the bioavailability of posaconazole following administration by oral suspension, which was the only formulation clinically available for many years, is highly variable and negatively influenced by several factors...
2016: Clinical Pharmacology: Advances and Applications
William G North, Fuli Liu, Ruiyang Tian, Hamza Abbasi, Bonnie Akerman
We have earlier demonstrated that breast cancer and small-cell lung cancer express functional NMDA receptors that can be targeted to promote cancer cell death. Human ovarian cancer tissues and human ovarian cancer cell lines (SKOV3, A2008, and A2780) have now been shown to also express NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen ovarian cancers in two arrays were screened by immunohistochemistry using polyclonal antibodies that recognize an extracellular moiety on GluN1 and on GluN2B...
2015: Clinical Pharmacology: Advances and Applications
Douglas S Kalman, Samantha Feldman, Adam Samson, Diane R Krieger
PURPOSE: The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of an oral inositol-stabilized arginine silicate dietary supplement. SUBJECTS AND METHODS: Ten healthy males, 26.7±5.4 years, took three 500 mg arginine silicate capsules (active product) for 14 days. The subjects attended test visits on Days 1 and 14. Fasting blood and saliva collections were performed predose and at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours postdose for plasma arginine, serum silicon, and salivary nitric oxide (NO) + nitrite...
2015: Clinical Pharmacology: Advances and Applications
Lance A Wollenberg, Donald T Corson, Courtney A Nugent, Farran L Peterson, Ann M Ptaszynski, Alisha Arrigo, Coralee G Mannila, Kevin S Litwiler, Stacie J Bell
BACKGROUND: Pexmetinib (ARRY-614) is a dual inhibitor of p38 mitogen-activated protein kinase and Tie2 signaling pathways implicated in the pathogenesis of myelodysplastic syndromes. Previous clinical experience in a Phase I dose-escalation study of myelodysplastic syndrome patients using pexmetinib administered as neat powder-in-capsule (PIC) exhibited high variability in pharmacokinetics and excessive pill burden, prompting an effort to improve the formulation of pexmetinib. METHODS: A relative bioavailability assessment encompassed three parallel treatment cohorts of unique subjects comparing the two new formulations (12 subjects per cohort), a liquid oral suspension (LOS) and liquid-filled capsule (LFC) and the current clinical PIC formulation (six subjects) in a fasted state...
2015: Clinical Pharmacology: Advances and Applications
Shunsuke Kiuchi, Shinji Hisatake, Muneyasu Kawasaki, Osamu Hirashima, Takayuki Kabuki, Junichi Yamazaki, Takanori Ikeda
BACKGROUND: The aim of controlling hypertension is to protect against arteriosclerosis. Calcium channel blockers (CCBs) and renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to have antihypertensive effects, but their effect on the progression of arteriosclerosis is not fully understood. The cardio-ankle vascular index (CAVI) was developed to estimate arterial stiffness, which reflects arteriosclerosis. In this study, we investigated the longer term effects of CCBs and RAAS inhibitors on the progression of arteriosclerosis by monitoring the CAVI...
2015: Clinical Pharmacology: Advances and Applications
Resham Raj Poudel, Nisha Kusum Kafle
Cystitis is a possible adverse drug reaction associated with the use of tizanidine. Such cases have been rarely reported in literature because of the difficulty in establishing the causality. However, from a pharmacovigilance point of view, it is better to report such cases of a possible association between a drug's use and potential adverse drug reactions. We report a case of a 26-year-old Asian female on famotidine who presented with acute severe urinary burning after taking tizanidine.
2015: Clinical Pharmacology: Advances and Applications
Kazuaki Matsumoto, Masashi Kitaoka, Yuko Kuroda, Kazuro Ikawa, Norifumi Morikawa, Junichi Sasaki, Osamu Iketani, Satoshi Iwata, Tetsuya Horino, Seiji Hori, Junko Kizu
BACKGROUND: Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. MATERIALS AND METHODS: Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue...
2015: Clinical Pharmacology: Advances and Applications
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