URL Pharma Inc.

Philadelphia, PA, United States

URL Pharma Inc.

Philadelphia, PA, United States
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Terkeltaub R.A.,University of California at San Diego | Furst D.E.,University of California at Los Angeles | Bennett K.,Salamandra LLC | Kook K.A.,Salamandra LLC | And 2 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. Methods. This multicenter, randomized, doubleblind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was ≥50% pain reduction at 24 hours without rescue medication. Results. There were 184 patients in the intent-totreat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. Conclusion. Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo. © 2010, American College of Rheumatology.


Wason S.,URL Pharma Inc. | Wason S.,Mutual Pharmaceutical Company Inc. | DiGiacinto J.L.,Salamandra LLC | Davis M.W.,URL Pharma Inc. | Davis M.W.,Mutual Pharmaceutical Company Inc.
Clinical Therapeutics | Year: 2012

Background: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug- drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported. Objective: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers. Methods: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mgdose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes. Results: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered withSeville orange juice, a moderate inhibitor, Cmax and AUC were decreased by s≃24% and s≃20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in Tmax. Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events. Conclusions: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased Tmax, but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials. gov identifiers: NCT00960193 and NCT00984009.(Clin Ther. 2012;34:2161-2173) 2012 Elsevier HS Journals, Inc. All rights reserved.


Wason S.,URL Pharma Inc | Digiacinto J.L.,Salamandra LLC | Davis M.W.,URL Pharma Inc
Postgraduate Medicine | Year: 2012

Objective: Colchicine and cyclosporine are often administered together, particularly in patients who have undergone solid-organ transplantation. However, the potential for drug-drug interactions between these agents resulting in colchicine toxicity is high. Methods: This study sought to determine the effect of cyclosporine (100-mg capsule) on the pharmacokinetics of the US Food and Drug Administration-approved formulation of colchicine (0.6-mg tablet) after single oral-dose administration in 24 healthy subjects under fasted conditions in a phase 1, single-sequence, 2-period drug-drug interaction trial. Results: Coadministration of cyclosporine increased colchicine maximum observed plasma concentration, area under the plasma concentration-time curve to the last measurable time point, and area under the plasma concentration-time curve to time infinity on average by 224%, 216%, and 215% (ie, almost doubled), respectively, and decreased colchicine oral clearance on average by 72% (from 48.24 to 13.42 L/h), indicating substantially higher colchicine exposures when combined with cyclosporine, compared with colchicine alone. Conclusion: The dose of colchicine should be reduced by $ 50% when colchicine and cyclosporine are administered concurrently for treatment and prophylaxis of gout fares or treatment of patients with familial Mediterranean fever. Health care professionals should be vigilant for potential adverse events during colchicine/cyclosporine coadministration, notably in patients who have undergone solid-organ transplantation. © Postgraduate Medicine.


Dalbeth N.,University of Auckland | Lauterio T.J.,URL Pharma Inc | Wolfe H.R.,Kyowa Kirin Pharma Inc
Clinical Therapeutics | Year: 2014

Purpose: The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases. Methods: The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed. Findings: The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease. Implications: Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine. © 2014 The Authors.


Dalbeth N.,University of Auckland | Lauterio T.J.,URL Pharma Inc | Wolfe H.R.,Kyowa Hakko Kirin Pharma Inc.
Clinical Therapeutics | Year: 2014

Purpose The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases.Methods The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed.Findings The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease.Implications Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine. © 2014 The Authors. Published by Elsevier HS Journals, Inc.


Nasr A.,URL Pharma Inc. | Lauterio T.J.,URL Pharma Inc. | Davis M.W.,URL Pharma Inc.
Advances in Therapy | Year: 2011

Despite more than a century of evolving federal legislation, there remain many unapproved drugs on the United States (US) market. This article reviews the history of drug approval in the US, beginning with the landmark Pure Food and Drug Act of 1906, through to the development of the US Food and Drug Administration (FDA). The Pure Food and Drug Act of 1906 was the first comprehensive federal legislation covering drug regulation. Intervening legislation, such as the Federal Food, Drug, and Cosmetic Act of 1938 and Kefauver-Harris Amendments in 1962, was later instituted. In June 2006, a century after the development of the FDA as an enforcement body, an initiative was undertaken to remove unapproved drugs from the marketplace. The Marketed Unapproved Drugs - Compliance Policy Guide outlines enforcement policies aimed at efficiently and rationally bringing all unapproved and illegally marketed drugs into the approval process, or discontinuing their manufacture, distribution, and sale. The FDA has been actively pursuing control of unapproved drugs in recent years, with an approach concentrating on drug safety to ensure optimal public health and consumer protection. © 2011 Springer Healthcare.


Wason S.,URL Pharma Inc. | Faulkner R.D.,URL Pharma Inc. | Davis M.W.,URL Pharma Inc.
Advances in Therapy | Year: 2012

Introduction: The objective of this study was to compare the relative bioavailability of the US Food and Drug Administration-approved formulation of colchicine after a single 0.6 mg dose in young (18-30 years of age) and elderly (=60 years of age) healthy subjects to determine whether dosing adjustments are required in elderly patients. Methods: A single-dose, single-drug, parallelgroup study was performed in 20 young subjects with normal renal function (defined as creatinine clearance [CrCl] =80 mL/min) and 18 elderly subjects with normal or mild renal impairment (CrCl =50 mL/min) in otherwise good health. Blood samples were collected for up to 72 hours postdose and analyzed for colchicine using a validated liquid chromatography/tandem mass spectrometry method. Noncompartmental pharmacokinetic parameters were compared using analysis of variance methods. Results: There were no statistically significant (P < 0.05) differences in mean colchicine pharmacokinetic parameters between young and elderly subjects, including peak plasma concentration (Cmax) (2.53 vs. 2.56 ng/mL), time to Cmax (1.25 vs. 1.25 hours), area under the plasma concentration-time curve to infinity (22.29 vs. 25.01 ng/h/mL), elimination half-life (25.4 vs. 30.1 hours), oral clearance (0.40 vs. 0.35 L/h/kg), and apparent volume of distribution (14.3 vs. 14.8 L/kg), respectively. Conclusion: The lack of any significant differences in colchicine pharmacokinetic parameters between young and elderly healthy subjects, with some of the latter including mild renal impairment, suggests that dose modification of colchicine may not be necessary in healthy elderly patients. However, when evaluating the use of colchicine dosing in an elderly patient, the confounding effect on overall exposure and safety from comorbid conditions, the use of concomitant medications, and the administration of multiple doses should be considered. ClinicalTrials.Gov #NCT01001052. © Springer Healthcare 2012.


Wertheimer A.I.,Temple University | Davis M.W.,URL Pharma Inc | Lauterio T.J.,URL Pharma Inc
Current Medical Research and Opinion | Year: 2011

Background: Gout is a common inflammatory arthritis that affects ∼4% of the US population. Most patients with gout are >50 years of age and have multiple comorbidities. Gout is caused by the deposition of monosodium urate crystals in joints secondary to hyperuricemia. Gout typically presents as an acute painful inflammation (flare) involving one or more joint. Left untreated it can progress into a more chronic polyarthritis. Acute gout flare treatment options include colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. The safety and efficacy of colchicine, especially in the presence of comorbidity and potential contraindications, has only recently been systematically investigated. Methods: Through the use of a systematic computer-based literature analysis, this pharmacoeconomic review evaluated costs, risks, and benefits of Colcrys (colchicine) compared with other treatments for gout in the US. Results: Both colchicine and NSAIDs are historically associated with gastrointestinal (GI) adverse events (AEs). Colchicine has very low risk for AEs, even in patients with GI disorders; whereas, NSAIDS are contraindicated in patients with GI disorders, renal insufficiency, and heart failure. The monthly cost of treating 100 patients with Colcrys was $33,100 compared with $3000 for NSAIDs. However, hospitalization for GI complications (1.8%) and heart failure (1.9%) is common with NSAIDs and can increase the monthly cost of treating 100 patients with NSAIDs to $161,000, considering $15,000-20,000 per day of hospitalization. Conclusions: Considering high costs associated with treating patients with gout, it seems prudent to choose the treatment with greatest benefit, lowest cost, and least risk. Despite higher cost per dose, colchicine appears to be more cost effective for management of gout flares than NSAIDs. © 2011 Informa UK Ltd.


Trademark
URL Pharma Inc. | Date: 2012-10-23

medicines and medicaments for the treatment and prevention of malaria, blood disorders, namely, dyslipidemias, rheumatic disorders, inflammatory disorders, metabolic disorders, namely, gout and familial Mediterranean fever; a full line of prescription and non-prescription pharmaceuticals, medicines and medicaments.


Trademark
URL Pharma Inc. | Date: 2012-10-30

Medicines and medicaments for the treatment and prevention of malaria, blood disorders, namely, dyslipidemias, rheumatic disorders, inflammatory disorders, metabolic disorders, namely, gout and familial Mediterranean fever; a full line of prescription and non-prescription pharmaceuticals, medicines and medicaments.

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