Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50 mg oral doses

1980 ◽  
Vol 71 (2) ◽  
pp. 165-167 ◽  
Author(s):  
�ke Bertler ◽  
Sune Lindgren ◽  
Harry Malmgren
Keyword(s):  
Oral Doses ◽  
Dipotassium Chlorazepate

Methotrexate for psoriasis in weekly oral doses

1969 ◽  
Vol 99 (1) ◽  
pp. 86-93 ◽  
Author(s):  
H. H. Roenigk
Keyword(s):  
Oral Doses

Analgesic Efficacy of Dextropropoxyphene and Dextropropoxyphene-containing Combinations: a Review

1984 ◽  
Vol 3 (1_suppl) ◽  
pp. 191s-220S ◽  
Author(s):  
W.T. Beaver
Keyword(s):  
Clinical Trial ◽  
Analgesic Efficacy ◽  
Controlled Clinical Trial ◽  
Controlled Clinical Trials ◽  
Congressional Hearings ◽  
Clinical Assay ◽  
The Subject ◽  
Minimum Criteria ◽  
Oral Doses ◽  
Mild Analgesics

Twenty years ago, as part of a review of the clinical pharmacology of mild analgesics (Beaver, 1965, 1966), I evaluated reports of those analgesic trials of dextropropoxyphene that appeared to satisfy the minimum methodologic requirements for a controlled clinical trial of analgesic efficacy. On reviewing reports of studies that have been published since then, I find little need to modify my evaluation of the efficacy of dextropropoxyphene that appeared in 1966, at least in respect to the effect of single oral doses: In summary, dextropropoxyphene (hydrochloride) is a mild oral analgesic which has proven superior to placebo in doses of 65 mg or more but which is of questionable efficacy in doses lower than 65 mg. The drug is definitely less potent than codeine: the best available estimates of the relative potency of the two drugs indicating that dextropropoxyphene is approximately 1/2-2/3 as potent. Likewise, dextropropoxyphene in 32-65 mg doses is certainly no more, and possibly less, effective than the usually used doses of aspirin or A.P.C. (aspirin/phenacetin/caffeine). In the interim, the efficacy of dextropropoxyphene has been the subject of a number of other critical reviews (Miller et al., 1970; Miller, 1977), commentaries (Kiplinger & Nickander, 1971; Lasagna, 1976), and even congressional hearings (Beaver, 1979; Moertel, 1979). More importantly, new controlled clinical trials involving dextropropoxyphene hydrochloride or napsylate have been reported, and some of these use more sophisticated design and analysis than those available in 1966. I will therefore discuss the results of those newer studies of apparently suitable scientific design that meet at least the minimum criteria for a valid clinical assay of analgesic activity (Beaver, 1965; Houde et al., 1965,1966; Wallenstein & Houde, 1975; Beaver, 1983), and I will comment on only a few of the studies included in my previous review (Beaver, 1966).

scholarly journals SAT0315 INHIBITION OF MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES-1) BY GS-248 REDUCES PROSTAGLANDIN E2 BIOSYNTHESIS WHILE INCREASING PROSTACYCLIN IN HUMAN SUBJECTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1103.2-1103
Author(s):  
C. Edenius ◽  
G. Ekström ◽  
J. Kolmert ◽  
R. Morgenstern ◽  
P. Stenberg ◽  
...  
Keyword(s):  
Whole Blood ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Prostaglandin E ◽  
Maximum Plasma ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Oral Doses ◽  
Microsomal Prostaglandin E Synthase

Background:Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the formation prostaglandin (PG) E2from cyclooxygenase derived PGH2(1, 2). Inhibition of mPGES-1 leads to reduction of pro-inflammatory PGE2, while in vessels there is a concomitant increase of vasoprotective prostacyclin (PGI2) via shunting of PGH2(3,4). Apart from relieving symptoms in experimental animal models of inflammation, inhibitors of mPGES-1 cause relaxation of human medium sized arteries(4)and resistance arteries(5). The prostaglandin profile following mPGES-1 inhibition, explains the anti-inflammatory effects and also opens for the possibility of treating inflammatory diseases with concomitant vasculopathies. GS-248 is a potent and selective inhibitor of mPGES-1 exhibiting sub-nanomolar IC50in human whole bloodex vivo.Objectives:To evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of GS-248.Methods:Healthy males and females (age 18–73 years) were included in the study. Six cohorts were administrated single oral doses of 1-300mg GS-248 (n=36) or placebo (n=12), three cohorts were administered once daily doses of 20-180mg GS-248 (n=18) or placebo (n=12) over ten days. In addition, 8 subjects were treated in a separate cohort with 200mg celecoxib bid for ten days. Blood samples were drawn for measurement of GS-248 exposure and production of PGE2after LPS incubationex vivo. The content of PGE2and PGI2metabolites was measured in urine. All analyses were performed by LC-MS/MS.Results:GS-248 was safe and well tolerated at all tested dose levels. Maximum plasma concentration was achieved 1 - 2.5 hours after dosing, and half-life was about 10 hours. Induced PGE2formationex vivo,catalyzed by mPGES-1, was completely inhibited for 24 hours after a single low dose (40mg) of GS-248. In urine, GS-248 dose-dependently reduced the excretion of PGE2metabolite by more than 50% whereas the excretion of PGI2metabolite increased more than twice the baseline levels. In the celecoxib cohort urinary metabolites of both PGE2and PGI2were reduced with approx 50%.Conclusion:GS-248 at investigated oral doses was safe and well tolerated. There was a sustained inhibition of LPS induced PGE2formation in whole blood. In urine, there was a metabolite shift showing reduced PGE2and increased PGI2, while celecoxib reduced both PGE2and PGI2metabolites. This suggests that selective inhibition of mPGES-1 results in systemic shunting of PGH2to PGI2formation, leading to anti-inflammatory and vasodilatory effects, while preventing platelet activation. The results warrant further evaluation of GS-248 in inflammatory conditions with vasculopathies such as Digital Ulcers and Raynaud’s Phenomenon in Systemic Sclerosis.References:[1]Korotkova M, Jakobsson PJ. Persisting eicosanoid pathways in rheumatic diseases. Nat Rev Rheumatol. 2014;10:229-41[2]Bergqvist F, Morgenstern R, Jakobsson PJ. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat. 2019;147:106383[3]Kirkby NS, et al. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovasc Res. 2020[4]Ozen G, et al. Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition. Br J Pharmacol. 2017;174:4087-98[5]Larsson K, et al. Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone. Br J Pharmacol. 2019;176:4625-38Disclosure of Interests:Charlotte Edenius Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Gunilla Ekström Shareholder of: Gesynta Pharma, Consultant of: Gesynta Pharma,, Johan Kolmert Consultant of: Gesynta Pharma,, Ralf Morgenstern Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Patric Stenberg Shareholder of: Gesynta Pharma, Employee of: Gesynta Pharma, Per-Johan Jakobsson Shareholder of: Gesynta Pharma, Grant/research support from: Gesynta Pharma, AstraZeneca,, Göran Tornling Shareholder of: Gesynta Pharma, Vicore Pharma,, Consultant of: Gesynta Pharma, Vicore Pharma, AnaMar

scholarly journals The Topical Nanodelivery of Vismodegib Enhances Its Skin Penetration and Performance In Vitro While Reducing Its Toxicity In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 186
Author(s):  
Maria Natalia Calienni ◽  
Daniela Maza Vega ◽  
C. Facundo Temprana ◽  
María Cecilia Izquierdo ◽  
David E. Ybarra ◽  
...  
Keyword(s):  
Side Effects ◽  
Water Solubility ◽  
Polymeric Micelles ◽  
Skin Penetration ◽  
Distribution Volume ◽  
And Performance ◽  
Oral Doses ◽  
Advanced Basal Cell Carcinoma

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.

scholarly journals Action of vanillin (Vanilla planifolia) on the morphology of tibialis anterior and soleus muscles after nerve injury

2017 ◽  
Vol 15 (2) ◽  
pp. 186-191 ◽  
Author(s):  
Ana Luiza Peretti ◽  
Juliana Sobral Antunes ◽  
Keli Lovison ◽  
Regina Inês Kunz ◽  
Lidyane Regina Gomes Castor ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Tibialis Anterior ◽  
Morphological Analysis ◽  
Morphological Changes ◽  
Control Group ◽  
Vanilla Planifolia ◽  
Morphological Alterations ◽  
Injury Group ◽  
Fiber Atrophy ◽  
Oral Doses

ABSTRACT Objective To evaluate the action of vanillin (Vanilla planifolia) on the morphology of tibialis anterior and soleus muscles after peripheral nerve injury. Methods Wistar rats were divided into four groups, with seven animals each: Control Group, Vanillin Group, Injury Group, and Injury + Vanillin Group. The Injury Group and the Injury + Vanillin Group animals were submitted to nerve injury by compression of the sciatic nerve; the Vanillin Group and Injury + Vanillin Group, were treated daily with oral doses of vanillin (150mg/kg) from the 3rd to the 21st day after induction of nerve injury. At the end of the experiment, the tibialis anterior and soleus muscles were dissected and processed for light microscopy and submitted to morphological analysis. Results The nerve compression promoted morphological changes, typical of denervation, and the treatment with vanillin was responsible for different responses in the studied muscles. For the tibialis anterior, there was an increase in the number of satellite cells, central nuclei and fiber atrophy, as well as fascicular disorganization. In the soleus, only increased vascularization was observed, with no exacerbation of the morphological alterations in the fibers. Conclusion The treatment with vanillin promoted increase in intramuscular vascularization for the muscles studied, with pro-inflammatory potential for tibialis anterior, but not for soleus muscle.

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