Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model

The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 mug/mL and an IC(50) for R-ketoprofen of 1.6 mug/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.

Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in dog

The objectives of this study were to establish dose-response and blood concentration-response relationships for robenacoxib, a novel nonsteroidal anti-inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)-2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra-articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX-1 and COX-2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose-related improvement in weight-bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED(50) was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti-inflammatory effects of robenacoxib were significantly superior to placebo (0.25-4 mg/kg robenacoxib) and were non-inferior to meloxicam (0.5-4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose-related inhibition of COX-2 (estimated ED(50) was 0.52 mg/kg) but no inhibition of COX-1. At a dosage of 1-2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.

Palatability of crushed ß-blockers, converting enzyme inhibitors and thiazides

WHAT IS KNOWN AND OBJECTIVES: A problem that often affects antihypertensive drugs is the lack of formulations appropriate for childhood. Parents, therefore, crush tablets and administer the antihypertensive drug mixed with solid food or a palatable drink. Because palatability is a major modulator of adherence to prescribed medication, the palatability of crushed ß-blockers, converting enzyme inhibitors and thiazides was assessed among adult volunteers.

Stereoselective biotransformation of ketamine in equine liver and lung microsomes

Stereoselectivity has to be considered for pharmacodynamic and pharmacokinetic features of ketamine. Stereoselective biotransformation of ketamine was investigated in equine microsomes in vitro. Concentration curves were constructed over time, and enzyme activity was determined for different substrate concentrations using equine liver and lung microsomes. The concentrations of R/S-ketamine and R/S-norketamine were determined by enantioselective capillary electrophoresis. A two-phase model based on Hill kinetics was used to analyze the biotransformation of R/S-ketamine into R/S-norketamine and, in a second step, into R/S-downstream metabolites. In liver and lung microsomes, levels of R-ketamine exceeded those of S-ketamine at all time points and S-norketamine exceeded R-norketamine at time points below the maximum concentration. In liver and lung microsomes, significant differences in the enzyme velocity (V(max)) were observed between S- and R-norketamine formation and between V(max) of S-norketamine formation when S-ketamine was compared to S-ketamine of the racemate. Our investigations in microsomal reactions in vitro suggest that stereoselective ketamine biotransformation in horses occurs in the liver and the lung with a slower elimination of S-ketamine in the presence of R-ketamine. Scaling of the in vitro parameters to liver and lung organ clearances provided an excellent fit with previously published in vivo data and confirmed a lung first-pass effect.

In vitro metabolism of testosterone in the horse liver and involvement of equine CYPs 3A89, 3A94 and 3A95

Testosterone (TES) 6-β-hydroxylation is a significant metabolic step in the biotransformation of TES in human liver microsomes and reflects cytochrome P450 (CYP) 3A4/5 specific metabolic activity. Several CYP3A enzymes have been annotated in the horse genome, but functional characterization is missing. This descriptive study investigates TES metabolism in the horse liver in vitro and the qualitative contribution of three CYP3A isoforms of the horse. Metabolism of TES was investigated by using equine hepatocyte primary cultures and liver microsomes. Chemical inhibitors were used to determine the CYPs involved in TES biotransformation in equine microsomes. Single CYPs 3A89, 3A94, and 3A95, recombinantly expressed in V79 hamster lung fibroblasts, were incubated with TES and the fluorescent metabolite 7-benzyloxy-4-trifluoromethylcoumarin (BFC). The effect of ketoconazole and troleandomycin was evaluated on single CYPs. Testosterone metabolites were analyzed by HPLC and confirmed by GC/MS. In hepatocyte primary cultures, the most abundant metabolite was androstenedione (AS), whereas in liver microsomes, 6-β-hydroxytestosterone showed the largest peak. Formation of 6-β-hydroxytestosterone and 11-β-hydroxytestosterone in liver microsomes was inhibited by ketoconazole, troleandomycin, and quercetin. Equine recombinant CYP3A95 catalyzed 11-β-hydroxylation of testosterone (TES). Metabolism of BFC was significantly inhibited by ketoconazole in CYP3A95, whereas troleandomycin affected the activities of CYP3A94 and CYP3A95. Both inhibitors had no significant effect on CYP3A89. Metabolic reactions and effects of inhibitors differed between the equine CYP3A isoforms investigated. This has to be considered in future in vitro studies.

Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate

INTRODUCTION Herbal and dietary supplements are widely used as measures to improve and preserve health and well-being. Among the bestselling preparations are dietary supplement containing glucosamine and chondroitine sulfate taken to improve symptoms of osteoarthritis. METHODS AND RESULTS We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate. Response to steroids was favorable and resulted in complete remission of the patient. Diagnostic work-up of the case revealed no other possible cause of liver injury, and causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) resulted in a possible causal relationship between intake of glucosamine and chondroitine sulfate and the adverse hepatic reaction. CONCLUSION The present case recalls that products containing glucosamine and chondroitine sulfate can occasionally cause acute liver injury mimicking autoimmune hepatitis, and reminds of the potential dangers of compounds with poor efficacy and ill-defined safety records.

Perspectives on the 2014 ESC/EACTS Guidelines on Myocardial Revascularization: Fifty Years of Revascularization: Where Are We and Where Are We Heading?

The joint European Society of Cardiology and European Association of Cardio-Thoracic Surgery (ESC/EACTS) guidelines on myocardial revascularization collect and summarize the evidence regarding decision-making, diagnostics, and therapeutics in various clinical scenarios of coronary artery disease, including elective, urgent, and emergency settings. The 2014 document updates and extends the effort started in 2010, year of the first edition of these guidelines. Importantly, this latest edition provides a systematic review of all randomized clinical trials performed since 1980, comparing different strategies of myocardial revascularization, including coronary artery bypass graft (CABG), balloon angioplasty, percutaneous coronary intervention (PCI) with bare-metal stents (BMS) and first- and second-generation drug-eluting stents (DES). This review aims to highlight the most relevant novelties introduced by the 2014 edition of the ESC/EACTS myocardial revascularization guidelines as compared with the previous edition and to describe similarities and differences with the American societies' guidelines.

Account books of Thomas Cradock, 1786-1818 (inclusive)

Account books listing patients, medicines administered, and fees charged by Dr. Thomas Cradock (1752-1821), primarily in Maryland, from 1786 to 1818. In addition to recording names, Cradock occasionally noted demographic information, the patient's location, or their occupation: from 1813 to 1816, he treated Richard Gent, a free African-American man; in 1813, he attended to John Bell, who lived in the Foggy Bottom neighborhood of Washington, D.C. Cradock further noted if the patient was a slave and the name of his or her owner. He would also administer care on behalf of corporate entities, such as Powhatan Factory, which apparently refused him payment. He also sometimes included a diagnosis: in the cases of a Mr. Rowles and Mrs. Violet West, he administered unspecified medicines for gonorrhea at a cost of ten dollars. Commonly prescribed drugs included emetics, cathartics, and anodynes. Cradock also provided smallpox vaccination for his patients. He accepted both cash and payment-in-kind. Tipped into the first volume is an envelope containing a letter from the Medical and Chirurgical Faculty of Maryland to Mrs. Thomas Craddock in 1899 requesting a loan of portrait of Dr. Thomas Craddock [sic]. The three volumes also each contain an index to patient names.

Commonplace book of Moses Appleton, 1791-1815 (inclusive)

Volume containing medicinal recipes, medical notes, poetry, and obituaries written by Dr. Moses Appleton (1773-1849). Many of the recipes were copied from medical texts or other publications. His "cure for the dropsy," taken from the New York Herald, contained stale cider, parsley, horseradish, oxymel squills (sea onion in honey), and juniper berries. For diarrhea, he prescribed a blackberry syrup. Several entries indicate Appleton practiced Thomsonian medicine, an alternative system based on use of botanicals. The medical notes include an account of his treatment of a man with smallpox in 1815, and entries on patients he inoculated with cowpox matter. Another entry dated in 1796 provides instructions from the Massachusetts Humane Society for "treatment to be used with persons apparently dead from drowning," which included blowing tobacco smoke in the victim's lungs and applying warm blankets for several hours. Appleton adds a note questioning whether or not the lungs also should be "often artificially inflated." There is additionally a history of prominent physicians dating from ancient Greece.

Doctor Daniel Brigham's Book, 1789-1810 (inclusive)

Ledger maintained by Dr. Daniel Brigham (1760-1837) containing financial accounts for medical patients treated primarily in Northborough, Westborough, and Marlborough, Massachusetts from 1789 to 1837. The ledger details the charges for medical services and the corresponding payments, often made by payment-in-kind. Common charges included a shilling for a visit and administration of cathartics, emetics, or anodynes. Extraction of a tooth cost eight pence, and Brigham charged one woman nine shillings for delivering her son. A number of entries are obscured by pasted-in newspaper articles.

Account book of David Townsend, 1774-1791

Account book kept by Dr. David Townsend (1753-1829) that records patients treated, illnesses, and fees charged in Boston, Massachusetts, and neighboring towns from 1774 to 1791. His patients included a number of soldiers and sailors, as well as figures like the French-American writer John Hector St. John (1735-1813). Townsend's treatments typically consisted of delivering cathartics or emetics. For the family of Samuel Appleton, Townsend administered smallpox inoculation in 1776, charging him 4 pounds, 4 shillings. Townsend sometimes recorded the occupation or race of the patient. For example, he attended the delivery of a child of Sappho Henshaw, "black girl," in 1786; in 1787 he attended to an unnamed "black man at [who lived at the] corner of Board Alley" in the North End of Boston. Other patients included John Hancock (1736-1793) and members of Hancock's household, as well as Federalist publisher John Fenno (1751-1798).

Receipt book of Francis Kittredge, 1780

Contains instructions for preparing and administering medicine for adults and children, and generalized uses for certain ingredients, written by Dr. Francis Kittredge. Preparations include ointment for scurvy, bone ointment, nerve ointments, procedures to soothe a sore mouth and to stop excessive bleeding, and treatment to kill worms. The materials used to prepare bone ointment include fresh butter, hog fat, chamomile, garlic, and night shade, among other ingredients. The recipe for “simple nerve ointment” instructs the preparer to simmer half a pint of neet foot oil, a pint of rum, and one jell of oil of turpentine over a “gentle fire.” Kittredge writes that oil of St. John’s Wort is effective in treating swelling of the legs, for cold and aches, and for burning and scalds, while oil of Elderflower is indicated for belly aches. The manuscript is housed in a binding created by the Harvard Medical School library. Tipped into the binding is one letter from Frederick O. West, M.D., Harvard Medical School, Boston, Massachusetts, that accompanied his donation of the Kittredge receipt book to the library in 1919. There is also one letter of unknown provenance enclosed with the receipt book, which contains an inventory of the estate of Antipas Brigham, of Grafton, Massachusetts, signed by Worcester County Judge Joseph Wilder on 7 November 1749. It is unclear if this letter has any connection to Frederick O. West or Francis Kittredge.

Observations Medical & Chirurgical by John Perkins, 1724-1774 (inclusive)

Volume kept by Dr. John Perkins (1698-1781) from 1724 to 1774 recording observations on various diseases and medical conditions illustrated with cases from Perkins's practice in Boston, Massachusetts. The cases ranged from epileptic fits, various fevers, and rheumatism to melancholy. His treament methods were standard for the era, mainly prescribing vomits, purges, and spirits, and bleeding patients. Also includes a section listing contradictory opinions among prominent medical writers such as Dutch physician Herman Boerhaave and English physician Thomas Sydenham. An index is located at the end of the volume. Perkins likely began compiling the book in 1765. It contains cases dating from 1724 to 1774.