Liquid-filled hard gelatin capsules : excipient/capsule compatibility studies

Encapsulation of pharmaceutical formulations as liquids or semisolids, within hard gelatin capsules, presents an important oral dosage strategy for poorly water-soluble drugs, resulting in good bioavailability and reproducible drug absorption. In addition, this technology offers an inherently safer process than powder filled capsules and tablets for highly potent or cytotoxic drugs by avoiding dust generation. Here we present a compatibility study of hard gelatin capsules with common excipients in absence of active pharmaceutical

An Overview of the Methylxanthines and their Regulation in the Horse

Caffiene, theophylline and theobromine are naturally occurring members of the methylxanthine family;pentoxfylline, dyphylline and enprofylline are structurally related synthetic pharmaceuticals. Caffiene has predominantly central nervous system effects, theophylline, dyphylline and enprofylline have predominantly bronchodilator effects, while theobromine is associated with diuretic responses. Pentoxfylline is thought to increase red cell deformability and facillitate blood flow through capillary beds. The methylxanthines are not highly potent agents; they are typically administered in gram doses and they tend to have relatively long half-lives. They remain detectable in plasma and urine for relatively long periods. Similarly, traces of the naturally occurring members of this family are not uncommonly identified in forensic samples. In this review we report on the detection, actions, uses and regulatory control of this group of agents in performance horses

Stress corrosion in titanium alloys and other metallic materials

Multiple physical and chemical techniques including mass spectroscopy, atomic absorption spectroscopy, gas chromatography, electron microscopy, optical microscopy, electronic spectroscopy for chemical analysis (ESCA), infrared spectroscopy, nuclear magnetic resonance (NMR), X-ray analysis, conductivity, and isotopic labeling were used in investigating the atomic interactions between organic environments and titanium and titanium oxide surfaces. Key anhydrous environments studied included alcohols, which contain hydrogen; carbon tetrachloride, which does not contain hydrogen; and mixtures of alcohols and halocarbons. Effects of dissolved salts in alcohols were also studied. This program emphasized experiments designed to delineate the conditions necessary rather than sufficient for initiation processes and for propagation processes in Ti SCC

Surface Dynamics of Crude and Weathered Oil in the Presence of Dispersants: Laboratory Experiment and Numerical Simulation

Marine oil spills can have dire consequences for the environment. Research on their dynamics is important for the well-being of coastal communities and their economies. Propagation of oil spills is a very complex physical-chemical process. As seen during the Deepwater Horizon event in the Gulf of Mexico during 2010, one of the critical problems remaining for prediction of oil transport and dispersion in the marine environment is the small-scale structure and dynamics of surface oil spills. The laboratory experiments conducted in this work were focused on understanding the differences between the dynamics of crude and weathered oil spills and the effect of dispersants. After deposition on the still water surface, a drop of crude oil quickly spread into a thin slick; while at the same time, a drop of machine (proxy for weathered) oil did not show significant evolution. Subsequent application of dispersant to the crude oil slick resulted in a quick contraction or fragmentation of the slick into narrow wedges and tiny drops. Notably, the slick of machine oil did not show significant change in size or topology after spraying dispersant. An advanced multi-phase, volume of fluid computational fluid dynamics model, incorporating capillary forces, was able to explain some of the features observed in the laboratory experiment. As a result of the laboratory and modeling experiments, the new interpretation of the effect of dispersant on the oil dispersion process including capillary effects has been proposed, which is expected to lead to improved oil spill models and response strategies

Frequency distribution of post race urine pH from Standardbreds compared with Thoroughbreds: research and regulatory significance

The concentration of drugs and drug metabolites in urine samples of racing horses is strongly influenced by urine pH(Tobin, 1981), depending on whether the drugs are weak acids or weak bases. Drugs that are weak acids tend to concentrate in besic urine. In contrast, drugs that are weak bases tend to concentrate in acidic urine. These relationships have a well-established theoretical basis (the Henderson-Hasselbalch relationship) and have been demonstrated repeatedly in experimental animals and man (Tobin, 1981). More recently, evidence suggests that these relationships also occur with clinically and forensically significant agents in equine urine (Wood, et al. 1990; Gerken et al.1991.

Alteration of macroinvertebrate community in tropical aquatic systems in relation to sediment redox potential and overlaying water quality

Limnological studies in two tropical Indian aquatic habitats showed that macroinvertebrate communities have greater diversity than other biotic communities present there. Sediment redox potential is found to be an important factor for alteration of macroinvertebrate communities in aquatic bodies. Anthropogenic activities have influenced the changing of sediment redox potential values of the studied sites and there by affected the macroinvertebrate communities

Absence of detectable pharmacological effects after oral administration of isoxsuprine

Isoxsuprine is reported to be a peripheral vasodilator used in human and veterinary medicine to treat ischaemic vascular disease. In horses, it is generally administered orally to treat navicular disease and other lower limb problems. To deflne the scope and duration of its pharmacological responses after oral administration, 6 horses were dosed with isoxsuprine HCI (1.2 mg/kg bwt) q. 12 h for 8 days and then tested to assess the duration and extent of pharmacological actions. There was no significant difference between isoxsuprine and control treatment values for heart rate, spontaneous activity, sweat production, anal muscle tone, core and skin temperatures, and cutaneous blood flow. The lack of pharmacological effect following oral administration was in sharp contrast to the marked response following i.v. dosing reported in earlier experiments

A GC-MS Method for the Determination of Isoxsuprine in Biological Fluids of the Horse Utilizing Electron Impact Ionization

Isoxsuprine is used to treat navicular disease and other lower-limb problems in the horse. Isoxsuprine is regulated as a class 4 compound by the Association of Racing Commissioners, International (ARCI) and, thus, requires regulatory monitoring. A gas chromatography-mass spectrometry method utilizing electron impact ionization was developed and validated for the quantitation of isoxsuprine in equine plasma or equine urine. The method utilized robotic solid-phase extraction and tri-methyl silyl ether products of derivatization. Products were bis-trimethylsilyl (TMS) isoxsuprine and tris-TMS ritodrine, which released intense quantifier ions m/z 178 for isoxsuprine and m/z 236 for ritodrine that were products of C-C cleavage. To our knowledge, this procedure is faster and more sensitive than other methods in the literature. Concentrations in urine and plasma of isoxsuprine were determined from a calibrator curve that was generated along with unknowns. Ritodrine was used as an internal standard and was, therefore, present in all samples, standards, and blanks. Validation data was also collected. The limit of detection of isoxsuprine in plasma was determined to be 2 ng/mL, the limit of quantitation of isoxsuprine in plasma was determined to be \u3c 5 ng/mL. The mean coefficient of determination for the calibrator curves for plasma was 0.9925 ± 0.0052 and for calibrator curves for urine 0.9904 ± 0.0075. The recovery efficiencies at concentrations of 50, 200, and 300 ng/mL were 76%, 73%, and 76%, respectively, in plasma and 92%, 89% and 91% in urine

Development of a method for the detection and confirmation of the alpha-2 agonist amitraz and its major metabolite in horse urine

Amitraz (N′-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino] methyl]-N-methyl-methanimidamide) is an alpha-2 adrenergic agonist used in veterinary medicine primarily as a scabicide- or acaricide-type insecticide. As an alpha-2 adrenergic agonist, it also has sedative/tranquilizing properties and is, therefore, listed as an Association of Racing Commissioners International Class 3 Foreign Substance, indicating its potential to influence the outcome of horse races. We identified the principal equine metabolite of amitraz as N-2,4-dimethylphenyl-N′-methylformamidine by electrospray ionization(+)-mass spectrometry and developed a gas chromatographic-mass spectrometric (GC-MS) method for its detection, quantitation, and confirmation in performance horse regulation. The GC-MS method involves derivatization with t-butyldimethylsilyl groups; selected ion monitoring (SIM) of m/z 205 (quantifier ion), 278, 261, and 219 (qualifier ions); and elaboration of a calibration curve based on ion area ratios involving simultaneous SIM acquisition of an internal standard m/z 208 quantifier ion based on an in-house synthesized d6 deuterated metabolite. The limit of detection of the method is approximately 5 ng/mL in urine and is sufficiently sensitive to detect the peak urinary metabolite at 1 h post dose, following administration of amitraz at a 75-mg/horse intraveneous dose

Detection and Confirmation of Ractopamine and Its Metabolites in Horse Urine after Paylean® Administration

We have investigated the detection, confirmation, and metabolism of the beta-adrenergic agonist ractopamine administered as Paylean to the horse. A Testing Components Corporation enzyme-linked imunosorbent assay (ELISA) kit for ractopamine displayed linear response between 1.0 and 100 ng/ml, with an 1-50 of 10 ng/ml, and an effective screening limit of detection of 50 ng/mL. The kit was readily able to detect ractopamine equivalents in unhydrolyzed urine up to 24 h following a 300-mg oral dose. Gas chromatography-mass spectrometry (GC-MS) confirmation comprised glucuronidase treatment, solid-phase extraction, and trimethylsilyl derivatization, with selected-ion monitoring of ractopamine-tris(trimethylsilane) (TMS) m/z 267, 250, 179, and 502 ions. Quantitation was elaborated in comparison to a 445 Mw isoxsuprine-bis(TMS) internal standard monitored simultaneously. The instrumental limit of detection, defined as that number of ng on column for which signal-to-noise ratios for one or more diagnostic ions fell below a value of three, was 0.1 ng, corresponding to roughly 5 ng/mL in matrix. Based on the quantitation ions for ractopamine standards extracted from urine, standard curves showed a linear response for ractopamine concentrations between 10 and 100 ng/mL with a correlation coefficient r \u3e 0.99, whereas standards in the concentration range of 10-1000 ng/mL were fit to a second-order regression curve with r \u3e 0.99. The lower limit of detection for ractopamine in urine, defined as the lowest concentration at which the identity of ractopamine could be confirmed by comparison of diagnostic MS ion ratios, ranged between 25 and 50 ng/mL. Urine concentration of parent ractopamine 24 h post-dose was measured at 360 ng/mL by GC-MS after oral administration of 300 mg. Urinary metabolites were identified by electrospray ionization (+) tandem quadrupole mass spectrometry and were shown to include glucuronide, methyl, and mixed methyl-glucuronide conjugates. We also considered the possibility that an unusual conjugate added 113 amu to give an observed m/z 415 [M+H] species or two times 113 amu to give an m/z 528 [M+H] species with a daughter ion mass spectrum related to the previous one. Sulfate and mixed methyl-sulfate conjugates were revealed following glucuronidase treatment, suggesting that sulfation occurs in combination with glucuronidation. We noted a paired chromatographic peak phenomenon of apparent ractopamine metabolites appearing as doublets of equivalent intensity with nearly identical mass spectra on GC-MS and concluded that this phenomenon is consistent with Paylean being a mixture of RR, RS, SR, and SS diastereomers of ractopamine. The results suggest that ELISA-based screening followed by glucuronide hydrolysis, parent drug recovery, and TMS derivatization provide an effective pathway for detection and GC-MS confirmation of ractopamine in equine urine