Effect of rain on absorption after transdermal application of flunixin in calves.

Flunixin is a nonsteroidal anti-inflammatory drug (NSAID) that has anti-inflammatory, anti-pyretic, and analgesic effects. Recently, a novel transdermal formulation was developed (Finadyne® Transdermal, MSD Animal Health) and is now the first NSAID registered to be administered as a pour-on product in cattle. According to the manufacturer's instructions, the pour-on product should be applied only to dry skin and exposure to rain should be avoided for at least 6 hr after application. The objective of the study was to evaluate the effect of simulated exposure to light or heavy rain on flunixin absorption and bioavailability within the first 4 hr after administration. Therefore, an isocratic HPLC method was developed to quantify flunixin concentrations in bovine serum by UV detection. Light rain decreased flunixin absorption only when rain started immediately after flunixin administration, while light rain starting more than 30 min after administration of flunixin had no effect on absorption. Absorption and bioavailability of flunixin was impacted under simulated heavy rain conditions, when exposure to rain occurred within one hour after the application of the pour-on formulation, but not later.

Ultrasound versus landmark-based technique for ilioinguinal-iliohypogastric nerve blockade in children: the implications on plasma levels of ropivacaine.

BACKGROUND: Ilioinguinal-iliohypogastric nerve blockade (INB) is associated with high plasma concentrations of local anesthetics (LAs) in children. Ultrasonographic guidance enables exact anatomical administration of LA, which may alter plasma levels. Accordingly, we compared plasma levels of ropivacaine after ultrasonographic versus landmark-based INB. METHODS: After induction of general anesthesia, 66 children (8-84 mo) scheduled for inguinal hernia repair received INB with 0.25 mL/kg of ropivacaine 0.5% (1.25 mg/kg) either by a landmark-based (n = 31) or by an ultrasound-guided technique (n = 35). Ropivacaine plasma levels were measured before (0) and 5, 10, 20, and 30 min after the LA injection, using high-performance liquid chromatography. Maximum plasma concentrations (C(max)), time to C(max) (t(max)), the absorption rate constant (k(a)), the speed of rise of the plasma concentration at Time 0 (dC(0)/dt), and area under the curve value (AUC) were determined. RESULTS: The ultrasound-guided technique resulted in higher C(max) (sd), k(a), dC(0)/dt, and AUC values and shorter t(max) compared with the landmark-based technique (C(max): 1.78 [0.62] vs 1.23 [0.70] microg/mL, P < 0.01; k(a): 14.4 [10.7] vs 11.7 [11.4] h(-1), P < 0.05; dC(0)/dt: 0.26 [0.12] vs 0.15 [0.03] microg/mL . min, P < 0.01; AUC: 42.4 [15.9] vs 27.2 [18.1] microg . 30 min/mL, P < 0.001; t(max): 20.4 [8.6] vs 25.3 [7.6] min, P < 0.05). CONCLUSIONS: The pharmacokinetic data indicate faster absorption and higher maximal plasma concentration of LA when ultrasound was used as a guidance technique for INB compared with the landmark-based technique. Thus, a reduction of the volume of LA should be considered when using an ultrasound-guided technique for INB.

Amphetamines take two to tango: an oligomer-based counter-transport model of neurotransmitter transport explores the amphetamine action.

Amphetamine congeners [e.g., 3,4-methylenedioxymetamphetamine (MDMA), or "ecstasy"] are substrates for monoamine transporters (i.e., the transporters for serotonin, norepinephrine, and dopamine); however, their in vivo-action relies on their ability to promote monoamine efflux. The mechanistic basis for this counter transport remains enigmatic. We tested the hypothesis that outward transport is contingent on the oligomeric nature of neurotransmitter transporters by creating a concatemer of the serotonin transporter and the amphetamine-resistant GABA transporter. In cells expressing the concatemer, amphetamine analogs promoted GABA efflux and blunted GABA influx. In contrast, the natural substrates serotonin and GABA only cause mutual inhibition of influx via the other transporter moiety in the concatemer. GABA efflux through the concatemer that was promoted by amphetamine analogs was blocked by the protein kinase C inhibitors GF109203X (bisindoylmaleimide I) and Go6983 (2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide). Thus, based on our observations, we propose that, in the presence of amphetamine analogs, monoamine transporters operate as counter-transporters; influx and efflux occur through separate but coupled moieties. Influx and efflux are coupled via changes in the ionic gradients, but these do not suffice to account for the action of amphetamines; the activity of a protein kinase C isoform provides a second stimulus that primes the inward facing conformation for outward transport.

Simultaneous isocratic HPLC determination of vigabatrin and gabapentin in human plasma by dansyl derivatization.

A rapid and low-cost assay for simultaneous vigabatrin (VGA) and gabapentin (GBP) determination is described that can be performed with simple HPLC instrumentation. The method involves derivatization of the primary amine group of VGA and GBP with dansyl chloride followed by isocratic separation (column: microBondapak C-18, 10 microm, 300 x 3.9 mm; mobile phase: 50 mmol/L NaH(2)PO(4) in 40% acetonitrile) at 50 degrees C and fluorometric detection (excitation and emission wavelength: 318 and 510 nm, respectively) of the fluorescent product, which is stable for at least 7 days. Correlation coefficients of the calibration curves are >0.999 with a lower limit of detection of 0.3 microg/mL. Between- and within-run coefficients of variation are below 4.5%, and assay time is 15 minutes. This method may be used for therapeutic drug monitoring in the case of GBP and to control patient compliance in the case of VGA.

Dual rate-dependent cardiac electrophysiologic effects of haloperidol: slowing of intraventricular conduction and lengthening of repolarization.

Treatment with the neuroleptic agent haloperidol is sometimes associated with serious cardiac arrhythmias. The proarrhythmic potential of haloperidol may be linked to the drug's rate-dependent modulation of cardiac impulse conduction and repolarization. Herein these heart rate-dependent electrophysiologic actions of haloperidol are investigated in vivo. In anesthetized guinea pigs, haloperidol (0.02 mg/kg/min intravenously) produced significant rate-dependent slowing of intraventricular conduction. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing rapidly reached a new steady state with a rate constant of 0.80 per beat +/- 0.07. The time course of recovery from conduction slowing on interruption of rapid pacing at a cycle length of 250 ms was well described by two time constants, tau(rec1) = 18.9 ms +/- 8.0 and tau(rec2) = 141.8 ms +/- 87.1, suggesting rapid dissociation of the drug from the Na+ channel. During prolonged stimulation, conduction slowing had a biphasic dependence on heart rate: for each 10-bpm increment in heart rate, conduction slowing increased by 7.9% at rates <220 bpm and by 17% at rates >220 bpm. At all tested cycle lengths, haloperidol caused a significant lengthening of Q(T) intervals, which was inversely dependent on heart rate. Numeric analysis suggested that the excessive increase in conduction slowing at rates >220 bpm was due to the drug's Q(T)-prolonging effect, indicating that, at short cycle lengths, the impulses encroached on the refractory period. Thus, in vivo, haloperidol slows intracardiac conduction with rapid on/off kinetics, comparable to the class I antiarrhythmic agent lidocaine. The Q(T) prolongation by haloperidol may lead to an excessive conduction slowing at high heart rates.