The effect of dietary addition of nitrate or increase in lipid concentrations, alone or in combination, on performance and methane emissions of beef cattle.

Adding nitrate to or increasing the concentration of lipid in the diet are established strategies for reducing enteric methane (CH4) emissions, but their effectiveness when used in combination has been largely unexplored. This study investigated the effect of dietary nitrate and increased lipid included alone or together on CH4 emissions and performance traits of finishing beef cattle. The experiment was a 2×4 factorial design comprising two breeds (cross-bred Aberdeen Angus (AAx) and cross-bred Limousin (LIMx) steers) and four dietary treatments (each based on 550 g forage : 450 g concentrate/kg dry matter (DM)). The four dietary treatments were assigned according to a 2×2 factorial design where the control treatment contained rapeseed meal as the main protein source, which was replaced either with nitrate (21.5 g nitrate/kg DM); maize distillers dark grains (MDDG, which increased diet ether extract from 24 to 37 g/kg DM) or both nitrate and MDDG. Steers (n=20/dietary treatment) were allocated to each of the four treatments in equal numbers of each breed with feed offered ad libitum. After 28 days adaptation to dietary treatments, individual animal intake, performance and feed efficiency were recorded for 56 days. Thereafter, CH4 emissions were measured over 13 weeks (six steers/week). Increasing dietary lipid did not adversely affect animal performance and showed no interactions with dietary nitrate. In contrast, addition of nitrate to diets resulted in poorer live-weight gain (P<0.01) and increased feed conversion ratio (P<0.05) compared with diets not containing nitrate. Daily CH4 output was lower (P<0.001) on nitrate-containing diets but increasing dietary lipid resulted in only a non-significant reduction in CH4. There were no interactions associated with CH4 emissions between dietary nitrate and lipid. Cross-bred Aberdeen Angus steers achieved greater live-weight gains (P<0.01), but had greater DM intakes (P<0.001), greater fat depth (P<0.01) and poorer residual feed intakes (P<0.01) than LIMx steers. Cross-bred Aberdeen Angus steers had higher daily CH4 outputs (P<0.001) but emitted less CH4 per kilogram DM intake than LIMx steers (P<0.05). In conclusion, inclusion of nitrate reduced CH4 emissions in growing beef cattle although the efficacy of nitrate was less than in previous work. When increased dietary lipid and nitrate inclusion were combined there was no evidence of an interaction between treatments and therefore combining different nutritional treatments to mitigate CH4 emissions could be a useful means of achieving reductions in CH4 while minimising any adverse effects.

Effectiveness of nitrate addition and increased oil content as methane mitigation strategies for beef cattle fed two contrasting basal diets.

The objectives of this study were to investigate the effects of (1) the addition of nitrate and (2) an increase in dietary oil on methane (CH4) and hydrogen (H2) emissions from 2 breeds (cross-bred Charolais and purebred Luing) of finishing beef cattle receiving 2 contrasting basal diets consisting (grams per kilogram DM) of 500:500 (Mixed) and 80:920 (Concentrate) forage to concentrate ratios. Within each basal diet there were 3 treatments: (i) control treatments (mixed-CTL and concentrate-CTL) contained rapeseed meal as the protein source, which was replaced with either (ii) calcium nitrate (mixed-NIT and concentrate-NIT) supplying 21.5 g nitrate/kg DM, or (iii) rapeseed cake (mixed-RSC and concentrate-RSC) to increase dietary oil from 27 (CTL) to 53 g/kg DM (RSC). Following adaption to diets, CH4 and H2 emissions were measured on 1 occasion from each of the 76 steers over a 13-wk period. Dry matter intakes tended (P = 0.051) to be greater for the concentrate diet than the mixed diet; however, when expressed as grams DMI per kilogram BW, there was no difference between diets (P = 0.41). Dry matter intakes for NIT or RSC did not differ from CTL. Steers fed a concentrate diet produced less CH4 and H2 than those fed a mixed diet (P < 0.001). Molar proportions of acetate (P < 0.001) and butyrate (P < 0.01) were lower and propionate (P < 0.001) and valerate (P < 0.05) higher in the rumen fluid from steers fed the concentrate diet. For the mixed diet, CH4 yield (grams per kilogram DMI) was decreased by 17% when nitrate was added (P < 0.01), while H2 yield increased by 160% (P < 0.001). The addition of RSC to the mixed diet decreased CH4 yield by 7.5% (P = 0.18). However, for the concentrate diet neither addition of nitrate (P = 0.65) nor increasing dietary oil content (P = 0.46) decreased CH4 yield compared to concentrate-CTL. Molar proportions of acetate were higher (P < 0.001) and those of propionate lower (P < 0.01) in rumen fluid from NIT treatments compared to respective CTL treatments. Overall, reductions in CH4 emissions from adding nitrate or increasing the oil content of the mixed diet were similar to those expected from previous reports. However, the lack of an effect of these mitigation strategies when used with high concentrate diets has not been previously reported. This study shows that the effect of CH4 mitigation strategies is basal diet-dependent.

Psychomotor effects of zaleplon and thioridazine coadministration.

OBJECTIVE: To assess the potential pharmacokinetic and pharmacodynamic interaction of zaleplon and thioridazine administered concomitantly in healthy volunteers. METHODS: A three-period, double-blind, randomized crossover study of the psychomotor effects of single oral doses of zaleplon 20 mg alone, thioridazine 50 mg alone, or the two drugs administered concomitantly was performed in 12 healthy subjects. Pharmacodynamic testing was performed before, and at 1, 2, 4, and 8 h after drug administration. Critical flicker fusion (CFF), tapping rate (TR), reaction time (RT) with dominant and nondominant hands, and digit symbol substitution test (DSST) were used to assess psychomotor performance. RESULTS: Pharmacokinetic results showed that coadministration of zaleplon and thioridazine did not alter the pharmacokinetic profile of either drug. In both CFF and TR tests, values for change from baseline with combined treatment were not significantly different from those with thioridazine at any time point, indicating no pharmacodynamic interaction. RT test values with coadministered treatment were significantly different from those with thioridazine alone at 1 h after administration, indicating additivity. Supra-additivity was observed in DSST results at 1, 2, and 4 h. There was no interaction at 8 h. CONCLUSION: The results of single-dose administration showed an additive pharmacodynamic interaction between zaleplon and thioridazine at 1 h in one of four tests and supra-additivity for 4 h in another test. This interaction is relatively short in duration due to the short half-life of zaleplon.

Absence of an interaction between ibuprofen and zaleplon.

The potential interaction between zaleplon and ibuprofen was studied. Healthy adult volunteers were given a dose of zaleplon 10 mg alone, a dose of ibuprofen 600 mg alone, or a dose of zaleplon 10 mg and a dose of ibuprofen 600 mg concomitantly in an open-label, randomized, three-period crossover study. There was a seven-day washout period between treatments. Venous blood samples were collected for pharmacokinetic analysis at various intervals up to 14 hours after drug administration. A total of 17 subjects (11 men and 6 women) completed the study. There were no significant differences between zaleplon monotherapy and combination therapy in mean +/- SD, of zaleplon clearance (CL) (2.80 +/- 0.72 versus 2.72 +/- 0.89 L/hr/kg, respectively), maximum plasma concentration (Cmax) (37.1 +/- 17.9 versus 39.8 +/- 20.0 ng/mL), or area under the concentration-versus-time curve (AUC) (56.7 +/- 22.8 versus 59.2 +/- 22.0 ng.hr/mL). There were no significant differences between ibuprofen monotherapy and combination therapy in ibuprofen CL (71.6 +/- 17.0 versus 71.7 +/- 14.9 L/hr/kg), Cmax (40.8 +/- 10.2 versus 40.4 +/- 10.0 micrograms/mL), or AUC (127.6 +/- 29.6 versus 126.4 +/- 29.7 micrograms.hr/mL). Three subjects had one or more adverse effects with zaleplon alone, one subject had one or more with ibuprofen alone, and one subject had one or more with combination therapy. The adverse effects were mild and resolved without intervention. There was no evidence of a significant interaction between zaleplon and ibuprofen.

Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance.

Twenty-four healthy male and female subjects, who participated in this randomized, double-blind, crossover study, received single nighttime doses of zaleplon 10 mg (therapeutic dose), zaleplon 20 mg, zolpidem 10 mg (therapeutic dose), zolpidem 20 mg, triazolam 0.25 mg (positive control), and placebo. Subjective behavioral ratings and psychomotor tests were completed before and 1.25 and 8.25 hours after administration of the study drug. The Immediate and Delayed Word Recall tests and the Digit Span Test were used to assess memory. The Digit-Symbol Substitution Test, Paired Associates Learning Test, and Divided Attention Test were used to assess other cognitive skills. Zaleplon 10 mg did not produce any significant changes in memory or learning compared with placebo. All other active treatments, including zolpidem 10 mg, caused psychomotor impairment at the 1.25-hour test battery. Zolpidem 20 mg (twice the therapeutic dose) produced more psychomotor impairment at the 1.25-hour assessment than did any of the other active treatments, including zaleplon 20 mg. At the 8.25-hour time point, test scores for subjects who received zaleplon 10 mg and 20 mg did not differ from the test scores for those who received placebo. However, cognitive impairment persisted up to the 8.25-hour observation for subjects who were administered triazolam 0.25 mg and zolpidem 20 mg. Adverse events associated with the use of zaleplon were transient and mild-to-moderate in severity. Overall, this study shows that zaleplon is a safe hypnotic that does not affect memory, learning, or psychomotor skills associated with vigilance.

Rapid disappearance of zaleplon from breast milk after oral administration to lactating women.

Five lactating mothers were administered the therapeutic dose of zaleplon (10 mg) orally in an open-label, single-dose, pharmacokinetic study. Plasma and breast milk were sampled through 8 hours after dose administration for subsequent determinations of zaleplon and its major, though inactive, plasma metabolite 5-oxo-zaleplon. Zaleplon concentrations peaked in plasma and milk approximately 1 hour after dosing and then disappeared rapidly. The mean terminal half-life was slightly greater than 1 hour. Milk concentrations "mirrored" plasma concentrations closely with no discernible delay between peak times. The average milk-to-plasma (M/P) concentration ratio for zaleplon was approximately 0.50 over the time course. 5-oxo-zaleplon was undetectable in all but one milk sample. The maximum exposure of an infant to zaleplon during a feeding at peak milk concentrations was estimated to range from 1.28 micrograms to 1.66 micrograms, corresponding to 0.013% to 0.017% of the maternal dose or 0.320 microgram/kg to 0.415 microgram/kg for a 4 kg infant. The results indicate that zaleplon taken by a nursing mother is transferred through breast milk to her infant in very small quantities that are unlikely to be clinically important.

Zaleplon pharmacokinetics and absolute bioavailability.

The pharmacokinetics and absolute oral bioavailability of zaleplon were assessed to evaluate the extent of presystemic metabolism of this new nonbenzodiazepine hypnotic agent. A partially randomized, single-dose, four-period crossover study was conducted in 23 healthy subjects. Subjects received 1 and 2.5 mg intravenous (i.v.) infusions of zaleplon during the first and second periods, respectively, and then were randomly assigned to receive a 5 mg oral dose or 5 mg i.v. infusion of zaleplon in a crossover design during the final two periods. Zaleplon pharmacokinetics were determined in 20 subjects (ten men and ten women) after the two 5 mg treatments. The oral and i.v. doses of zaleplon administered in this study were safe and well-tolerated. Following i.v. administration, zaleplon had a moderate to high systemic clearance (mean +/- S.D., 0.94 +/- 0.20 L/h/kg), rapid elimination (half-life, t1/2 = 1.05 +/- 0.13 h), and a steady-state volume of distribution of 1.27 +/- 0.25 L/kg, indicating substantial distribution into extravascular tissues. Zaleplon was rapidly absorbed after oral administration, and the mean apparent elimination t1/2 was similar to that obtained after i.v. infusion. The absolute bioavailability was 30.6 +/- 10.2%.

Reduction of pain-related behaviors with either cold or heat treatment in an animal model of acute arthritis.

OBJECTIVE: To assess the effects of heat and cold on quantifiable pain behaviors in an animal model of arthritis that minimizes the motivational-affective component of pain. DESIGN: The effects of superficial heat (40 degrees C) and cold (4 degrees C) on pain behaviors in rats with knee joint inflammation were tested before and after induction of inflammation and after treatment with heat or cold. SUBJECTS: Joint inflammation was induced in male Sprague-Dawley rats by intra-articular injection of the knee joint with 3% kaolin and 3% carrageenan. MAIN OUTCOME MEASURES: Withdrawal latency to heat applied to the paw (PWL) assessed secondary hyperalgesia; spontaneous pain behaviors assessed degree of weight bearing/ guarding; and joint circumference assessed joint swelling. RESULTS: Cold treatment of the inflamed knee joint significantly reversed the PWL immediately after treatment (p = .003) without affecting spontaneous pain behaviors orjoint circumference. In contrast, heat treatment produced a small but significant decrease in spontaneous pain behaviors (p = .03) without affecting PWL or joint circumference. CONCLUSION: Acute arthritic pain can be treated with either superficial heat for reducing guarding or with cold for reducing pain or hyperalgesia outside the injury site.

The influence of cimetidine on the disposition kinetics of the antidepressant venlafaxine.

The influence of cimetidine on the disposition pharmacokinetics of the antidepressant drug, venlafaxine, and its active metabolite, O-desmethylvenlafaxine, was examined in 18 healthy young men and women. The steady-state pharmacokinetic profiles of venlafaxine and O-desmethylvenlafaxine were evaluated during a 24-hour period after 5 days of treatment with venlafaxine (50 mg three times a day) and during a second 24-hour period after 5 days of combination treatment with venlafaxine (50 mg three times a day) and cimetidine (800 mg once a day). The apparent oral clearance of venlafaxine decreased significantly in the presence of cimetidine and the average steady-state plasma concentration of venlafaxine increased significantly in the presence of cimetidine, but there were no changes in the corresponding concentrations of the active metabolite. However, O-desmethylvenlafaxine exhibits pharmacologic activity that is approximately equimolar to that of venlafaxine, and the sum of venlafaxine plus O-desmethylvenlafaxine plasma concentrations was increased by an average of only 13%. Therefore, the effect of cimetidine coadministration is not expected to result in clinically important alterations in the response to venlafaxine in patients with depression. This may not be true, however, for patients with compromised hepatic metabolic function.

Pharmacokinetics and effect of food on the bioavailability of orally administered venlafaxine.

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two-period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model-dependent calculation of the first-order absorption rate constant, and a model-independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O-demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50-mg tablet. A standard, medium-fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation.

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and ethanol.

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self-medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double-blind, placebo-controlled, two-period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O-desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.

Pharmacokinetic interaction between multiple-dose venlafaxine and single-dose lithium.

Venlafaxine is a structurally novel antidepressant. Because lithium and antidepressants may be administered concomitantly, it is important to determine whether the disposition of venlafaxine and lithium is affected by coadministration. An open-label study was conducted to evaluate the effects of multiple-dose, steady-state venlafaxine administration on the pharmacokinetics of a single oral dose of lithium. Analogously, the effects of administration of a single-dose of lithium on the disposition of venlafaxine and its active metabolite, O-desmethylvenlafaxine, after multiple-dose administration of venlafaxine were assessed. Administration of 600 mg lithium carbonate did not affect venlafaxine absorption. Lithium significantly reduced the renal clearance of venlafaxine from 0.053 to 0.027 L/h/kg. However, renal excretion is not a major elimination pathway for venlafaxine; thus, lithium did not affect the total clearance of venlafaxine. Lithium administration had similar effects on elimination of O-desmethylvenlafaxine. Multiple-dose administration of 50 mg of venlafaxine every 8 hours produced a slight increase in the rate of lithium absorption, but did not affect the extent of lithium absorption. Total clearance (0.026 L/h/kg) and steady-state volume of distribution (0.71 L/kg) of lithium were not affected by administration of venlafaxine. Thus, there were no clinically significant pharmacokinetic interactions between venlafaxine and lithium.

The pharmacokinetics of venlafaxine when given in a twice-daily regimen.

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O-desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open-label, randomized, two-period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O-desmethylvenlafaxine were obtained during a 24-hour steady-state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0-24), trough concentration, or fluctuation ratio for venlafaxine or O-desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0-24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150-mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O-desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

The effect of renal disease on the disposition of venlafaxine.

The pharmacokinetics of venlafaxine and its active metabolite O-desmethylvenlafaxine were studied in subjects with various degrees of renal dysfunction, including subjects requiring maintenance hemodialysis. Venlafaxine was administered as a single 50 mg dose, with blood and urine samples obtained at intervals up to 48 hours after administration for the subjects receiving dialysis or 72 hours for the subjects not receiving dialysis. Six subjects receiving dialysis also completed an intradialysis evaluation to estimate dialysis clearance. Concentrations of venlafaxine and O-desmethylvenlafaxine in plasma, urine, and dialysate fluid were determined by high-performance liquid chromatography. Apparent total clearance of venlafaxine and O-desmethylvenlafaxine were both significantly decreased by approximately 55% in the subjects receiving dialysis, and terminal disposition half-life was significantly prolonged for both compounds. Venlafaxine and O-desmethylvenlafaxine are poorly dialyzable. In conclusion, the disposition of venlafaxine and O-desmethylvenlafaxine is markedly altered in renal disease; therefore dosage adjustment is warranted for patients with creatinine clearance values below 30 ml/min.

The effect of renal disease on tolrestat pharmacokinetics.

Many patients with diabetes who may benefit from treatment with tolrestat, a new aldose reductase inhibitor, will have nephropathy. Therefore the effect of renal dysfunction on the pharmacokinetics of tolrestat was evaluated in eight subjects maintained on hemodialysis, 11 subjects with partial renal impairment (creatinine clearance values ranging from 14 to 80 ml/min/1.73 m2), and eight normal subjects. Each subject received a single oral dose of 200 mg tolrestat. Blood and urine samples were collected during a 48-hour period, and tolrestat concentrations were measured by HPLC. Renal dysfunction had no apparent effect on the rate of absorption or volume of distribution of tolrestat. However, tolrestat clearance was significantly reduced from 30 +/- 3 (SD) ml/hr/kg in the normal subjects to 15 +/- 5 ml/hr/kg in the subjects receiving dialysis, and tolrestat half-life was prolonged from 11 to 16 hours. Therefore a reduction in tolrestat dose is suggested for patients with severe renal impairment.

Stochastic methods for short term projections of symptomatic HIV disease.

We designed and implemented stochastic methods for short term projections of HIV disease at the local level, that accommodate various states or stages of the disease. We gave particular attention to projection of the number of patients with HIV disease who need care, when durations of stay in these various states depend on current methods for treating opportunistic infections. We consider two types of data as input to these projections. One concerns seroprevalence surveys conducted over time and from which we can obtain time series estimates of the numbers of HIV-infected individuals. The other is a reported time series of AIDS cases adjusted for delays in reporting. Several projections, with data from the City of Philadelphia, illustrate this method. In addition, we consider a Monte Carlo method for computing confidence bounds on a projection.

The absolute bioavailability and dose proportionality of intravenous and oral dosage regimens of recainam.

Recainam is a novel class I antiarrhythmic agent with electrophysiologic characteristics of all three subclasses. The authors evaluated the absolute bioavailability and dose proportionality of three oral doses and two 2-stage intravenous (IV) infusion doses. Single oral doses of 200, 400, and 800 mg and IV infusions consisting of 0.8 mg/kg/5 min + 1.2 mg/kg/hr (3.75 mg/kg) and 1.6 mg/kg/5 min + 1.2 mg/kg/hr for 4 hours and 55 minutes (7.50 mg/kg) were administered to 15 healthy men. Plasma and urine samples were collected during the 36-hour period after drug administration and analyzed for recainam concentrations by HPLC. No significant differences were found in any of the pharmacokinetic parameters between the two IV dosage regimens. The absolute bioavailability of orally administered recainam increased from 73% for the 200 mg dose to 81% and 84% for the 400 and 800 mg doses, respectively. Dose proportionality deviated from linearity by 13% for the 200 vs. 400 mg doses, and 10% for the 400 vs. 800 mg doses. The slight deviation from linearity was apparently caused by increased absorption at the higher oral doses. The slight disproportionality in the disposition of recainam is not expected to be clinically significant.

Species differences in the pharmacokinetics of recainam, a new anti-arrhythmic drug.

The pharmacokinetics of recainam, an anti-arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man. Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non-linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mg kg-1 oral doses and rhesus monkeys between 1 and 15 mg kg-1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54-208 mg kg-1 in mice, 25-110 mg kg-1 in rats, and 50-100 mg kg-1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1-5h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (l kg-1 .h) was 4.9-5.2 in rats and rabbits and 0.4-1.9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2-5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10-45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6 h post-dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.

Effect of chronic renal failure on oxaprozin multiple-dose pharmacokinetics.

The effects of renal disease on the steady-state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half-lives were not different. The mean total AUC, peak concentration, average steady-state plasma concentration, and trough concentration for total and unbound oxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozin in patients on hemodialysis. The higher dose-averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozin may not need to be reduced when albumin levels are normal.