Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis.

1. Patients suffering from rheumatoid arthritis received oral doses of 600 mg racemic ibuprofen (n = 25; RAC) or 400 mg (S)-ibuprofen (n = 25; S-IBU) in a double-blind, randomized parallel-group study. 2. The pharmacokinetic parameters of (S)-ibuprofen were not statistically different between treatments (P > 0.05). Comparing (S)- and (R)-ibuprofen within the group receiving the racemate significantly higher Cmax (20.3 +/- 5.3 vs 17.7 +/- 4.4 micrograms ml-1; P < 0.02; 95% confidence interval for differences (CI): 0.5-4.6), AUC (86.2 +/- 23.5 vs 67.6 +/- 26.6 micrograms ml-1 h; P < 0.001; CI: 9.5-27.6), mean residence time (4.5 +/- 1.1 vs 4.1 +/- 1.2 h; P < 0.01; CI: 0.1-0.6) and renal clearance (0.8 +/- 0.6 vs 0.0 +/- 0.0 ml min-1; P < 0.001; CI: 0.5-1.0) values were observed for the (S)-enantiomer. 3. No difference was found (P > 0.05) between treatments in the percentage of the dose recovered in the urine as (R)- or (S)-ibuprofen plus metabolites (S-IBU: 80.2 +/- 8.47 vs RAC: 74.1 +/- 14.0%). 4. Interindividual variation in the pharmacokinetics of (S)-ibuprofen following administration of the racemate was similar to that following the administration of the single isomer suggesting that chiral inversion is not a major factor contributing to variability in the disposition of this drug.     

Renal effects of TAPP, a highly selective mu-opioid agonist.

1. The effect of i.v. administration of TAPP, a highly selective and exclusively peripherally-acting mu-opioid receptor agonist, on urine output, urinary sodium, potassium and cyclic GMP, and on plasma immunoreactive atrial natriuretic factor (IR-ANF) levels was studied in conscious normally hydrated female rats (200-250 g). 2. TAPP treatment produced a significant dose-dependent increase of urine output and urinary sodium, potassium and cyclic GMP excretion during the first hour. The highest TAPP dose used (2.5 mg kg-1. body weight) elicited a 10 fold elevation of urine output from 0.23 +/- 0.06 ml h-1 to 2.5 +/- 0.3 ml h-1 (n = 18) accompanied by augmented sodium [from 17.0 +/- 4.7 mu Eq h-1 to 79 +/- 12.7 mu Eq h-1, n = 18 (P < 0.001)], potassium [from 9.5 +/- 2.5 mu Eq h-1 to 39.4 +/- 6.6 mu Eq h-1, n = 18 (P < 0.005)], and cyclic GMP excretion [from 191 +/- 21 pmol h-1 to 1340 +/- 322 pmol h-1, n = 18 (P < 0.001)]. Plasma IR-ANF rose from 22 +/- 4 pg ml-1 to 508 +/- 22 pg ml-1 (n = 18) (P < 0.001) 5 min after administration of TAPP (2500 micrograms kg-1). 3. TAPP lowered systemic blood pressure, also in a dose-related manner, 1-5 min after injection. This decrease in blood pressure was transient and did not last more than 10 min. 4. Pretreatment with the opioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, natriuretic and kaliuretic effect of TAPP (250 micrograms kg-1); urine output dropped from 1.16 +/- 0.15 ml h-1, n = 12, to the control value of 0.15 +/- 0.06 ml h-1, n = 12 (P < 0.001), sodium excretion fell from 57.5 +/- 11 mu Eq h-1, to 21.3 +/- 8.5 mu Eq h-1, n = 12 (P < 0.001), and potassium excretion decreased from 45.4 +/- 9.7 mu Eq h-1, n = 12, to 16.1 +/- 7.0 mu Eq h-1, (P < 0.001). 5. Pretreatment with anti-ANF serum (0.4 ml) abolished the diuretic effect of TAPP: urine output diminished significantly from 1.93 +/- 0.28 to 0.88 +/- 0.29 ml h-1 (P < 0.01) (n = 6). The TAPP-induced diuretic action, increased sodium/potassium excretion and elevated urinary cyclic GMP levels were also reversed by anti-ANF antibodies. 6. Since TAPP is totally unable to cross the blood-brain barrier, the ensemble of these observations led to the conclusion that the diuretic, natriuretic, kaliuretic and hypotensive effects produced by this mu-opioid agonist through interaction with peripheral mu-opioid receptors occur via ANF release.     

Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation.

1. Felodipine 10 mg extended release was administered with 250 ml regular-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. The pharmacokinetics of felodipine and primary oxidative metabolite, dehydrofelodipine, were evaluated. 2. Initial grapefruit juice treatment increased felodipine AUC (mean +/- s.d.; 56.6 +/- 21.9 vs 28.1 +/- 11.5 ng ml-1 h; P < 0.001) and Cmax (8.1 +/- 2.5 vs 3.3 +/- 1.2 ng ml-1; P < 0.001) compared with water. Felodipine tmax (median; 2.8 vs 3.0 h) and t1/2 (7.3 +/- 3.7 vs 6.9 +/- 3.6 h) were not altered. 3. Readministration of felodipine with grapefruit juice produced mean felodipine AUC (61.5 +/- 32.2 ng ml-1 h) and Cmax (8.4 +/- 4.8 ng ml-1) which were similar to the initial grapefruit juice treatment 1-3 weeks previously. Felodipine AUC (r = 0.73, P < 0.01) and Cmax (r = 0.69, P < 0.02) correlated between grapefruit juice treatments among individuals. 4. The % increase in felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in felodipine Cmax among individuals (r = 0.80, P < 0.01). Dehydrofelodipine AUC (74.7 +/- 28.7 vs 48.5 +/- 16.3 ng ml-1 h; P < 0.01) and Cmax (12.1 +/- 2.9 vs 7.9 +/- 2.6 ng ml-1; P < 0.01) were augmented with grapefruit juice compared with water.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of tachykinin receptors mediating plasma extravasation and vasodilatation in normal and acutely inflamed knee joints of the rat.

1. Inflammatory actions of tachykinins in normal rat knee joints were compared with those of animals with acutely inflamed joints induced by intra-articular injection of 2% carrageenan. Plasma protein extravasation in rat knee joints, measured by protein micro-turbidimetry, was induced by intra-articular perfusion of selective tachykinin receptor agonists. Changes in joint blood flow, measured by laser Doppler perfusion imaging, were produced by topical applications of selective tachykinin receptor agonists to the joint capsule. 2. Carrageenan-injected rat knee joints showed significantly higher (P < 0.001) basal plasma extravasation (56 +/- 4 micrograms ml-1, n = 5) than normal rat knee joints (10 +/- 4 micrograms ml-1, n = 6). Intra-articular perfusion of the selective neurokinin1 (NK1) receptor agonist [Sar9, Met(O2)11]-substance P (0.8 nmol min-1) for 60 min elevated the basal plasma extravasation to 90 +/- 17 micrograms ml-1 (n = 6, P < 0.001) in normal joints, and to 150 +/- 14 micrograms ml-1 (n = 5, P < 0.001) in inflamed joints. Perfusion of the selective NK1 receptor antagonist N2-[(4R)-4-hydroxy-1-(1-methyl-1H- indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)- L-alaninamide (FK888; 0.8 nmol min-1) for 20 min followed by co-perfusion with the NK1 receptor agonist (0.8 nmol min-1) produced complete inhibition of the NK1 receptor agonist-induced plasma extravasation in the two groups of animals (for both groups; n = 3, P < 0.001). 3. Intra-articular perfusion of the selective NK receptor agonist [Nle10]-neurokinin A4-10 (0.8 nmol min-1) and the selective NK3 receptor agonist [MePhe7]-neurokinin B (0.8 nmol min1) produced no increase in plasma extravasation in normal or in inflamed rat knee joints (n = 4 and 11, P > 0.05). 4. Topical bolus applications of the NK1 receptor agonist [Sar9, Met(O2)11]-substance P onto normal joint capsules produced dose-dependent vasodilatation expressed as a voltage increase from control level. The maximum increase in blood flow was 2.05-0.21 V from a basal voltage of 3.42 +/- 0.07 V (n = 13, P < 0.001). To a much lesser extent, administration of the NK2 receptor agonist [Nle10]-neurokinin A4-10 also produced dose-dependent vasodilatation with maximum increase of 0.46 +/- 0.08 V from a basal level of 3.38 +/- 0.1 V (n = 7, P < 0.01). Animals with acutely inflamed joints showed enhanced vasodilator responses to the NK1 and NK2 receptor agonists (for both: P vs non-inflamed joints < 0.001). Thus, the NK1 and NK2 receptor agonists produced maximum increases of 2.56 +/- 0.19 V (basal level = 5.84 +/- 0.07 V; n = 7, P < 0.001) and 1.97 +/- 0.26 V (basal level = 6.31 +/- 0.23 V; n = 11, P < 0.001), respectively. The NK3 receptor agonist [MePhe7]-neurokinin B produced no change in blood flow in normal or in inflamed rat knee joints (n = 7 and 5, P > 0.05). 5. Bolus administration of the NK1 receptor antagonist FK888 (10 pmol) alone followed 5 min later by another dose of 10 pmol FK888 (i.e. total dose of 2 x 10 pmol) applied together with the NK1 receptor selective agonist [Sar9, Met(O2)11]-substance P produced partial, but significant inhibition of the NK1 receptor agonist-induced vasodilatation in both normal (maximum response reduced by 51.9 +/- 5.4%; n = 6, P < 0.001) and inflamed rat knee joints (maximum response reduced by 49.3 +/- 6.1%; n = 5, P < 0.001). The NK2 receptor agonist [Nle10]-neurokinin A4-10-induced vasodilator responses in inflamed joints were not affected by this treatment (n = 6, P > 0.05). However, with two higher doses of FK888 (both 1 nmol), the NK1 and the NK2 receptor agonist-induced vasodilator responses were abolished in the two groups of animals (n = 6-8, P < 0.005). 6. Administration of two doses of the selective NK2 receptor antagonist (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) -butyl]benzamide (SR48968;...     

Effect of dexamethasone and endogenous corticosterone on airway hyperresponsiveness and eosinophilia in the mouse.

1. Mice were sensitized by 7 intraperitoneal injections of ovalbumin without adjuvant (10 micrograms in 0.5 ml of sterile saline) on alternate days and after 3 weeks exposed to either ovalbumin (2 mg ml-1 in sterile saline) or saline aerosol for 5 min on 8 consecutive days. One day before the first challenge, animals were injected intraperitoneally on a daily basis with vehicle (0.25 ml sterile saline), dexamethasone (0.5 mg kg-1) or metyrapone (30 mg kg-1). 2. In vehicle-treated ovalbumin-sensitized animals ovalbumin challenge induced a significant increase of airway responsiveness to metacholine both in vitro (27%, P < 0.05) and in vivo (40%, P < 0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected after saline challenge, whereas the numbers of eosinophils were significantly increased (P < 0.01) at both 3 and 24 h after the last ovalbumin challenge (5.48 +/- 3.8 x 10(3) and 9.13 +/- 1.7 x 10(3) cells, respectively). Furthermore, a significant increase in ovalbumin-specific immunoglobulin E level (583 +/- 103 units ml-1, P < 0.05) was observed after ovalbumin challenge compared to saline challenge (201 +/- 38 units ml-1). 3. Plasma corticosterone level was significantly reduced (-92%, P < 0.001) after treatment with metyrapone. Treatment with metyrapone significantly increased eosinophil infiltration (17.4 +/- 9.93 x 10(3) and 18.7 +/- 2.57 x 10(3) cells, P < 0.05 at 3 h and 24 h, respectively) and potentiated airway hyperresponsiveness to methacholine compared to vehicle-treated ovalbumin-challenged animals. Dexamethasone inhibited both in vitro and in vivo hyperresponsiveness as well as antigen-induced infiltration of eosinophils (0, P < 0.05 and 0.7 +/- 0.33 x 10(3) cells, P < 0.05 at 3 h and 24 h, respectively). Metyrapone as well as dexamethasone did not affect the increase in ovalbumin-specific immunoglobulin E levels after ovalbumin challenge (565 +/- 70 units/ml-1; P < 0.05; 552 +/- 48 units ml-1, P < 0.05 respectively). 4. From these data it can be concluded that exogenously applied corticosteroids can inhibit eosinophil infiltration as well as airway hyperresponsiveness. Vise versa, endogenously produced corticosteroids play a down-regulating role on the induction of both eosinophil infiltration and airway hyperresponsiveness.     

Factors affecting the absolute bioavailability of nifedipine.

1. Nifedipine was administered to eight volunteers (seven Caucasian, one East Asian of Chinese origin) as a single 10 mg capsule orally and as 2.5 mg intravenously. The pharmacokinetics were determined under fasting conditions and following 200 ml double strength grapefruit juice taken orally both 2 h before and at the time of dosing. 2. In a separate study, the pharmacokinetics of nifedipine were defined in eight South Asian volunteers (with both parents originating from the Indian subcontinent) following 10 mg nifedipine orally and 2.5 mg intravenously. 3. The administration of grapefruit juice did not alter the pharmacokinetics of intravenous nifedipine, but resulted in a significantly increased area under the plasma concentration-time curve (AUC) (191 +/- 59 c.f. 301 +/- 95 ng ml-1 h, P < 0.05) and bioavailability (0.63 +/- 0.18 c.f. 0.86 +/- 0.15, P < 0.05) following oral nifedipine. The elimination half-life was unchanged by administration of grapefruit juice and there was no evidence of decreased formation of the nitropyridine first-pass metabolite. 4. The AUC of nifedipine after intravenous administration was significantly higher in South Asian subjects than in Caucasians (146 +/- 39 c.f. 74 +/- 18 ng ml-1 h, P < 0.002). This was due to a lower systemic clearance in the South Asians which was 50% of that in the Caucasians. The half-life was markedly prolonged in South Asians (4.1 +/- 1.9 c.f. 1.7 +/- 0.5 h, P < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of gender and sex steroid hormones on the plasma binding of propranolol enantiomers.

1. Plasma binding of tritium-labelled racemic propranolol (P) was measured by equilibrium dialysis. The unbound enantiomers were separated by h.p.l.c. after chiral derivatization. The binding of (-)-P was higher than that of (+)-P. 2. Contrary to previous suggestions, a sex difference in the plasma binding of the P enantiomers (9 young women, 12 young men) was not observed. The unbound percentage of (-)-P was 9.2 +/- 1.8 (mean +/- s.d.) in women vs 9.1 +/- 1.7 in men; for (+)-P it was 10.8 +/- 1.8 vs 10.8 +/- 2.1. 3. In the nine women, the binding did not change with fluctuating plasma oestradiol concentrations during the menstrual cycle. Testosterone cypionate doubled the circulating concentrations of testosterone in eight men but had no effect on P binding. 4. Ethinyl oestradiol (50 micrograms day-1) alone or together with norethindrone (OCD) in eight of the women produced an increase in the unbound percentage of both (-)-P (11.4 +/- 2.6 vs 9.5 +/- 1.6 for control; P < 0.001) and (+)-P (13.2 +/- 2.5 vs 11.2 +/- 1.5 for control; P < 0.001). This was due to a decrease in the plasma concentrations of alpha 1-acid glycoprotein from 0.54 +/- 0.11 mg ml-1 in control to 0.37 +/- 0.08 mg ml-1 (P < 0.001) during ethinyl oestradiol treatment. 5. Enantioselectivity in the unbound fraction of P increased with increasing total binding from a (-)/(+)-ratio of 0.93 at 84% binding to a (-)/(+)-ratio of 0.78 at 94% binding (P < 0.001).     

Ethnic differences in nifedipine kinetics: comparisons between Nigerians, Caucasians and South Asians.

Nifedipine was administered to 12 healthy Nigerian volunteers as a single oral dose of 20 mg capsule under fasting conditions. The pharmacokinetic results were compared with published data using the same protocol and analytical method for 27 Caucasians and 30 South Asians. The area under the plasma concentration-time curve (AUC) of nifedipine in Nigerians (808 +/- 250 ng ml-1 h) was significantly higher (P < 0.001) than that in Caucasians (323 +/- 116 ng ml-1 h) and the difference remained significant (P < 0.001) when corrected for body weight. The elimination half-life was also significantly higher (P < 0.01) in Nigerians (5.03 +/- 1.96 h) than in Caucasians (2.78 +/- 1.11 h). No significant differences were observed between Nigerians and South Asians in either AUC or half-life of nifedipine. The AUC of the nitropyridine metabolite was higher (P < 0.01) in Nigerians (220 +/- 51 ng ml-1 h) compared with that in Caucasians (154 +/- 56 ng ml-1 h) but the difference was not maintained when corrected for body weight. The AUC corrected for body weight and the elimination half-life of the metabolite were significantly higher in South Asians compared with those of Nigerians and Caucasians. The pharmacokinetics of oral nifedipine in Nigerians were similar to those in South Asians and therefore may also arise from a lower systemic clearance compared with Caucasians as has been reported previously for South Asians.     

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients.

Ten patients with head trauma received an intravenous bolus of sufentanil (2 micrograms kg-1) followed at 30 min by infusion of sufentanil (median 150 micrograms h-1) and midazolam (median 9.0 mg h-1) over 48 h. Median (range) values of pharmacokinetic parameters for sufentanil were: t1/2,z = 16 (7-49) h; CL = 1215 (519-2550) ml min-1; CLR = 7 (2-38) ml min-1; Vss = 10.0 (6.8-24.2) 1 kg-1. Decreases in intracranial pressure (ICP) (from 16.1 +/- 1.7 to 10.8 +/- 1.3 mm Hg; P < 0.05) and mean arterial blood pressure (MAP) (from 85.5 +/- 3.9 to 80.2 +/- 4.9 mm Hg; P < 0.05) were observed within 15 min of the bolus injection of sufentanil and remained unchanged thereafter. Thus, cerebral perfusion pressure (CPP = MAP-ICP) was stable.     

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.     

Preliminary investigation of the efficacy of sublingual verapamil in the management of acute atrial fibrillation and flutter.

The antiarrhythmic properties of sublingual verapamil were investigated in seven patients with acute fast atrial flutter (n = 2) or fibrillation (n = 5). A rapid and significant (P < 0.05) reduction in the ventricular rate was achieved in all seven patients. The ventricular rate at peak plasma verapamil concentration (+/- s.d.) was significantly slower than on admission (101.6 +/- 11.3 and 159 +/- 5.3 beats min-1 respectively, P < 0.01). The ventricular rate remained controlled for over 4 h. Sublingual verapamil was rapidly absorbed with the maximum peak plasma concentration (153.3 +/- 15.5 ng ml-1) being achieved after 1.21 +/- 0.18 h. Side-effects of sublingual verapamil were limited to one report of a bitter taste. The sublingual administration of verapamil may provide an alternative method for the control of acute fast atrial fibrillation and flutter in selected patients.     

Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers.

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration-time curve six-fold (P < 0.001), the peak concentration 2.5-fold (P < 0.001) and the elimination half-life two-fold (P < 0.001) compared with placebo and terbinafine pretreatments. The pharmacokinetic parameters did not differ between placebo and terbinafine phases. The higher concentrations of midazolam during the itraconazole phase were associated with increased effects. In contrast to itraconazole, terbinafine had no effect on midazolam pharmacokinetics and psychomotor performance tests were unchanged from placebo.     

Pharmacokinetics of the enantiomers of bupivacaine following intravenous administration of the racemate.

1. The pharmacokinetics of R(+)-bupivacaine and S(-)-bupivacaine were investigated following a 10 min intravenous infusion of the racemate (dose 30 mg) in 10 healthy males. 2. The fractions unbound of R(+)- and S(-)-bupivacaine in pre-dose plasma were determined for each subject after in vitro addition of rac-bupivacaine (concentration of each enantiomer: approximately 300 ng ml-1). 3. The total plasma clearance of R(+)-bupivacaine (mean +/- s.d.: 0.395 +/- 0.076 l min-1) was greater (P < 0.0001) than that of S(-)-bupivacaine (0.317 +/- 0.067 l min-1). The volumes of distribution of R(+)-bupivacaine at steady state (84 +/- 29 l) and during the terminal log-linear phase (117 +/- 47 l) were larger (P < 0.0002) than those of S(-)-bupivacaine (54 +/- 20 l and 71 +/- 34 l, respectively). The terminal half-life (210 +/- 95 min) and mean residence time (215 +/- 74 min) of R(+)-bupivacaine were longer than those of S(-)-bupivacaine (157 +/- 77 min, P < 0.01, and 172 +/- 55 min, P < 0.02, respectively). 4. The free percentage of R(+)-bupivacaine (6.6 +/- 3.0 %) was greater (P < 0.0002) than that of S(-)-bupivacaine (4.5 +/- 2.1 %). 5. The plasma clearance of unbound R(+)-bupivacaine (7.26 +/- 3.60 1 min-1) was smaller (P < 0.01) than that of S(-)-bupivacaine (8.71 +/- 4.27 l min-1). Volumes of distribution based on unbound R(+)-bupivacaine concentrations (Vuss: 1576 +/- 934 l; Vu: 2233 +/- 1442 l) did not differ from those of S(-)-bupivacaine (Vuss: 1498 +/- 892 l; Vu: 1978 +/- 1302 l). 6. The enantioselective systemic disposition of bupivacaine can to a large extent be attributed to differences in the degree of plasma binding of the enantiomers.     

Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.

1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of substance P-induced microvascular leakage by inhaled methoxamine in rat airways.

1. The effect of the inhaled alpha-adrenoceptor agonist, methoxamine (MTX), was studied on experimental airway oedema induced by injection of substance P (SP) in the rat. Sprague-Dawley rats (300-350 g) were anaesthetized with sodium thiopentone, tracheotomized and artificially ventilated. 2. MTX or its vehicle was administered by inhalation. Airway resistance and blood pressure were monitored continuously. Evans Blue dye (EB, 20 mg kg-1) was injected through a jugular catheter 1 min before SP (14.8 nmol kg-1). Airways were dissected out, weighed and placed in formamide for EB extraction and determination by spectrophotometry. 3. EB extravasation induced by SP was significantly reduced in distal intraparenchymal bronchi by inhaled MTX at doses of 50 micrograms kg-1 (58 +/- 9 vs 96 +/- 9 ng EB mg-1 tissue after vehicle, P < 0.001) and 100 micrograms kg-1 (69 +/- 11 vs 137 +/- 26 ng EB mg-1 tissue after vehicle, P < 0.01). Inhaled MTX by itself (100 micrograms kg-1) increased blood pressure: 172 +/- 6 vs 132 +/- 10 mmHg baseline (P < 0.02), but neither induced extravasation nor increased airway resistance. 4. In another set of experiments without SP, MTX was administered intravenously 1 min after EB. At 100 micrograms kg-1, i.v. MTX increased blood pressure to a similar extent as inhaled MTX (180 vs 147 mmHg baseline, P < 0.01), increased airway resistance and caused leakage of plasma proteins in distal intraparenchymal bronchi (79 +/- 7 vs 47 +/- 1 ng EB mg-1 tissue, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Neither cimetidine nor probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.

The effect of pretreatment with cimetidine (1 g day-1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml-1 alone, 3.5 micrograms ml-1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.     

Allopurinol and amlodipine improve coronary vasodilatation after myocardial ischaemia and reperfusion in anaesthetized dogs.

1. We have assessed the effect of allopurinol, amlodipine and propranolol pretreatment on both endothelium-dependent and endothelium-independent coronary vasodilatation in vivo, by comparing pre-ischaemic responses with those measured after 60 min of coronary artery occlusion and 30 min of reperfusion in anaesthetized dogs. 2. In 15 untreated dogs ischaemia and reperfusion attenuated the increases in coronary blood flow produced by either acetylcholine (0.01-0.05 micrograms kg-1, i.a.) or glyceryl trinitrate (0.05-0.2 micrograms kg-1, i.a.), to an average of 39 +/- 4% and 42 +/- 5% of the pre-ischaemic control response, respectively (both P < 0.05). 3. In 5 dogs treated with allopurinol (25 mg kg-1, orally, 24 h previously, plus 50 mg kg-1, i.v., 5 min before occlusion), the increases in coronary blood flow after ischaemia and reperfusion (acetylcholine: 78 +/- 12%, glyceryl trinitrate: 60 +/- 3% of pre-ischaemic response) were significantly larger than post-ischaemic responses in untreated dogs (both P < 0.05). 4. Similarly, amlodipine treatment (3 micrograms kg-1 min-1, i.v., starting 90 min before occlusion) in 5 dogs improved post-ischaemic increases in blood flow (acetylcholine: 58.5%, glyceryl trinitrate: 66 +/- 6% of pre-ischaemic response, significantly greater than post-ischaemic responses in untreated dogs, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscarinic effect of atrial natriuretic peptide on rabbit airways.

1. The aim of the present work was to investigate under which circumstances atrial natriuretic peptide (ANP) modulates airway resistance. 2. Of the six groups of rabbits (n = 5) studied, three received an infusion of ANP (80 ng min-1 kg-1 i.v.) for a period of 100 min, while the other three were infused with the vehicle. Before receiving the infusion of ANP or the vehicle, the animals were pretreated with atropine (0.5 mg kg-1 i.v.), propranolol (2 mg kg-1 i.v.) or not pretreated. After 75 min of infusion of ANP, bronchoconstriction was induced by inhalation of histamine. Respiratory resistance (Rrs) was measured before and 3, 5, 10, 15 and 20 min post-histamine challenge. 3. Following 75 min of ANP infusion, plasma ANP concentration increased from 153 +/- 52 (mean +/- s.e.mean) to 1441 +/- 203 pg ml-1 (P < 0.05) without affecting baseline Rrs. Control Rrs values (12.5-20.4 cmH2O l-1 s) were significantly increased following the inhalation of histamine (P < 0.001). By themselves, atropine, propranolol or ANP did not modify the histamine-induced increase in Rrs. However, when the animals were pretreated with atropine, ANP infusion significantly reduced the increase in Rrs induced by histamine (30 +/- 2 vs 51 +/- 6 cmH2O l-1 s; P < 0.05). 4. These data suggest that ANP has an indirect modulating effect on the airway smooth muscle and will decrease Rrs when muscarinic receptors are blocked.