Decrease in penbutolol central response as a cause of changes in its serum protein binding

Penbutolol is a beta-adrenoceptor antagonist that is extensively bound to alpha 1-acid glycoprotein (alpha 1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P less than 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in alpha 1-AGP concentration, which reduces their central pharmacological effect.     

Effect of caffeine on the plasma protein binding and the disposition of ceftriaxone

The effects of caffeine on the in-vitro protein binding and the pharmacokinetics of ceftriaxone (a highly protein bound cephalosporin) were investigated. Caffeine failed to decrease in-vitro protein binding of ceftriaxone. Rabbit plasma concentrations of ceftriaxone (30 mg kg-1 i.v.) were elevated significantly (P less than 0.05 at 0.3, 0.6 and 1 h after injection) when caffeine 5 or 10 mg kg-1 i.v. was co-administered compared with ceftriaxone given alone. Caffeine increased the volume of distribution of the central compartment (V1) for ceftriaxone significantly from 49 +/- 38 ml kg-1 (mean +/- s.d., n = 6) to 97 +/- 33 ml kg-1 (caffeine 5 mg kg-1, P less than 0.05), and 94 +/- 8 ml kg-1 (caffeine 10 mg kg-1, P less than 0.05) and decreased the volume of distribution of the peripheral compartment (V2) from 145 +/- 106 ml kg-1 (mean +/- s.d., n = 6) to 31 +/- 18 ml kg-1 (caffeine 5 mg kg-1, P less than 0.5) and 36 +/- 31 ml kg-1 (caffeine 10 mg kg-1, P less than 0.1). The rate of transfer of ceftriaxone to the peripheral compartment (k12) was also decreased significantly (P less than 0.05) after caffeine. The elevated plasma concentration of ceftriaxone, increased V1 value and the decreased V2 and k12 values are probably the result of caffeine altering the distribution of ceftriaxone to the central and the peripheral compartments.     

The effect of fever on quinine and quinidine disposition in the rat.

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.     

Sex-related differences in disposition and response to phenprocoumon in rats

The pharmacokinetics and the pharmacological response to phenprocoumon have been studied in female and male inbred Lewis-Wistar rats. A significantly lower clearance was found in female than in male rats (7.9 +/- 1.4 vs 24.5 +/- 2.5 mL h-1 kg-1, respectively; t = 15.09, P less than 0.001) as well as a lower apparent volume of distribution (288 +/- 46 vs 617 +/- 105 mL kg-1; t = 7.58, P less than 0.001) and a longer half-life (25.5 +/- 3.4 vs 17.5 +/- 1.8 h; t = 5.16, P less than 0.001). The binding of phenprocoumon was higher in female than in male rats (fu: 0.0096 +/ 0.0008 vs 0.0124 +/- 0.0007, respectively; t = 6.66, P less than 0.001). The total (C) as well as the unbound concentration (Cu) needed to elicit a 50% decrease in the prothrombin complex synthesis rate was substantially higher in female rats: C50 was 377 +/- 98 ng mL-1 in female and 155 +/- 29 ng mL-1 in male rats (t = 5.32, P less than 0.001), whereas Cu50 was 3.6 +/- 0.7 ng mL-1 in female and 1.9 +/- 0.3 ng mL-1 in male rats (t = 5.50, P less than 0.001). However, because of the lower clearance and volume of distribution and the longer half-life in female rats, the female rats experienced a higher cumulative effect than male rats to 0.34 mg kg-1 i.v. doses.     

The role of vagal adrenergic activity in the mechanism of gastric acid secretion after pylorus-ligation in the rat

The role of the vagus nerve and adrenoceptor stimulation in acid secretion after pylorus-ligation in the rat has been examined. All drugs were administered intraperitoneally. Atropine (5 mg kg-1) depressed the H+ output (111 mumols +/- 33.8 vs 412.5 mumols +/- 62.2, mean +/- s.e.m., n = 10, P less than 0.001); cimetidine (40 mg kg-1) did not enhance this action, while vagotomy was more effective than atropine (32.7 mumols +/- 4.9, mean +/- s.e.m., n = 10, P less than 0.05). Atropine (10 mg kg-1) produced a similar depression to the 5 mg kg-1 dose. Cimetidine (100 mg kg-1) depressed the H+ output (248.5 mumols +/- 46.8, mean +/- s.e.m., n = 10, P less than 0.05). Propranolol (5-20 mg kg-1) had no significant effect on the H+ output but dose-dependent inhibition was produced by phenoxybenzamine or phentolamine; an inhibition similar to that achieved by vagotomy was seen with the 20 mg kg-1 dose. Both these drugs (5 or 10 mg kg-1) had no significant effect on the H+ output when given with atropine (5 mg kg-1) but the H+ output was significantly lower than that produced by either drug at the same dose given alone. Atropine (5 mg kg-1) with phenoxybenzamine or phentolamine (20 mg kg-1) produced H+ output not significantly different from that with vagotomy or either alpha-adrenoceptor given alone at 20 mg kg-1, but the result was significantly (P less than 0.05) lower than the H+ output with atropine (5 mg kg-1) alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative pharmacokinetics of coumarin anticoagulants XLIII: Concentration-dependent hepatic uptake of warfarin in rats

The purpose of this study was to determine if hepatic warfarin uptake, which has a major quantitative effect on warfarin distribution in rats, is concentration dependent. Adult male rats received either 0.1 or 1.0 mg of racemic warfarin/kg iv and were killed 6 hr later. With increasing dose, the concentrations of free and total (free plus protein-bound) serum warfarin increased much more than proportionally, and the total warfarin concentration in the liver increased much less than proportionally. The liver to serum total warfarin concentration ratios 6 hr after injection of the 0.1- and 1.0-mg/kg doses were 11.3 +/- 1.7 and 0.814 +/- 0.222, respectively (mean +/- SD, n = 6, p less than 0.001). The ratio of the total drug concentration in the liver to the free drug concentration in serum (mean +/- SD) was 866 +/- 105 in animals that received the 0.1-mg/kg dose and 111 +/- 42 in animals that received the 1.0-mg/kg dose (p less than 0.001). It is concluded that hepatic warfarin uptake decreases with increasing drug concentration and that this may cause the apparent volume of distribution of warfarin to decrease with increasing dose in rats.     

Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo.

The adenosine receptor has been implicated in the central mechanism of action of benzodiazepines. The specific binding of an A1-selective adenosine antagonist radioligand, [3H]8-cyclopentyl-1,3-dipropylxanthine, was measured in-vivo in mice treated with alprazolam (2 mg kg-1, i.p.), lorazepam (2 mg kg-1, i.p.) and vehicle. Binding studies were performed in-vivo and ex-vivo in mice receiving continuous infusion of alprazolam (2 mg kg-1 day-1), lorazepam (2 mg kg-1 day-1) and vehicle by mini-osmotic pumps for 6 days. Continuous infusion of alprazolam and lorazepam significantly decreased specific binding by 34 and 53%, respectively, compared with vehicle treatment (P less than 0.01). Single doses of alprazolam and lorazepam induced a similar trend in specific binding in-vivo (P = 0.07). There were no alterations in A1-receptor density (Bmax) or affinity (Kd) in cortex, hippocampus or brainstem in ex-vivo studies. Benzodiazepine treatment may diminish A1- receptor binding in-vivo by inhibiting adenosine uptake or by direct occupancy of the A1 adenosine receptor recognition site.     

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.     

Pharmacokinetics of ketoprofen in the elderly.

Pharmacokinetic constants of ketoprofen (Orodis, Profenid) were determined in 10 young adults (24.9 +/- 1.3 years) and seven elderly patients (86.3 +/- 2.4). Following oral administration of a 150 mg dose of ketoprofen, no difference in tmax was observed between the two groups. However, compared with younger subjects elderly patients showed a significant increase in t1/2,z (2.72 +/- 0.22 vs 1.77 +/- 0.16 h; P less than 0.01) and AUC (70.4 +/- 6.4 vs 29.13 +/- 2.02 mg l-1 h; P less than 0.001), a non-significant reduction of Vd/F per kg bodyweight (0.145 +/- 0.016 vs 0.213 +/- 0.028 l kg-1) and a decrease in total clearance CLT/F (0.037 +/- 0.002 vs 0.071 +/- 0.004 l h-1 kg-1, P less than 0.05). These results suggest that the glucuroconjugation of ketoprofen is slowed down by age.     

The disposition of chloramphenicol in colostrum-fed and colostrum-deprived newborn pigs

The pharmacokinetics of chloramphenicol (CAP) were studied in four colostrum-deprived and 4 colostrum-fed newborn piglets after an intravenous bolus dose of CAP, 77 mumol kg-1 (25 mg kg-1). The elimination half-lives in the colostrum deprived piglets had a tendency to be longer (17.2 +/- 3.9 hrs) than in the colostrum-fed piglets (12.7 +/- 1.1 hrs) and in both groups they were considerably longer than reported in older pigs. The long half-lives of CAP in the newborn pigs were a reflexion of very low clearance (Cl) values, 0.0391 +/- 0.007 and 0.0512 +/- 0.007 1 kg-1 hr-1, in the two groups, while the volume of distribution was of the same size in the two groups, 0.9549 +/- 0.247 and 0.9411 +/- 0.211 1 kg-1. The protein binding of CAP in pooled piglet plasma was concentration dependent, 53-45%, (P less than 0.001) in the concentration range 31-232 microM (10-75 micrograms ml-1) and the binding degree was significantly higher in plasma from colostrum deprived piglets, 53.0 +/- 0.8% compared to plasma from colostrum fed, 47.5 +/- 1.3% (P less than 0.01).     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

Effect of L-arginine on restraint stress induced modulation of immune responses in rats and mice.

The present study investigates the role of nitric oxide (NO) on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses in rats and mice. RS produced suppression of humoral immune response, i.e., anti-SRBC antibody titre ( 7.38 +/- 0.32 versus 4.13 +/- 0.30; mean +/- S.E.M., P < 0.001). In case of cell-mediated immunity, in delayed type hypersensitivity (DTH) response the change in paw volume decreased from 0.069 +/- 0.003 mm (mean +/- S.E.M.) in control non-stressed group to 0.038 +/- 0.002 mm in the stressed group (P < 0.001) while percentage leucocyte migration inhibition (% LMI) decreased from 39.7 +/- 1.95 in control non-stressed animals to 15.2 +/- 1.07 in animals subjected to stress (P < 0.01). Pretreating the animals with an NO precursor, L-arginine (1000 mg kg-1, i.p.) antagonized the effect of RS on humoral (anti-SRBC antibody titre 6.50 +/- 0.27 versus 4.13 +/- 0.30, P < 0.001 ) and cell-mediated (DTH response 0.066 +/- 0.002 mm versus 0.038 +/- 0.002 mm, P < 0.001; % LMI 41.5 +/- 1.46 versus 15.2 +/- 1.07, P < 0.01) immune responses. Administration of 7-nitroindazole (7-NI, 50 mg kg-1, i.p.), an inhibitor of neuronal NO synthase, alone further enhanced the immunosuppressive effect of RS (anti-SRBC antibody titre 2.75 +/- 0.25 versus 4.13 +/- 0.30, P < 0.001; DTH response 0.019 +/- 0.002 mm versus 0.038 +/- 0.002 mm, P < 0.001; % LMI 5.0 +/- 1.08 versus 15.2 +/- 1.07, P < 0.01). However, when given before L-arginine treatment, 7-NI reversed the effect of the latter drug on stress-induced immunomodulation (anti-SRBC antibody titre 3.00 +/- 0.27 versus 6.5 +/- 0.27, P < 0.001; DTH response 0.043 +/- 0.003 mm versus 0.066 +/- 0.002 mm, P < 0.001; % LMI 12.0 +/- 0.93 versus 41.5 +/- 1.46, P < 0.01). Unlike its effect on RS-induced immune responsiveness, L-arginine (250, 500, 1000 mg kg-1) when given for 5-7 days to naive non-stressed animals produced dose dependent suppression of both humoral (anti-SRBC antibody titre 6.4 +/- 0.32 versus 5.4 +/- 0.32, 4.0 +/- 0.27, 3.1 +/- 0.30, respectively) and cell-mediated (DTH 0.065 +/- 0.003 mm versus 0.064 +/- 0.004 mm, 0.039 +/- 0.003 mm, 0.020 +/- 0.002 mm, respectively and % LMI 37.52 +/- 1.58 versus 30.48 +/- 1.07, 28.18 +/- 1.22, 19.76 +/- 0.83, respectively) immune responses. 7-NI significantly blocked these immunosuppressive effects of L-arginine (anti-SRBC antibody titre 6.0 +/- 0.38 versus 3.1 +/- 0.030, P < 0.01; DTH response 0.056 +/- 0.004 mm versus 0.020 +/- 0.002 mm, P < 0.001; % LMI 34.76 +/- 1.31 versus 19.76 +/- 0.83, P < 0.01). However, 7-NI when given to non-stressed animals failed to modulate immune responsiveness. Thus, NO appears to play an important role in RS-induced immunomodulation and these effects are different from its effect on immune responsiveness in non-stressed animals.     

Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhanced by antidepressant drugs and ECS.

1 Intraperitoneal injection to mice of the gamma-aminobutyric acidB (GABAB) receptor agonist (+/-)-baclofen induces a dose-dependent decrease in rectal temperature. 2 Injection of (-)-baclofen intracerebroventricularly at doses that had no effect when given peripherally induced a marked hypothermia. (+)-Baclofen was without effect. 3 The decrease in rectal temperature induced by (-)-baclofen when injected intraperitoneally was highly correlated with an increase in sedation. 4 Repeated administration of amitriptyline (10 mg kg-1 daily for 14 days) resulted in mice displaying an enhanced temperature and sedation response to injection of (+/-)-baclofen (5 mg kg-1) 24 h after the last dose of antidepressant. 5 An enhanced hypothermic response was also seen following repeated administration of zimeldine, mianserin or desipramine (all 10 mg kg-1 daily for 14 days) or repeated electroconvulsive shock (ECS; 5 ECS over 10 days) 24 h after the last treatment. 6 A single administration of any of the antidepressant drugs or ECS or repeated administration of the anxiolytic drug flurazepam (20 mg kg-1 daily for 14 days) did not alter the baclofen-induced hypothermic response. 7 Administration of (+/-)-baclofen (5 mg kg-1) daily for 5 or 14 days attenuated the baclofen-induced hypothermic response. However, one pretreatment dose did not alter the response. 8 It has previously been reported that repeated baclofen administration decreases GABAB receptor number in the brain while repeated administration of antidepressant drugs and ECS increases the density of this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic mianserin treatment decreases 5-HT2 receptor binding without altering 5-HT2 receptor mRNA levels

Rats were injected with 15 mg/kg (i.p.) mianserin or vehicle (saline) for 4, 10 or 21 days and 5-HT2 receptor binding and mRNA levels measured. Treatment with mianserin induced a substantial decrease in 5-HT2 radioligand binding (44-59% decrease; P less than 0.05 vs. control). No changes in the amount of 5-HT2 or, as a control, beta-actin mRNAs were found (P greater than 0.05 vs. control). These results indicate that mianserin decreases 5-HT2 radioligand binding without altering steady-state 5-HT2 mRNA levels.     

The effects of acute and repeated administration of various antidepressant drugs on clonidine-induced hypoactivity in mice and rats

Small doses of clonidine produce hypoactivity in mice and rats, probably by stimulating pre-synaptic alpha 2-adrenoceptors in the brain. When mice were injected with desmethylimipramine (DMI, 5 mg/kg) before clonidine it attenuated the hypoactivity, while pretreatment with amitriptyline (5 mg/kg) or mianserin (5 mg/kg) potentiated this behaviour. In rats, desmethylimipramine (20 mg/kg) inhibited and mianserin (5 mg/kg) potentiated the clonidine-induced hypoactivity. Amitriptyline (20 mg/kg), however, had no effect on this behaviour in rats. Mice were also given repeated injections of these 3 antidepressant drugs (5 mg/kg twice daily for 14 days) and were tested with clonidine 12 and 60 hr after the final treatment. At 12 hr desmethylimipramine and amitriptyline both attenuated the hypoactivity responses while the reduction by mianserin was marginal (potency DMI greater than amitriptyline greater than mianserin). At 60 hr, however, amitriptyline and mianserin both decreased the clonidine-induced responses while the attenuation by desmethylimipramine was slight (potency amitriptyline congruent to mianserin greater than DMI). In rats, repeated injections of desmethylimipramine (20 mg/kg), administered twice daily for 14 days, attenuated the clonidine-induced hypoactivity 12 hr after the final treatment and this effect persisted for at least 72 hr. Furthermore, the degree of inhibition of the behavioural responses did not correlate with plasma concentrations of desmethylimipramine and persisted after disappearance of the drug from plasma. In conclusion, these data suggest that after repeated injection, desmethylimipramine, amitriptyline and mianserin all produce an adaptive decrease in the function of central alpha 2-adrenoceptors but the time course of this change differs with the individual antidepressant drug administered.     

Pharmacokinetics of the trimethoprim-sulphamethoxazole combination in the elderly.

The pharmacokinetics of a co-trimoxazole preparation (Bactrim Forte) containing trimethoprim (TMP) 160 mg and sulphamethoxazole (SMZ) 800 mg were determined in six young adults (29.3 +/- 4.4 s.d. years) and six elderly people (78.6 +/- 6.6 s.d. years). Following oral administration of a single dose, the pharmacokinetic parameters of SMZ and its N4-acetylated metabolite (N4SMZ) were similar in both groups. However Cmax of TMP was greater (2.06 +/- 0.29 s.d. vs 1.57 +/- 0.32 s.d. mg l-1; P less than 0.01) and its area under the curve was larger (34.30 +/- 6.98 s.d. vs 23.87 +/- 3.82 s.d. mg l-1 h; P less than 0.001) in elderly people than in younger subjects. Total clearance (CL/F) of TMP normalized to body weight was not significantly different in the two groups. There was no significant difference in serum protein binding of TMP and SMZ between the two groups. Urinary excretion of TMP, SMZ and N4SMZ was reduced by about 50% in the elderly compared to the young subjects. Renal clearance of TMP was significantly lower in the elderly group (19 +/- 10 s.d. vs 55 +/- 14 s.d. ml h-1 kg-1; P less than 0.001). Renal clearance of SMZ was not significantly different in the two groups. A study of plasma concentrations of TMP, SMZ and N4SMZ during continuous dosing in seven elderly patients treated for urinary or respiratory infections showed that steady state was reached after 3 days of treatment and that plasma drug concentrations were about two to three times higher than those observed after a single dose.     

Protein binding and CSF penetration of phenytoin following acute oral dosing in man.

Prophylactic phenytoin (DPH) has been evaluated in 20 patients undergoing diagnostic myelography. DPH (0.75 g) was ingested at 20.00 h the night before and 0.5 g at 08.00 h on the morning of the procedure. Total DPH concentrations at myelography (mean +/- s.d.: 12.7 +/- 4.3 mg l-1; range 6.3-21.5 mg l-1) correlated with CSF values (1.3 +/- 0.46 mg l-1; range 0.7-2.2 mg l-1; r = 0.83, P less than 0.001). DPH protein binding at that time varied two-fold (9.2-18.5%) and free drug levels (1.7 +/- 0.6 mg l-1) correlated with CSF (r = 0.83, P less than 0.001) and total (r = 0.89, P less than 0.001) plasma DPH concentrations. There were significant negative correlations between patient weight (n = 17) and total (r = 0.57, P less than 0.05) and CSF (r = -0.55, P less than 0.05) DPH concentrations at myelography. Total plasma DPH levels 8 h (14.5 +/- 3.9 mg l-1; range 7.3-20.6 mg l-1) and 24 h (12.3 +/- 3.8 mg l-1; range 5.0-19.8 mg l-1) after myelography were largely within the 'therapeutic range' of 10-20 mg l-1 for the drug. No patient suffered a seizure although, in two, spike discharges were seen on a post-myelography electroencephalogram. A simple regime involving two doses of DPH would provide acceptable plasma CSF concentrations as a basis for controlled studies in seizure prophylaxis following neuroradiological investigations involving intrathecal contrast.     

Pharmacokinetics of valproic acid in the elderly

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.     

Effect of trazodone (KB-831) and its metabolites on brain monoamines in rat

The effects of trazodone (KB-831) and its metabolites on the uptake, turnover and contents of monoamines in rats were studied in comparison with those of imipramine and mianserin. Trazodone exhibited a more potent inhibitory effect on the uptake of [3H] 5-hydroxytryptamine (5-HT) into brain synaptosomes than on the uptake of [3H]norepinephrine (NE). Trazodone at 10-30 mg/kg, p.o., also inhibited the p-chloramphetamine-induced depletion of 5-HT in rat brain, but not the 6-hydroxydopamine-induced NE depletion in rat heart. Trazodone was the most selective 5-HT uptake inhibitor among the drugs tested in vitro. Its metabolite, m-chlorophenyl-piperazine (m-CPP), inhibited 5-HT and NE uptake in vitro, but not in vivo. Trazodone (100 mg/kg) and imipramine (30-100 mg/kg) inhibited the depletion of NE induced by alpha-methyl-p-tyrosine, whereas mianserin (100 mg/kg) facilitated it. At 1 hr after a single administration of each drug, an increase in 5-HT content and a decrease in 5-hydroxyindole-3-acetic acid (5-HIAA) content were observed when 30 mg/kg trazodone was used. At 100 mg/kg, trazodone increased the levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the NE content. m-CPP (10-30 mg/kg) produced similar effects on monoamine contents to those of trazodone. Imipramine and mianserin had no effect on monoamine contents even at a dose of 100 mg/kg. After 3 weeks of successive administration, an increase in 5-HT and a decrease in 5-HIAA were induced by trazodone and m-CPP at 1 hr, but not at 17 hr, after the final administration. Imipramine decreased the contents of NE and 5-HIAA, and its effects lasted for 17 hr. These results suggest that trazodone is a selective 5-HT uptake inhibitor and that its neurochemical profile is different from those of imipramine and mianserin.     

Obesity effects on nitrazepam disposition

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)