Population pharmacokinetics of intravenous valproic acid in Korean patients.

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.

Synthesis and pharmacological evaluation of dimeric muscarinic acetylcholine receptor agonists.

Two dimeric analogs of the muscarinic acetylcholine receptor (mAChR) agonist phenylpropargyloxy-1,2,5-thiadiazole-quinuclidine (NNC 11-1314) were synthesized and pharmacologically evaluated. In radioligand binding assays on Chinese hamster ovary (CHO) cell membranes expressing the individual human M(1) to M(5) mAChR subtypes, both dimers [(3S)-1,4-bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl)benzene,2-L-(+)-tartrate (NNC 11-1607) and (3S)-1,3-bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl)benzene,2-L-(+)-tartrate (NNC 11-1585)] exhibited higher binding affinities than the monomeric NNC 11-1314. Only NNC 11-1585, however, displayed significant selectivity for the M(1) and M(2) mAChRs relative to the other subtypes. Although binding studies in rat brain homogenates supported the selectivity profile of NNC 11-1585 observed in the CHO membranes, rat heart membrane experiments revealed complex binding behavior for all three agonists that most likely reflected differences in species and host cell environment between the heart and CHO cells. Subsequent functional assays with phosphatidylinositol hydrolysis revealed that all three novel ligands were partial agonists relative to the full agonist oxotremorine-M at the CHO M(1), M(3), and M(5) mAChRs, with NNC 11-1607 displaying the highest functional selectivity. In the CHO M(2) and M(4) mAChR cells, agonist-mediated effects on forskolin-stimulated cAMP accumulation were characterized by bell-shaped concentration-response curves, with the exceptions of NNC 11-1607, which had no discernible effects at the M(2) mAChR, and NNC 11-1585, which could only inhibit cAMP accumulation at the M(4) mAChR. Thus, we identified NNC 11-1607 as a novel functionally selective M(1)/M(4) mAChR agonist. Our data suggest that dimerization of mAChR agonists is a viable approach in designing more potent and functionally selective agonists, as well as in providing novel tools with which to probe the nature of agonism at these receptors.

Human jejunal permeability of two polar drugs: cimetidine and ranitidine.

PURPOSE: To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs. METHODS: A sterile multi-channel perfusion tube, Loc-I-Gut, was inserted orally and positioned in the proximal region of the jejunum. A solution containing cimetidine or ranitidine and phenylalanine, propranolol, PEG 400, and PEG 4000 was perfused through a 10 cm jejunal segment in 6 and 8 subjects, respectively. RESULTS: The mean Peff (+/- se) of cimetidine and ranitidine averaged over both phases were 0.30 (0.045) and 0.27 (0.062) x 10(-4) cm/s, respectively, and the differences between the two were found to be statistically insignificant. The mean permeabilities for propranolol, phenylalanine, and PEG 400 averaged over both phases and studies were 3.88 (0.72), 3.36 (0.50), and 0.56 (0.08) x 10(-4) cm/s, respectively. The differences in permeability for a given marker were not significant between phases or between the two studies. CONCLUSIONS: The 10-fold lower permeabilities found for cimetidine and ranitidine in this study, compared to propranolol and phenylalanine, appear to be consistent with their less than complete absorption in humans.

Effect of water deprivation for 48 hours on the pharmacokinetics and pharmacodynamics of azosemide in rats.

The effect of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of azosemide was examined after intravenous (i.v., 10 mg/kg) and oral (20 mg/kg) administration of azosemide to the control and the water-deprived rats. After i.v. administration of azosemide, the area under the plasma concentration-time curve from time 0 to time infinity and the unbound fraction of azosemide to plasma proteins increased by 36 and 40%, respectively, and total body, renal (CLR), and nonrenal clearances, apparent volume of distribution at steady state, and total amount of azosemide excreted in urine (AeAZ0) decreased by 30, 44, 20, 25, and 33%, respectively, in the water-deprived rats (p < 0.05 vs controls). After oral administration of azosemide, the values of AeAZ0 (591 vs 318 micrograms) and CLR (2.22 vs 0.875 mL/min/kg) decreased significantly in the water-deprived rats. The 12-h urine output per g kidney was also reduced significantly in the water-deprived rats after both i.v. (70.3 vs 24.6 mL) and oral (70.7 and 20.7 mL) administration of azosemide. This could be due to the significantly reduced amount of azosemide excreted in 12 h urine, significantly higher plasma osmolarity, and increased blood vasopressin concentration in the water-deprived rats. The 12-h urinary excretion of sodium, potassium, and chloride per g kidney was also reduced significantly in the water-deprived rats after both i.v. and oral administration. The diuretic efficiency decreased significantly in the water-deprived rats after both i.v. and oral administration. The 12-h urine output per g kidney of i.v. and oral administration of azosemide in the control rats were similar (70.3 +/- 17.3 vs 70.7 +/- 13.8 mL), although the AeAZ0 after oral administration was significantly smaller than that after i.v. administration (473 +/- 98.5 vs 285 +/- 76.3 micrograms), and similar results were also obtained from the water-deprived rats. This could be rationalized by the concept of a single maximally efficient excretion rate of the drug in the pharmacodynamic model (sigmoid Emax), as shown for furosemide.

Intrathecal administration of sodium nitroprusside, a nitric oxide donor, increases blood pressure in anesthetized rats.

The present study was performed to investigate the role of spinal nitric oxide (NO) in the central regulation of blood pressure (BP). Experiments were carried out in anesthetized artificially ventilated male Wistar rats. Intrathecal (i.t.) administration of drugs was made at the thoracic spinal level. I.t. injection of a NO donor, sodium nitroprusside (SNP; 1, 5, and 15 nmol) increased BP dose-dependently. Intrathecal pretreatment of methylene blue (200 nmol) significantly attenuated the pressor response evoked by SNP (15 nmol, i.t.). I.t. administration of nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (100 and 1000 nmol), caused decreases in BP. These results suggest that NO plays a tonic excitatory role in the central regulation of BP in the rat spinal cord.

Effects of water deprivation for 48 hours on the pharmacokinetics and pharmacodynamics of furosemide in rats.

The effects of water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of furosemide were examined after intravenous, 8 mg/kg body weight, and oral administration, 16 mg/kg body weight, of furosemide to control and water deprived rats. After i.v. administration, the total body and nonrenal clearances decreased significantly in water-deprived rats. The urine output, urinary excretion of sodium, potassium and chloride based on grams of kidney weight, and the diuretic, natriuretic and chloruretic efficiencies decreased significantly in water-deprived rats after both intravenous and oral administration of furosemide, suggesting that the dose of furosemide for water-deprived patients may require modification.

Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats.

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg-1 to control and water deprived rats (n = 7). The values of AUC, t1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CLNR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CLNR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 micrograms), desbutylbumetanide (170 vs 113 micrograms) and its glucuronide conjugation (191 vs 125 micrograms), and sum of the three metabolites (414 vs 229 micrograms), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8-h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 micrograms) and/or reduced kidney function in water deprived rats. The kidney function based on CLIot (9.87 vs 2.14 ml min-1 kg-1) reduced significantly in water deprived rats. The 8-h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.

Effects of tacrine on brain muscarinic-receptor-mediated second-messenger signals.

The purpose of this study was to investigate the effects of 9-amino-1,2,3,4-tetrahydroacridine (THA; Tacrine) on muscarinic-receptor-linked second-messenger systems in rat brain and to determine the selectivity and mechanisms of these effects. Both competitive and noncompetitive antagonism was revealed in saturation radioligand binding studies performed in cortical and striatal tissue, depending on THA concentration. Micromolar THA concentrations blocked muscarinic-receptor-mediated inhibition of cAMP formation and stimulation of phosphoinositide (PI) hydrolysis with poor selectivity between the two responses. While both responses were blocked in the same concentration range (4-60 mumol/l), non-competitive antagonism of PI hydrolysis occurred at THA concentrations greater than 10 mumol/l while competitive antagonism was displayed for the cAMP response at concentrations of THA up to 40 mumol/l. THA was equally effective at inhibiting PI hydrolysis stimulated by histamine, phenylephrine or oxotremorine-M, when these agonists were employed in concentrations equal to their EC50s for the response. THA did not antagonize PI hydrolysis mediated by the quisqualate receptor at any agonist concentration used. Furthermore, THA blocked carbachol- but not morphine-induced inhibition of forskolin-stimulated cAMP formation in the striatum.

[A study comparing the perception of patients, nurses and doctors about the educational needs of cancer patients].

Because of the advances in the treatment of cancer, patients live longer and require more comprehensive information in order to understand their illness, treatment procedure and role in the health care process. Each treatment involves combined therapeutic approaches, so information must be presented to the patient in such a way as to promote maximum understanding and acceptance. The purposes of this study were to explore and compare patients', nurses' and doctors' perception of the educational needs of cancer patients and to identify areas of agreement and disagreement in the perception of these needs by patients, nurses and doctors. Three groups took part in the study; 78 cancer patients, 39 nurses and 35 doctors. They all were selected from one general teaching hospital. Data were collected using a questionnaire, developed by the investigators. The questionnaire was made up of 2 sections; an importance rating scale and a knowledge/providing information rating scale. Each rating scale consisted of 20 specific informational items that were elicited through interviews with 60 cancer patients. The data were analyzed using percentages, means, Pearson correlation coefficients, t-test, and ANOVA. The results of this study were as follows; 1. Nurse subjects achieved a higher total score (85.6154) on the rating of importance than did the patients (81.5238) or the doctors (79.3125). The difference between the three group's total score was significant (F = 6.164, p less than .01) and the difference between the nurses' total score and doctors' was also statistically significant (t = 3.95, p less than .001). 2. On the whole, the rankings for the mean score of importance for the 20 items differed among the three groups of subjects. For the patient subjects, the highest mean ratings were for "the symptoms of recurring illness", "progress of illness", and "plan and duration of treatment" showing these to be the items that they considered important. The nurse subject felt that it was most important for oncology patients to know about "plan and duration of treatment", "how to minimize problems with loss of appetite, nausea, vomiting", and "amount of activity the patient can do around the work setting". Doctors felt it was most important for the patient to know about "prognosis of illness", "progress of illness", and "plan and duration of treatment". "Plan and duration of treatment" was the common item that all three groups perceived as important for patient learning.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of aging on the interaction of quinuclidinyl benzilate, N-methylscopolamine, pirenzepine, and gallamine with brain muscarinic receptors.

The objective of the present study was to investigate the effects of senescence on the binding characteristics of muscarinic receptors by using [3H]quinuclidinyl benzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS) as ligands in young (3 months), middle-age (10 months) and old (24 months) male Fischer 344 rats. Muscarinic receptor density was found to decrease significantly with aging in certain brain regions, depending on the ligand employed. Moreover, the relative proportions of M1 and M2 muscarinic receptor subtypes was not significantly altered by aging, except in the aged striatum. Furthermore, the dissociation kinetics of [3H]NMS in the cerebral cortex and their allosteric modulation by gallamine were only slightly influenced by age.

[Synthesis and pharmacokinetic characteristics of 14CH3-polymethacryloyl lupinine--a heparin antagonist]. / Sintez i farmakokineticheskie kharakteristiki polimetakriloil-lupinina 14CH3--antagonista geparina.

The quaternary salt of 1-14C-polymetacryloyl lupinine with a specific activity of 1 microCi/mM has been synthesized. It has been shown that intravenous injection of the polymer after heparin administration leads to uneven distribution of the label in the organs. The most intensive reduction of the label was observed in the kidneys. During 10 days, 85% of the label is eliminated from the body with urine and feces (76 and 9% respectively).

[Binding of gamma-aminobutyric acid in the synaptic membranes of rat brain]. / Sviazyvanie gamma-aminomaslianoi kisloty s sinapticheskimi membranami mozga krys.

The Na+-dependent and Na+-independent (receptor) binding of [3H] GABA is measured in rat brain synaptic membranes. The receptor binding is presented by at least 3 types of binding sites differing in kinetic parameters (dissociation constants and maximal concentration of binding sites). Phenyl-GABA and pyracetam do not affect receptor binding while 4-hydroxybutyric acid, apamine and bicuculline inhibit it with inhibition constants K1=100, 2 and 1 micron, respectively. Solubilization of synaptic membranes with 2% potassium cholate in the presence of total brain phospholipids does not inactivate [3H] GABA receptor binding.