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Biomedical subjects

M Nadai

Publications and source records attributed to M Nadai.

At least 55 records · Page 3Linked to original sources
PubMed1991

Protein binding of xanthine derivatives to guinea pig serum albumin.

Binding of the bronchodilators N3-alkylxanthine and N3-alkyl-N1-methylxanthine derivatives to guinea pig serum albumin was investigated in vitro using the ultrafiltration method. A marked difference in the binding parameters of xanthine derivatives was observed, and binding was shown to be concentration dependent. Significant relations were observed among their binding parameter, dissociation constant (Kd), and hydrophobicity (log PC). The extent of binding of xanthine derivatives was increased both when a N3-methyl group was replaced by a longer alkyl chain and when a N3-alkylxanthine molecule was additionally replaced by a methyl group. Reversed-phase HPLC retention, as an index of hydrophobicity of xanthine derivatives, was also determined. Significant relationships were found between the adjusted retention time data for each xanthine derivative and their hydrophobicity or biological activities, such as their abilities to cause muscle relaxation and cyclic AMP phosphodiesterase (PDE) inhibition. These findings indicate that the difference in the extent of binding among xanthine derivatives is related to hydrophobicity, which is an important determinant of their biological activities.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Dose-dependent pharmacokinetics of enprofylline and its renal handling in rats.

The effect of dosage on the pharmacokinetics of the potent bronchodilator enprofylline (3-propylxanthine; PX) and its renal handling were investigated in rats. Enprofylline (PX) was administered iv in dosages of 2.5, 10, 20, and 40 mg/kg, and PX concentration in plasma and urine was determined by HPLC. The pharmacokinetic parameters were estimated by model-independent methods. The disappearance of PX from plasma was delayed as dosage was increased. The corresponding pharmacokinetic parameters also showed dose dependency; increases in the volume of distribution (Vd) and mean residence time (MRT) and a decrease in total body clearance (CLT) were observed as dosage was increased from 2.5 to 40 mg/kg. Approximately 80% of the dose, however, was excreted in urine as unchanged PX. Plasma protein binding studies of PX showed concentration dependency and allowed determination of binding parameters, with an apparent dissociation constant (Kd) of 162.50 microM and a binding capacity (nP) of 565.23 microM. Some pharmacokinetic parameters for unbound PX calculated by total plasma concentration and binding parameters also showed dose-dependent characteristics. However, no significant change in Vd for unbound PX was observed among administered doses, indicating that the distribution of PX into the body tissues is not changed by an increase in dosage. Renal clearance of unbound PX significantly increased as plasma concentration decreased. The maximum transport capacity (Vmax) and the Michaelis-Menten constant (Km) for tubular secretion were 60.53 micrograms/min and 2.27 micrograms/mL, respectively. The aim of the present study is to demonstrate that both saturable tubular secretion and concentration-dependent protein binding are responsible for the dose-dependent pharmacokinetics of PX in rats.

Animals↗
PubMed1991

Pharmacokinetic characteristics of N7-substituted theophylline derivatives and their interaction with quinolone in rats.

Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CLT) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 L/h/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal clearance (CLR) was 1.75 L/h/kg, approximately 13-fold the CLR for PXP (0.13 L/h/kg) and sevenfold the rat glomerular filtration rate. This study indicates that in rats, DPP is mainly excreted by active tubular secretion and that renal tubular reabsorption contributes to renal excretion of PXP with glomerular filtration. No significant changes in any pharmacokinetic parameters of the two drugs were observed when they were coadministered with enoxacin, compared with the drug administered alone, suggesting that enoxacin had no effect on the pharmacokinetics of either drug.

Aminophylline↗
PubMed1991

Structure-related inhibitory effect of quinolones on alkyl-xanthine elimination in rats.

To investigate the relationship between the chemical structures of quinolones, enoxacin (ENX) and its analogues, and their metabolic inhibitory effects on theophylline, a xanthine derivative closely related to theophylline, 1-methyl-3-propylxanthine (MPX), was used as a model of theophylline in rats. The disappearance of MPX from plasma was significantly delayed by treatment with ENX and analogue A (derivatives without substituent group at both 3'- and 5'- carbon atom in the piperazinyl ring): total body clearance of MPX was significantly decreased by approximately 50%. However, analogue A was converted into ENX in the rat body (about 14% of dose). Analogues B and C (derivatives with substituent group at 3'- or 5'-carbon atom in the piperazinyl ring) had little or no effect on MPX disposition. No significant change in the volume of distribution of MPX was observed after coadministration with these quinolones. The results of this study indicate that the substitutions on 3' and 5'-carbon atoms of piperazinyl ring at 7-position of the quinolone molecule may play important role in the inhibition of theophylline metabolism.

Animals↗
PubMed1991

Structure-pharmacokinetic relationships among the N1,N3-alkylxanthines in rats.

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1,N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P less than 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.

Animals↗
PubMed1991

Effect of a new quinolone, sparfloxacin, on the pharmacokinetics of theophylline in asthmatic patients.

Recently, it has become evident that some quinolones affect the processing of theophylline in the human system. The effect of a new quinolone, sparfloxacin, on the pharmacokinetics and metabolism of theophylline was investigated in six asthmatic patients receiving chronic theophylline therapy (a sustained-release theophylline tablet formulation of 200 to 300 mg twice daily at 12-h intervals). To these patients, sparfloxacin (200 mg once daily) was coadministered for 1 week. Plasma and urine samples were analyzed by high-performance liquid chromatography for theophylline and its metabolites. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of sparfloxacin were compared. The total body clearance of theophylline after coadministration of sparfloxacin, 42.81 +/- 6.64 ml/h/kg (mean +/- standard error of the mean), was not significantly different from that after the administration of theophylline alone, 47.11 +/- 7.61 ml/h/kg. Also, no significant change in the urinary excretion of theophylline and its metabolites was observed for subjects receiving or not receiving sparfloxacin. These findings indicate that a once-daily dose of 200 mg of sparfloxacin has no significant effect on the pharmacokinetics and metabolism of theophylline and that it would be safe to coadminister this quinolone to asthmatic patients receiving chronic theophylline therapy.

4-Quinolones↗
PubMed1990

Effect of mequitazine on the pharmacokinetics of theophylline in asthmatic patients.

The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200-400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.

Aged↗
PubMed1990

The possible mechanism of interaction between xanthines and quinolone.

To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4-oxo-enoxacin, on the disposition of new xanthine derivatives, 1-methyl-3-propylxanthine (MPX) and 3-propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg-1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4-Oxo-enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY-198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4-oxo-enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N-demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines.

Animals↗
PubMed1990

Effects of enoxacin on renal and metabolic clearance of theophylline in rats.

The effects of enoxacin and its metabolite 4-oxoenoxacin on the disposition of theophylline were investigated in rats. Systemic clearance of theophylline was significantly decreased by approximately 40, 46, and 50% after oral coadministration of 25, 100, and 200 mg of enoxacin per kg, respectively. No significant changes in the volume of distribution of theophylline were observed. 4-Oxoenoxacin had no direct effect on theophylline disposition. Significant changes in urinary excretion of theophylline and its metabolites were observed. (i) Urinary excretion of unchanged theophylline was significantly increased in proportion to increases in enoxacin dosage. (ii) Decreases in renal clearance of theophylline and metabolic clearance of 1-methyluric acid and 1,3-dimethyluric acid were observed. (iii) The percent decreases in the metabolic clearance of 1-methyluric acid were dependent on enoxacin dosage. It is likely that enoxacin inhibits the elimination process, which depends on cytochrome P-450-mediated isozymes for N demethylation and oxidation, and that the capacity of the inhibitory effect of enoxacin is greater in the N-demethylation pathway than it is in oxidation.

Animals↗
PubMed1989

Correlation between hydrophobicity of N-alkylxanthine derivatives and their biological activities on guinea-pig isolated tracheal smooth muscle.

Cyclic (c) AMP phosphodiesterase (PDE) inhibitory activities of N-alkylxanthine derivatives (3-methyl-,3-ethyl-,3-propyl-,3-butyl-,1,3-dimethyl-,1-methyl-3-ethyl-,1-methyl - 3-propyl- and 1-methyl-3-butyl xanthines) and their relaxant effects on carbachol-induced contraction and on resting tone guinea-pig isolated tracheal smooth muscle have been investigated. The PDE inhibition constant (Ki) and the concentration producing 50% tracheal smooth muscle relaxation in-vitro (EC50) were determined. Significant correlations between the -log Ki values and the -log EC50 values on the carbachol-induced contraction or on the resting tone were found (r = 0.902 and 0.892). The apparent partition coefficient (P) between n-octanol and pH 7.4 phosphate-buffered saline (PBS) was measured as an index of hydrophobicity of the xanthine derivatives. There were significant correlations between log P and both -log EC50 values and between the log P and -log Ki values. These findings suggest that the cAMP PDE inhibitory activity of N-alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Kinetic interaction between theophylline and a newly developed quinolone, NY-198.

The effect of a newly developed quinolone, NY-198, on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in six male healthy volunteers, in a crossover fashion. A sustained-release theophylline formulation (200 mg twice daily at 12 h intervals) was received as monotherapy or coadministration with NY-198 (200 mg twice daily at 12 h intervals). No significant change in the pharmacokinetic parameters of theophylline was observed during coadministration of NY-198. No significant change in urinary excretion of theophylline and its metabolites was also observed. These findings indicate that NY-198 does not influence the pharmacokinetics of theophylline and we can suggest that quinoline derivatives have less effect on theophylline disposition than 1,8-naphthyridine derivatives among quinolones.

4-Quinolones↗
PubMed1989

Protein binding characteristics of a new bronchodilator, 1-methyl-3-propylxanthine (MPX), in different species.

The protein binding of a new bronchodilator, 1-methyl-3-propylxanthine (MPX), in different animal species sera (human, dog, rabbit, rat and mouse) was investigated in vitro by ultrafiltration method. Interspecies differences in the binding affinity and binding capacity for MPX were observed. The dissociation constant (Kd1) for the high affinity binding site of human serum was approximately 17 times higher than that of rat serum. Those of rat serum and rabbit serum were nearly equal. On the other hand, the binding indices (n1p1/kd1) of human serum and rat serum were comparable. The binding of MPX to various proteins such as human serum albumin (HSA), alpha 1-acid glycoprotein (AGP) and isolated human lipoproteins was also investigated. The binding of MPX to HSA was lower than that of human serum protein but the number of specific binding sites (n1) in human serum was in agreement with that in HSA. The binding curves of MPX to AGP and lipoproteins were almost linear and the binding percentages were less than 7% in both cases. These data suggest that MPX is exclusively bound to albumin and that AGP and lipoproteins are of little importance in the protein binding of MPX. The present data appear to be useful for predicting the role of protein binding on the pharmacokinetics of MPX in different animal species.

Animals↗
PubMed1988

Studies on alkyl-xanthine derivatives. II. Pharmacokinetic and pharmacodynamic studies of a new bronchodilator, 1-methyl-3-propylxanthine (MPX).

A new xanthine derivative bronchodilator, 1-methyl-3-propylxanthine (MPX), and 1-methyl-3-butylxanthine (MBX) were synthesized. We evaluated their relaxant effects on tracheal smooth muscle isolated from guinea pigs and pharmacokinetic characteristics in rats using 1,3-dimethylxanthine (theophylline, TPH) as the reference drug. Dose-dependent relaxant effects were observed in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, and both MPX and MBX exert very much stronger relaxant effects than TPH with nearly equal potency. There were significant differences in the pharmacokinetic and physico-chemical properties among these drugs, both MPX and MBX having shorter half-lives, higher plasma protein binding in vivo and stronger hydrophobicity compared to TPH. The present study suggested that the N3-alkyl chain length is significant for increasing the relaxant effect and affecting the pharmacokinetic and physico-chemical properties of these drugs.

Animals↗
PubMedDate not supplied

[Urinary disorders in the puerperium. Study of the major risk factors].

BACKGROUND: There is a very wide range of genitourinary disorders which can follow vaginal birth, including slight and occasional problems as well as serious disorders which could affect a woman's social and sexual life, for example the effects of dyspareunia on a woman's sexual identity, social marginalization as an inevitable result of symptoms like urinary incontinence, urgency and fecal incontinence. The aim of this study was to identify elements which may be of use in understanding the pathogenetic mechanisms of these disorders. METHODS: Three weeks after birth 537 mothers underwent a clinical genitourinary evaluation including: collection of data regarding pregnancy development and birth, genitourinary history (urinary problem data collected in accordance with the proposal of the International Continence Society), an objective genitourinary examination with a PC-test and identification of possible antagonist abdominal-diaphragmatic muscular synergies, instrumental tests in cases of post-partum urinary incontinence. RESULTS: Maternal age at birth, parity, weight before pregnancy and at term, weight increase, gestational age, duration of the second stage of labour, development and characteristics of birth, perineal condition and neonatal weight were the variables considered as risk factors while genuine stress urinary incontinence, urge incontinence, frequency, urgency, dysuria and inability to interrupt urination were the disorders whose dependence on the various risk factors were to be studied. The analysis of the association of the various pairs of variables recorded both positive and negative correlations, whether the population taken was that of all puerperae or that of only primiparae. CONCLUSIONS: Maternal age at birth, parity and duration of the second stage of labour, even if not always separable from other co-existing risk conditions, are the main responsible risk factors in the pathogenesis of urination disorders in puerperium. These results once again confirm the fundamental role of birth in the pathogenesis of female pelvic statics anomalies and of the genitourinary disorders which are their most evident chemical demonstration.

Adult↗