Biomedical subjects

P Lluel

Publications and source records attributed to P Lluel.

9 recordsLinked to original sources

PubMed2004

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans.

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax=1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax=0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1.

Administration, Oral↗

PubMed2003

Increased adrenergic contractility and decreased mRNA expression of NOS III in aging rat urinary bladders.

Our objective was to study age-related changes in adrenergic contractility and gene expression profile in the rat urinary bladder. Young (3-month old), adult (10-month old) and senescent (30-month old) male WAG/Rij rats were used. Gene expression profile in the rat urinary bladder was defined using Atlas microarray technology. In vitro contractile responses induced by KCl, phenylephrine (PHE) and norepinephrine (NE) were compared in isolated urinary bladders dissected from young, adult and senescent rats. Among a total of 1176 genes present on the arrays, 15 genes showed an increase in expression and 10 genes a decrease with age. Four genes related to nerve growth factor were upregulated whereas NOS type III was downregulated in aging rats. Intrinsic contractility of isolated rat urinary bladders was not changed between adult and aging rats as judged by the response curves to KCl. In contrast, an age-related increase in the maximal contractile responses to NE, but not PHE, was noticed (13 +/- 1, 48 +/- 2% and 59 +/- 2% at 3, 10 and 30 months, respectively). The alpha1D-adrenoceptor antagonist BMY7378 antagonized NE-induced contractions with low potency in both groups suggesting the involvement of the alpha1A-adrenoceptor subtype. This was confirmed by microarray, which demonstrated mRNA expression for the alpha1A-adrenoceptor subtype only. These results suggest that aging of the urinary bladder is associated with an increase in the maximal contractile response to NE which could be due to NO shortage resulting from downregulation of urothelial NOS III.

Adrenergic Fibers↗

PubMed2002

Age-related changes in urethrovesical coordination in male rats: relationship with bladder instability?

The micturition profile in conscious animals and the urethrovesical coordination in anesthetized conditions were investigated in 6- and 24-mo-old male Sprague-Dawley rats. The in vitro pharmacological responses to KCl, electrical field stimulation (EFS), carbachol, phenylephrine, and isoprenaline were determined in the isolated bladder body, the bladder neck, and urethra. A morphometric and immunohistological study has been included. During conscious cystomanometry, 63% of the aging rats but only 25% of the adult rats showed spontaneous contractions during the bladder-filling phase. In conscious aging rats, basal pressure, threshold pressure, and micturition pressure were also significantly increased. In anesthetized aging rats, a decrease in resting urethral pressure at micturition threshold and the occurrence of a significant delay in urethral relaxation during micturition were associated with an increased residual volume. In all isolated tissues, contractile response to KCl was not modified with aging, whereas age-related decreases in maximal responses to carbachol in the bladder body and to phenylephrine and carbachol in the urethra were observed. In the bladder neck only, we found a significant decrease in the amplitude of neurogenic contractions associated with fibrosis but without decrease in nerve density. These experiments show significant modifications in the voiding pattern of aging rats associated with urethral dysfunction and with regionally specific pharmacological and structural changes of the urinary tract. We propose that aging in rats is characterized by an impairment of the urethrovesical coordination, leading to bladder dysfunctions similar to those induced by bladder outlet obstruction.

Adrenergic Agents↗

PubMed2000

Functional and morphological modifications of the urinary bladder in aging female rats.

In female Wistar/Rij rats, 10 and 30 mo old, the micturition profiles in conscious animals, the contractile responses of the isolated urinary bladder, and the histology of the vesical tissue have been investigated. During cystomanometry, 60% of conscious senescent rats, but only 25% of young adult rats, showed spontaneous contractions during the bladder-filling phase. In aging rats, micturition pressure and duration of micturition were significantly higher by approximately 40-50%. In contrast, bladder capacity, bladder compliance, micturition volume, and residual volume were not modified with age. In vitro, the contractile responses of the bladder body to KCl, carbachol, arecoline, and alpha,beta-MeATP were similar in tissues from young adult and senescent rats. In contrast, maximum responses to noradrenaline, but not phenylephrine, were two times greater in the older rats. Isoprenaline exhibited the same potency in relaxing KCl-precontracted bladder body of 10- and 30-mo-old animals. Morphometric analysis showed a significant increase in the mean thickness of the muscularis layer with age, whereas the collagen density significantly decreased in the muscularis and in the lamina propria layers. The fact that the majority of senescent rats displayed bladder instability and increased response to alpha-adrenergic agonists suggests that this strain of rat seems a good model for the aged human. However, other characteristics of the aging human urinary tract (urinary frequency, decreased cystometric capacity, and decreased detrusor contractility associated with fibrosis) are not present.

Adenosine Triphosphate↗

PubMed1999

Pharmacological and urodynamic changes in rat urinary bladder function after multiple pregnancies.

OBJECTIVE: To investigate the changes in bladder function after multiple pregnancies and parturition in rats, and to establish links between the changes in voiding profiles and in vitro pharmacological responses. MATERIALS AND METHODS: Cystometry was used in conscious virgin and multiparous female Wistar rats (2 weeks after the last parturition) with chronically implanted lines to continuously record bladder pressure during five reproducible voiding cycles. In vitro, detrusor muscle contractile responses induced by cumulative concentrations of KCl, carbachol, noradrenaline and alpha, beta-methylene-ATP (mATP) were compared. RESULTS: In multiparous rats, there was a significant increase in the amplitude of voiding pressure (+31%), bladder capacity (+83%) and residual volume (about threefold); 60% of the multiparous rats but only 10% of the virgin rats showed bladder instability during the filling phase. Cumulative concentration-response curves to KCl, expressed as the tension developed vs tissue weight, were identical in the two groups of rats. Contractile responses induced by carbachol (0.1-30 micromol/L) were significantly larger in multiparous than in virgin rats. Similarly, noradrenaline-induced contractions (0.3-10 micromol/L) were significantly higher for multiparous animals. However, the sensitivity of the detrusor muscle to mATP was not modified by multiple pregnancies. CONCLUSION: After multiple gestations, female rats develop bladder hypertrophy, bladder instabilities and a higher amplitude of voiding pressure associated with an increased residual volume. These altered patterns are similar to those found in rats after chronic infravesical outlet obstruction. We propose that pregnancies and parturition modify urinary bladder function, leading to a dysfunction similar to that induced by obstruction, and involving an increased sensitivity to adrenergic and cholinergic stimulation.

Adenosine Triphosphate↗

PubMed1998

Relationship between the effects of alfuzosin on rat urethral and blood pressures and its tissue concentrations.

This study was undertaken in order to establish the alpha1-antagonist effects of alfuzosin on phenylephrine-induced increases in urethral and arterial blood pressures at 1 and 6 hours post dosing (10 mg/kg, p.o.). At each time, plasma and prostatic concentrations of alfuzosin were measured and correlations between tissue concentrations and pharmacological effects were calculated. At one and six hours post dosing, alfuzosin markedly shifted the urethral and arterial dose response curve to phenylephrine. At one hour, prostatic concentration was 4.1 times greater than plasma concentration (363 ng/g vs 88 ng/ml) and at 6 hours this ratio reached 8.6 times (167 ng/g vs 20 ng/ml). By taking together the data points obtained at 1 and 6 hours we showed that the effects of alfuzosin on urethral pressure were correlated with prostate levels (r=0.906, p<0.01) and the effects on arterial blood pressure were correlated with plasma levels (r=0.941, p<0.01). These results suggest that a preferential distribution of alfuzosin in prostatic tissue may play a role in its functional uroselectivity.

Adrenergic alpha-Antagonists↗

PubMed1998

Experimental bladder instability following bladder outlet obstruction in the female rat.

PURPOSE: In rats, urethral obstruction was previously shown to lead to detrusor instability, but bladder instability in conscious animals has not been well characterized. The present study was designed to describe the consequences of bladder outlet obstruction on urodynamic parameters in the conscious rat. A categorization of different types of bladder instability in conscious rats is described. MATERIALS AND METHODS: Cystometry was performed on conscious animals with chronically implanted lines. Recordings of the micturition pattern and the bladder pressure during the micturition cycle were made from normal female rats and those with instability caused by infravesical outflow obstruction. RESULTS: In control rats, the peak micturition pressure was low (45.6+/-2.5 cm. H2O) and only small pressure fluctuations occurred before or after micturition. Rats with outlet obstruction exhibited bladder hypertrophy, high micturition pressure (95.5+/-6.8 cm. H2O) as well as marked spontaneous activity throughout the micturition cycle. According to the spontaneous activity profile we identified four main patterns of abnormal micturition cycles. CONCLUSION: Urethral obstruction in rats leads to a significant increase in bladder weight and to altered micturition patterns which reveal clear similarities with features of the cystometric profiles performed in men with infravesical outflow obstruction. These modifications are not consistently correlated with an increase in bladder weight.

Animals↗

PubMed1997

Vasopressin V2 receptor mRNA expression and cAMP accumulation in aging rat kidney.

The ability of the kidney to regulate water balance is impaired with age, although the secretion of vasopressin is maintained in senescent animals. This suggests that the cellular response to antidiuretic hormone is reduced in aging kidney. To test this hypothesis, the relationship between the expression of the vasopressin. V2 receptor mRNA and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was investigated in the medullary thick ascending limb of Henle's loop (MTAL) of adult and aging rats. Tubular suspensions of MTAL were prepared from 10- and 30-mo-old female WAG/Rij rats. The accumulation of cAMP for maximal concentration of vasopressin was 34% larger in adult than in old animals (9.5 +/- 0.5 pmol/4 min, n = 16, and 7.1 +/- 0.6 pmol/4 min, n = 12, respectively). The concentration of vasopressin corresponding to half-maximal stimulation was similar in the two groups (0.66 +/- 0.20 and 0.52 +/- 0.09 nmol, n = 5, in adult and old animals), indicating comparable sensitivity of the renal cells with age. The age-related impaired response to vasopressin of the V2 receptor was specific for females and was not observed in males. Direct stimulation of adenylyl cyclase by forskolin induced a comparable accumulation of cAMP in adult and senescent rats. The V2 receptor mRNA level in the MTAL was constant between 10 and 30 mo whether the animals were normally hydrated or dehydrated for 2 days. These data indicate that, in MTAL, the age-related impaired cAMP accumulation by vasopressin would be linked to a change either in the translation of V2 mRNA or in posttranslational processing mechanisms or in the coupling between the V2 receptor and adenylyl cyclase.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Comparative alpha-1 adrenoceptor subtype selectivity and functional uroselectivity of alpha-1 adrenoceptor antagonists.

We investigated the relevance of selectivity for a given alpha-1-adrenoceptor subtype for in vivo uroselectivity of several alpha-1-adrenoceptor antagonists (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin and 5-Me-urapidil). Comparison of the affinities of these alpha-1-adrenoceptor antagonists at the cloned alpha-1a, alpha-1b and alpha-1d-adrenoceptor subtypes revealed that tamsulosin and 5-Me-urapidil showed selectivity for the alpha-1a subtype. No significant correlations were found between the affinities for alpha-1b or alpha-1d-adrenoceptors and the pK(B) values obtained against phenylephrine-induced contraction of the rabbit prostate in vitro. In contrast, the antagonist potencies in rabbit prostate were correlated (r = 0.89, P < .05) with the pKi values for the alpha-1a-adrenoceptor subtype. However, the pK(B) values were consistently smaller (by 0.6 to 1.9 log unit) than the pKi values for the alpha-1a-adrenoceptor subtype, a result that suggests that the alpha-1-adrenoceptor mediating urethral contractions does not have all the characteristics of the alpha-1a-adrenoceptor. The simultaneous measurement of urethral and arterial pressures in the same conscious male rat allows evaluation of the functional uroselectivity of these antagonists based on their respective effects on both pressures. Dose ranges were selected according to effects on urethral pressure and most antagonists were found effective within the 3 to 100 microg/kg i.v. range. Alfuzosin markedly decreased urethral pressure and either did not decrease blood pressure (10-30 microg/kg) or slightly decreased it at the highest dose tested (100 microg/kg). Doxazosin did not produce sustained reductions in urethral pressure until a dose of 30 microg/kg. Blood pressure was not reduced until 100 microg/kg. Prazosin reduced urethral pressure and blood pressure within the same dose-range whereas terazosin did not decrease urethral pressure at doses that significantly decreased blood pressure (30 and 100 microg/kg). 5-Me-urapidil, an alpha-1a-selective compound did not significantly modify urethral and blood pressure whereas tamsulosin, another alpha-1a-selective compound reduced urethral pressure and blood pressure within the same dose range. In conclusion, in the conscious male rat the functional uroselectivity is not correlated with a selective affinity for the alpha-1a-adrenoceptor subtype.

Adrenergic alpha-1 Receptor Antagonists↗