[Stress urinary incontinence treatment using Surgimesh® Sling, evolution on patient quality of life and sexual activity during 12 months follow-up]. / Traitement de l'incontinence urinaire d'effort par Surgimesh(®) Sling, évolution de la qualité de vie et de la qualité de la sexualité des patientes sur une période de 12 mois.

INTRODUCTION: Evaluation of quality of life (QOL) and sexual activity after using sub-urethral Surgimesh® Sling for female stress urinary incontinence (SUI). METHODS: Study with a total duration of 12 months. One hundred and sixty-eight patients presenting a SUI underwent surgery for a Surgimesh® Sling implantation. RESULTS: QOL was significantly improved on the International Consultation Continence Questionnaire (ICIQ) scale with an increase of the average score from 2.79±1.75 to 8.48±1.7 at 12 months (P<0.05). The percentage of patients undergoing sexual intercourses remains at a high level during the study (76.87% versus 78.33%). The number of patients with pain during sexual intercourse significantly decreased (15% versus 2.1%). The QOL score is significantly better in post-operation conditions (7.84 versus 9.20; P=0.001). In terms of continence at 12 months, 75.6% of women declared recovery and 23.53% observed improvements. CONCLUSION: SUI correction using Surgimesh® Sling induces a very significant improvement in patients' QOL and sexual activity.

Role of the nicotinic acid group in NAADP receptor selectivity.

Nicotinic acid adenine dinucleotide phosphate (NAADP) has been shown to be an intracellular Ca2+-releasing messenger in a wide variety of systems to date. Its actions are both potent and highly specific despite differing structurally from the endogenous cellular co-factor and its precursor, NADP, only in the substitution of a hydroxyl for the amine group at the 3' position of the pyridine ring. This substitution allows NAADP to bind to a membrane-localized binding site in sea urchin egg homogenates with an IC50 at least 1000-fold greater than that of NADP as measured by competition radioligand binding assays. This suggests that the NAADP receptor protein must include certain features in the NAADP binding site that regulate this specificity. In order to investigate this interaction, we synthesised a series of NAADP analogues differing from NAADP at the 3' position of the pyridine ring that included both simple carboxylic acid analogues as well as a series of chemical isosters. We then investigated both their affinity for the NAADP binding site in sea urchin egg homogenates and their ability to activate the NAADP sensitive Ca2+ channel. We hereby show that a negative charge at the 3' position is an important determinant of affinity but the protein displays a large tolerance for the size of the group. Furthermore, the protein does not easily accommodate multiple charged groups or large uncharged groups.

Water soluble furoxan derivatives as NO prodrugs.

The synthesis, characterization, NO donor properties, and in vitro vasodilating activity of a series of water soluble furoxans (5-14a,b) are described. All of the compounds released NO when treated with a large excess of cysteine under physiological conditions (pH 7.4; 37 degrees C). The amount of NO produced after 1 h of incubation was evaluated by detecting nitrites, via the Griess reaction. Derivatives 5b, 7b, and 14b were able to release nitric oxide also in the absence of the thiol cofactor. The initial rates of NO release were determined at different concentrations, using a spectrophotometric technique based on the NO-induced oxidation of oxyhemoglobin (HbO2) to methemoglobin (MetHb). The initial rates of NO release were linearly dependent on the concentrations of the single compounds. The vasodilating potency (EC50) of all the derivatives was assessed on rat aortic strips precontracted with noradrenaline. Correlation between potency and initial NO release rate is discussed.

Characterization of an accessory binding area in the histamine H2 receptor.

The histamine H2 receptor-blocking activity of ranitidine and lamtidine analogues has been investigated to gain information on the structure of the receptor area adjacent to the site fitted by the polar group. The introduction of differently shaped alkyl moieties on the polar group is always accompanied by maintenance or by an increase of H2 receptor antagonism with respect to the starting lead compound (KB on guinea-pig isolated atria ranging from 49 nM to 1.5 nM). The results seem to indicate the presence in the histamine H2 receptor of an area of a predominantly hydrophobic nature located at the boundary of the site fitted by the polar group.

Furosemide and 11beta-hydroxysteroid dehydrogenase activity, in man.

Mineralocorticoid receptors possess the same affinity for aldosterone and for cortisol and preferential binding of aldosterone is modulated by the 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) enzyme, which converts cortisol to its inactive metabolite cortisone. Several endogenous or exogenous compounds able to inhibit the enzyme have been described and, as a consequence, produce the syndrome of apparent mineralocorticoid excess (AME) characterized by hypertension, hypokalemia, volume repletion and suppression of the renin-angiotensin-aldosterone system. High doses of furosemide, a diuretic that works in the luminal surface of the thick ascending limb of Henle's loop, have been reported to inhibit 11 beta-OHSD activity to the same extent as licorice in vivo and in vitro, in rat. The aim of our study was to verify the effect of the drug on 11 beta-OHSD activity in man at the doses currently used in clinical practice. We tested the activity of 11 beta-OHSD following both acute and protracted administration of furosemide. In the acute study, the drug was administered at low (40 mg i.v. in bolo) and high doses (infusion of 10 mg/kg bw i.v for six hours); the protracted furosemide administration consisted in 50 mg/day for 20 days, by mouth. The ratios between the cortisol metabolites tetrahydrocortisol plus allo-tetrahydrocortisol to tetra-hydrocortisone and urinary free cortisol to urinary free cortisone were used to measure the activity of 11 beta-OHSD. Urinary cortisol, cortisone and their metabolites were tested by a gas-chromatographic/mass spectrometric method. Neither acute nor prolonged administration of furosemide did affect the activity of 11 beta-OHSD although the drug was able to modify plasma aldosterone and PRA secretion and to determine hypokalemia. Our results suggest that furosemide does not play a significant role in 11 beta-OHSD modulation in humans, at least at the dosage used in clinical practice.

Pharmacological profile of new histamine H2-receptor antagonists related to cimetidine, ranitidine and lamtidine.

New compounds structurally related to cimetidine, ranitidine and lamtidine have been prepared and tested for their histamine H2-receptor blocking activity on guinea-pig atria, rat perfused stomach and frog isolated gastric mucosa. These derivatives contain as a polar group, a diaminofurazan moiety, a 3-amino-4-methylfurazan or a 3-amino-4-phenylfurazan moiety. Ranitidine and lamtidine analogues display strong H2-antagonist activity in-vitro (KB on atria 0.037 microM and 0.0039 microM, respectively) and in-vivo on the lumen-perfused stomach of the anaesthetized rat (ID50 0.13 mumol kg-1 and 0.023 mumol kg-1 i.v., respectively). However, lamtidine analogues are ineffective in blocking the histamine-induced increase of H+ output in the frog isolated gastric mucosa. On the basis of the anomalous results in the frog, it is concluded that caution must be exercised in extrapolating information from amphibian to mammalian tissues with regard to the structure and the function of histamine receptors.

Pharmacochemistry of the furoxan ring: recent developments.

In the present work recent results obtained in the pharmacochemistry of the furoxan system are reported. In particular, after a brief description of the salient points of the furoxan chemistry, the synthesis and the properties of a series of Nifedipine and Prazosin analogues, containing this heterocyclic system, are described. Since we observed that a few furoxan derivatives are able to elicit both a dose-dependent rise in platelet cGMP levels and to promote a dose-dependent inhibition of AA-induced [Ca++] rise, and that many substituted furoxans show potent vasodilating and antiaggregatory activity, the possibility of using the furoxan system as a lead in the design of new vasodilators is also discussed.

Synthesis and H2-antagonist properties of some 1,2,5-thiadiazole-1-oxide derivatives.

A series of 1,2,5-thiadiazole-1-oxide derivatives has been synthesized and studied for its H2-antagonist properties. These derivatives can be considered derived from classical H2-antagonists in which the structure was deeply modified in order to evidence the minimal structural requirements for the activity. It was found that it is sufficient to have the 1,2,5-thiadiazole-1-oxide ring substituted with an alkylamino moiety and with an aliphatic chain linked to the hydroxy or ether group to achieve compounds as active as cimetidine. A few considerations on the binding on guinea-pig cerebral cortex of a series of H2-antagonists with more and more simplified structures are also reported.

SAR studies on H2 antagonists containing alkylamino substituted 1,2, 5-thiadiazole 1-oxide moieties.

A number of ranitidine analogues in which the diamino-1,2,5-thiadiazole 1-oxide substructure bearing alkyl chains of different length is present as the urea equivalent group, were synthesised and studied for their lipophilic and H2 antagonist properties. Derivatives which displayed a logP < or = 3 behaved as competitive antagonists of histamine at H2 receptors present on guinea pig right atrium. The remaining more lipophilic members of the series showed an insurmountable antagonism not completely reversible after prolonged washing. A binding study suggested that an increase in the length of alkyl chain gave rise to hydrophobic interactions with the receptor which were responsible for the apparent irreversible H2 antagonism shown by the higher homologues of the series.

Potential histamine H2-receptor antagonists. Synthesis, structure and activity of a few open models related to classical H2-antagonists.

A few ethers and oximes structurally related to classical H2-antagonists have been synthetized and tested for their in vitro H2-antagonist activity. The compounds in which cyclic "urea equivalent" groups are joined to a cyclohexylmethyl moiety showed a high increase of activity in comparison with the unsubstituted analogues. This finding supports the hypothesis of the existence of an accessorial binding area on H2-receptor near the site fitted by cyclic "urea equivalent" groups.

Synthesis and cardiovascular properties of furazanyl-1,4-dihydropyridines and of furoxanyl analogues.

A series of furazanyl- and furoxanyl-1,4-dihydropyridines has been synthesized and tested for their cardiovascular activity. The new compounds showed a modest activity in comparison with nifedipine and some selectivity for the myocardial muscle. The most active compound was diethyl 1,4-dihydro-2,6-dimethyl-4-(3-phenyl-4-furoxanyl)-3,5-pyridine dicarboxylate, 4d.

Mixed antisecretory and gastroprotective activities of a new H2-antagonist containing a nitric oxide-donor furoxan moiety.

The effect of a new histamine H2-receptor antagonist derived from the lamtidine molecule and containing a nitric oxide (NO)-donor furoxan moiety (derivative 1) was studied for its gastric antisecretory activity and for a possible gastroprotective effect, in comparison with the analog without the furoxan moiety (derivative 2). The H2-receptor antagonistic activity was also investigated in the isolated guinea pig papillary muscle. Derivative 1 was approximately 10 times less potent than derivative 2 at the H2-receptor level; conversely, it was about 10 times more effective as a gastroprotective agent against ethanol- and 0.6 N HCl-induced gastric lesions. The mechanism of the gastroprotection exerted by derivative 1 is probably connected with the release of NO, whose vasodilating action on gastric mucosa vessels is crucial. The combined antisecretory and gastroprotective activity of derivative 1 allows this compound to be considered as a prototype of a new class of antiulcer agents.

Effects of naloxone infusion on gonadotrophin and prolactin concentrations in patients with chronic renal failure.

Serum prolactin, luteinising hormone and follicle-stimulating hormone, determined by radioimmunoassay were measured during the infusion of 10mg naloxone or saline in eight male patients with chronic renal failure on regular dialysis and in seven normal controls. Neither saline nor naloxone caused any significant change in luteinising hormone, follicle-stimulating hormone or prolactin in patients with chronic renal failure. On the contrary, luteinising hormone secretion was significantly stimulated by naloxone in normal controls. Since naloxone is a specific antagonist of opiate receptors, the results would suggest a reduced hypothalamic opiate tone in patients with chronic renal failure. The data does not support the concept that the high circulating met-encephalin reported in chronic renal failure represents the pathogenetic cause of hyperprolactinaemia in chronic renal failure.

Alpha 1-adrenoceptor blocking activity of some ring-open analogues of prazosin.

Synthesis and structural characterization of some ring-open analogues of Prazosin containing either the guanidine substructure or urea-equivalent groups are described. The opening of the pyrimidine ring in Prazosin is very important as far as the affinity for alpha 1-adrenoceptor is concerned. The pA2 values of the ring-open derivatives are 10(4)-10(5) fold lower than that of the parent. It is probable that the affinity decrease principally reflects a negative influence of the conformational factors in the interaction with the alpha 1-receptor. The derivative 5 containing the guanidine moiety, charged at physiological pH, is as active as the other derivatives containing the uncharged urea-equivalent groups. This behaviour indicates, in this class of compounds, the importance of H-bonding interactions with the receptor. When in the ring-open models the ethanediamino substructure is substituted for the piperazine ring additional decrease in activity occurs.

The cyano-NNO-azoxy function in the design of an irreversible label for alpha 1 adrenoreceptors.

A potential alpha 1-adrenergic irreversible antagonist 6, containing the cyano-NNO-azoxy function was synthesized and tested. The effects of norepinephrine on rat thoracic aorta were irreversibly blocked by this compound at the concentration of 1 x 10(-5) M after 60 minutes. Binding studies showed that 6, at 1 x 10(-6) M, did not modify the KD of Prazosin and caused a 30% decrease of the Bmax. Substitution in 6 of the bis (2-chloroethyl)amino moiety for the cyano-NNO-azoxy function afforded 7 which behaves as an irreversible antagonist able to change KD of Prazosin without influencing Bmax.

Potential histamine H2-receptor antagonists: synthesis and pharmacological activity of derivatives containing acylamino-furazan moieties.

Analogues of 3-amino-4-[2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino] furazan (1) containing carbonyl groups joined to the amino functions linked to the furazan system have been synthetized and investigated for their H2-antagonist properties on the isolated guinea pig right atrium. The presence of the carbonyl group lowers the activity in respect to the corresponding leads. The decrease in activity is only by 1-2 orders of magnitude in the 3-acylamino-furazan series versus inactivity in the 4-acylamino isomers and in the diacylated series.

Does kidney transplantation normalise cortisol metabolism in apparent mineralocorticoid excess syndrome?

The syndrome of apparent mineralocorticoid syndrome (AME) results from defective 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and converts cortisol to its inactive metabolite cortisone. Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, suppression of PRA and hypertension. Thus, the syndrome is a disorder of the kidney. We present here the first patient affected by AME cured by kidney transplantation. Formerly, she was considered to have a mild form of the syndrome (Type II), but progressively she developed renal failure which required dialysis and subsequent kidney transplantation. To test the ability of the transplanted kidney to normalise the patient's cortisol metabolism, we gave, in two different experiments, 25 and 50 mg/day of cortisone acetate or 15 and 30 mg/day of cortisol after inhibition of the endogenous cortisol by synthetic glucocorticoid (methylprednisolone and dexamethasone). The AME diagnostic urinary steroid ratios tetrahydrocortisol+5alphatetrahydrocortisol/tetrahydrocortisone and cortisol/cortisone were measured by gas chromatography/mass spectrometry. Transplantation resulted in lowering blood pressure and in normalization of serum K and PRA. After administration of a physiological dose of cortisol (15 mg/day), the urinary free cortisol/cortisone ratio was corrected (in contrast to the A-ring reduced metabolites ratio), confirming that the new kidney had functional 11beta-HSD2. This ratio was abnormally high when the supra-physiological dose of cortisol 30 mg/day was given. After cortisone administration, the tetrahydrocortisol+5alphatetrahydrocortisol/tetrahydrocortisone ratio resulted normalised with both physiological and supra-physiological doses, confirming that the hepatic reductase activity is not affected. As expected, the urinary free cortisol/cortisone ratio was normal with physiological, but increased after supra-physiological doses of cortisone. The described case indicates a normalisation of cortisol metabolism after kidney transplantation in AME patient and confirms the supposed pathophysiology of the syndrome. Moreover, it suggests a new therapeutic strategy in particularly vulnerable cohorts of patients inadequately responsive to drug therapy or with kidney failure.