[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.

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.

Predilution haemofiltration--the Second Sardinian Multicentre Study: comparisons between haemofiltration and haemodialysis during identical Kt/V and session times in a long-term cross-over study.

BACKGROUND: The potential superiority of various renal replacement treatment modalities consisting largely of convective mass transfer as opposed to primarily diffusive mass transfer, is still a matter of debate. The objective of the present study was to evaluate acute and long-term clinical effects of varying degrees of convection and diffusion in a group of 24 clinically stable patients with end-stage renal disease. METHODS: The patients were prospectively assigned to three consecutive treatment schedules of 6 months each: phase I (HF1) (on-line predilution haemofiltration)-->phase II (HD) (high-flux haemodialysis)-->phase III (HF2; as phase I). We used the AK100/200 ULTRA monitor (Gambro), which prepares ultrapure dialysis fluid for HD and sterile, pyrogen-free substitution solution for HF. The membrane (polyamide), fluid composition, and treatment time were the same on HF and HD. The targeted equilibrated Kt/V was 1.2 for both treatment modes, creating a similar urea clearance. RESULTS: Fifteen patients, mean age 62.8+/-8.4 years, completed the study according to the above conditions. Urea kinetics, nutritional parameters, and dry weight were similar in the three periods. The frequency of intra-treatment episodes of hypotension/patient/month was significantly lower on HF1 (1.24) and HF2 (1.27) than on HD (1.80) (P<0.04). It decreased progressively on HF1, then increased on HD, and decreased again during HF2. Patients had fewer muscular cramps on HF than on HD (P<0.03) and required significantly less saline and plasma expander during HF than HD sessions. The prevalence of inter-treatment symptoms, including fatigue and hypotension, was lower on HF than on HD (score difference P=0.04). Quality of life, determined by the Laupacis method in all three periods, showed a tendency towards improvement during the study, reaching the best values during HF2. CONCLUSIONS: HF has a progressive stabilizing haemodynamic effect, producing a more physiological cardiovascular profile than HD. This long-term effect, observed in stable patients treated under strictly identical conditions, is probably due to the mechanism of convection, and is different from the acute effect observed mainly in unstable patients.

Anti-Helicobacter pylori agents endowed with H2-antagonist properties.

New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.

Adequacy in pre-dilution haemofiltration: Kt/V or infusion volume? The Sardinian Collaborative Study Group on Haemofiltration On-line.

Kt/V is the main index of adequacy for diffusive and diffusive convective methods of extracorporeal depuration, yet there exists no universally acceptable validation of an adequacy index for the solely convective methods such as haemofiltration (HF). The aim of the present study is to analyse which of the parameters of adequacy used in two multicentre HF studies, Kt/V for urea or infusion volume, correlate best with nutritional parameters and can therefore be utilized for the evaluation of treatment dose in on-line pre-dilution HF. Twenty-three clinically stable patients were enrolled in the first study [3 months of haemodialysis (HD)+ 3 months of HF]. In the second study, 24 stable patients were studied in three phases: 6 months in HF, 6 months in HD and a further 6 months in HF; in this study, a target of Kt/V= 1.2 in all three periods was preestablished: 15 patients completed the full study. In both studies, we utilized the same monitor (AK 100/200 Ultra, Gambro), the same membrane (polyamide) and the same on-line prepared ultrapure dialysis fluid and sterile infusion solution. In both studies, we ensured that HF fulfilled the following parameters of adequacy: urea kinetics, cardiovascular and blood pressure stability (better in HF than in HD), common haematochemical and nutritional parameters, reduction in beta2-microglobulin levels, a good intra- and extra-session clinical outcome, and a good quality of life with morbidity and mortality rates no different from those of HD. HF proved to be an efficacious method of ensuring adequate depuration and a good quality of life for uraemic patients. We have shown that in longer periods of HF, a notable correlation between Kt/V and normalized protein catabolic rate (nPCR) and an equally good correlation between total ultrafiltration (UF)/dry weight ratio and nPCR could be achieved. In both studies, the patients showed a good level of epuration adequacy when total UF per session was at least 1.3 times the dry body weight. The total UF/body weight ratio thus seems to be an easy method in HF because of its greater ease of predictability and measurement, also when it is used independently of the Kt/V index.

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.

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.

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.

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.

On-line predilution hemofiltration versus ultrapure high-flux hemodialysis: a multicenter prospective study in 23 patients. Sardinian Collaborative Study Group of On-Line Hemofiltration.

The aims of the present prospective multicenter study were to assess the clinical tolerance and well being, the correlation between nPCr and Kt/V and the pretreatment beta 2-microglobulin level in patients sequentially treated with high-flux dialysis with ultrapure bicarbonate hemodialysis (HD; phase 1) and predilution hemofiltration (HF) with on-line prepared bicarbonate substitution fluid (phase II). The same monitor (Gambro AK 100 ULTRA) and membrane (polyamide) were used. Twenty-three patients, all in a stable clinical condition, entered the study. The treatment was targeted to an equilibrated Kt/V (eqKt/V) of 1.4 for HD and 1.0 for HF. No mortality or relevant morbidity were observed. The number of hypotensive episodes was 1.78 +/- 2.8 per patient and month during HD vs. 1.17 +/- 3.1 during HF (p = 0.003) and the number of the hypertensive episodes 1.28 +/- 2.8 during HD vs. 0.42 +/- 0.8 during HF (p = 0.04). Incidences of arrhythmia, muscular cramps and headache were significantly less frequent during HF. Interdialytic cramps, arthralgia and fatigue were also significantly less frequent during the HF period. The average beta 2-microglobulin level was 27.1 +/- 14.7 mg/dl at the start of the study, 22.9 +/- 4.9 mg/dl at the beginning of phase II and 22.4 +/- 4 mg/dl at the end of phase II (p = 0.01 compared to the start). A significant linear correlation between the normalized protein catabolic rate and eqKt/V was obtained faster during HD than during HF (45 vs. 120 days) indicating that HF affects the nutritional status with mechanisms different from HD. The present study is in agreement with the hypothesis that HF gives and adequate nutritional status with improved clinical stability and well being at a lower Kt/V compared to HD. Both therapies were efficient in controlling the pretreatment beta 2-microglobulin level.

Low-dosage ibopamine treatment in progressive renal failure: a long-term multicentre trial.

A multicentre trial (11 nephrology centres) was carried out to test the effects of ibopamine, an orally active dopamine-like drug, on the progression of chronic renal failure. For a 2-year period 189 chronic renal failure patients (serum creatinine level 1.5-4.0 mg/dl) were observed. They were homogeneous for basic nephropathy, degree of residual renal function, blood pressure, and proteinuria. The patients were randomly divided into two groups: 96 took ibopamine at a dosage of 100 mg/day (group A) and 93 served as controls (group B). All were on a low-protein diet (mean 0.8 g/kg body weight). By the end of the observation period, the rate of decrease of the renal function indexes in time proved significantly slower (1.8 times) in group A than in group B. The survival curves for renal function (pre-established end points were creatinine level increases equal to or > 20% and equal to or > 40% of the basal values) proved significantly better (p < 0.02 and p < 0.002 respectively) in group A than in group B. The mean plasma creatinine values rose by 17% in group A and by 36% in group B. The creatinine clearance decreased by 5% in treated patients and by 14% in the controls. Statistical analysis ruled out any possible centre effect. The trial suggests that low-dosage ibopamine administration may be used as a valid and safe pharmacological adjunct for retarding the progression of renal failure in patients with mild or moderate chronic renal impairment.

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.

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.