[Economic and organizational impact of the use of a disposable sheath with a flexible cystoscope]. / Cystoscope flexible à gaine stérile à usage unique: impact organisationnel et économique et sécurité bactériologique.

PURPOSE: To assess both economical and organizational impact as well as bacteriologic safety of a flexible cystoscope with sterile disposable sheath (FCSDS) compared to standard flexible cystoscopy (SFC) in two French urologic academic units. PATIENTS: Two-center prospective study, comparing the use of the FCSDS to the SFC on two consecutive periods of time. Two hundred and five patients were included and divided into each group. Duration procedures and costs were analysed in the two techniques. The urinary tract infection rate was also described. A dedicated sheaths leaks test after use was performed systematically. RESULTS: The preparation time of the fibroscope was longer for the sheathed cystoscopy group: 16.2 minutes versus 10.9 minutes for the standard group. The mean duration of disinfection was significantly shorter for the sheathed cystoscopy group: 53.8 minutes saved compared to the standard group; 99.01% of the tested sheaths, after their use, had no breaches. Urinary tract infections rate were similar in the two groups. The average cost of a sheathed cystoscopy compared to the standard was significantly cheaper in Lyon and almost equivalent in Marseille. CONCLUSION: The FCSDS allows significant saving over the disinfection duration, consumable costs and staff costs, while ensuring patient bacteriologic safety similar to SFC.

[Female stress incontinence treatment: urethral slings]. / Traitement de l'incontinence urinaire d'effort féminine : les bandelettes sous-urétrales.

Female stress incontinence is often the consequences of obstetrical traumatisms. They are responsible of a weakness of perineal musculoaponevrotic structures. Until 1996, the reference treatment of this pathology was the "Burch" colposuspension, by laparotomy, then laparoscopic way. After 1996, a new procedure was developped by Ulmten, reproducible, easy, safe and mini-invasive: the tension free-vaginal-tape (TVT) followed by the trans-obturator-tape (TOT). This therapeutic tool has become the reference for the treatment of the female stress incontinence. There are now 15 years from the beginning of this procedure and still 80% of the patients are improved.

Intermediate chains of exopolysaccharides from Lactobacillus rhamnosus RW-9595M increase IL-10 production by macrophages.

AIMS: To evaluate the immunosuppressive properties of the exopolysaccharide (EPS) from high-EPS producer Lactobacillus rhamnosus RW-9595M on inflammatory cytokines produced by macrophages. METHODS AND RESULTS: The conditioned media (CM) were produced by macrophages treated with parental Lact. rhamnosus ATCC 9595 and its isogenic variant, the high-EPS producer Lact. rhamnosus RW-9595M, and the levels of TNF-alpha, IL-6, IL-10 and IL-12 were evaluated. Results revealed that CM from parental Lact. rhamnosus induced higher levels of TNF-alpha, IL-6 and IL-12 but inhibited IL-10 production, whereas its mucous variant induced low or no TNF-alpha and IL-6. Addition of purified EPS to macrophages treated with parental Lact. rhamnosus decreased the inflammatory cytokines and inhibited the metabolic activity of lymphocytes. The intermediate polysaccharide chains (16-30 units) produced by time-controlled hydrolysis of EPS increased the IL-10 produced by macrophages. CONCLUSIONS: Polysaccharide chains of EPS induced immunosuppression by the production of macrophagic anti-inflammatory IL-10. SIGNIFICANCE AND IMPACT OF THE STUDY: These results indicate that the EPS from Lact. rhamnosus RW-9595M may be useful as a new immunosuppressive product in dairy food.

[Economic evaluation of deflexible ureteroscopy with laser]. / Evaluation économique de l'urétéroscopie souple laser.

PURPOSE: The purpose of our study was to make an evaluation of the effective cost of a session of deflexible ureteroscopy with laser to cure kidney stones and kidney urothelials tumors. MATERIAL: This cost was calculated based on 103 sessions (83 kidney stones, 18 urothelials tumors, one cyst and one endopyelotomy) carried out on 73 patients and was including (1) staff expenses in the operation room (based on work time stated on the anesthesia sheet); (2) material expenses: technically specific or not. Reusable or single use; (3) amortisement of medical supply calculated on a seven year basis; (4) hospital stay. In this study medical logistic expenses and administrative expenses were not taken into account as well as structural expenses which were considered apart of this activity. RESULTS: Cost of a laser deflexible ureteroscopy was estimated by more or less 4237.3euro, including 1677.6euro for hospital charges. The cost of a session was 4490.5euro for a tumor and 4141.4euro for a stone, however the difference was not significant. Cost without hospital charges was estimated by 1196.5euro. CONCLUSION: The main part of a laser deflexible ureteroscopy session cost was the consequence of hospital expenses. It could only be obtained in a structure running a sufficient activity level depend on amortisement of medical supply.

Comparative study of transfer factor and acyclovir in the treatment of herpes zoster.

Reactivation of varicella herpes virus (VHV), latent in individuals who have previously suffered varicella, gives rise to herpes zoster and in some cases leads to a sequela of post herpetic neuritis with severe pain which is refractory to analgesics. Many different antiviral agents have been tried without achieving satisfactory results. Of all the antiviral agents employed, acyclovir has been the most successful in reducing post herpetic pain. However acyclovir has not been as reliable as interferon alpha (IFN-alpha). We have previously looked into the use of transfer factor (TF) as a modulator of the immune system, specifically with respect to its effectiveness in the treatment of herpes zoster. In this work findings from a comparative clinical evaluation are presented. A double blind clinical trial of TF vs acyclovir was carried out in which 28 patients, presenting acute stage herpes zoster, were randomly assigned to either treatment group. Treatment was administered for seven days and the patients were subsequently submitted to daily clinical observation for an additional 14 days. An analogue visual scale was implemented in order to record pain and thereby served as the clinical parameter for scoring results. The group treated with TF was found to have a more favorable clinical course, P < or = 0.015. Laboratory tests to assess the immune profile of the patients were performed two days prior and 14 days after initial treatment. The results of these tests showed an increase in IFN-gamma levels, augmentation in the CD4+ cell population but not the percentage of T rosettes in the TF treated group. These parameters were however insignificantly modified in patients receiving acyclovir. Although TF treated patients showed an increase in CD4+ counts these cells remained below the levels for healthy individuals. The fact that IFN-gamma levels as well as the counts for CD4+ cells rose in the TF treated group and not in the acyclovir one is very significant and confirms the immunomodulating properties of TF.

Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.

Calcium channel blockers correct in vitro mitochondrial toxicity of cellulose acetate.

We studied the action of rinse solutions from cellulose acetate hemodialyzers on isolated mitochondria. We showed that concentrates from the rinses impaired the adenosine 5'-triphosphate (ATP) synthesis as reflected by the decrease in respiration during state 3 and in P/O ratio. This impairment results from a calcium release from mitochondria that is induced by rinse solution concentrates. The release, triggering the mitochondrial calcium carrier, would explain the decrease in ATP synthesis. Moreover, rinse solution concentrates hinder mitochondrial calcium storage. The rise in cytosolic calcium in hemodialyzed patients may be related, at least in part, to these findings, since a lack of ATP impairs the ATP-dependent cellular calcium-extrusion pumps. We also showed that calcium channel blockers, at therapeutically relevant doses, restore ATP synthesis and calcium storage in mitochondria impaired by rinse solution concentrates. Finally, these in vitro results were confirmed by experiments on cells in culture proving that Diltiazem counteracts the cytotoxicity of rinse solution concentrates. These findings are consistent with observations that these drugs suppress the increase in leukocyte cytosolic calcium in dialyzed patients. Moreover, this would help explain the efficiency of calcium channel blockers in cells without L-calcium channels.

Differential effects of zidovudine and zidovudine triphosphate on mitochondrial permeability transition and oxidative phosphorylation.

1. The effects of zidovudine (ZDV) and zidovudine triphosphate (ZDV-3P) on Ca2+-induced mitochondrial permeability transition (MPT), respiratory control ratio (RCR) and ATP synthesis have been investigated on isolated rat liver mitochondria. 2. ZDV slightly but significantly decreased RCR and ATP synthesis but was ineffective in inhibiting MPT. In contrast, ZDV-3P did not alter RCR and ATP synthesis but strongly inhibited MPT (IC50 = 3.0 +/- 0.9 microM). 3. The effect of ZDV-3P on mitochondrial swelling required a preincubation time. When incubated 10 min with mitochondria, ZDV-3P (8 microM) totally inhibited the rate of swelling. 4. ADP, ATP and atractyloside, which are agents known to interact with the mitochondrial adenine nucleotide carrier (ANC), antagonized the effect of ZDV-3P on mitochondrial swelling. Indeed, the IC50 value of ZDV-3P increased from 3.0 to 17.4, 93.6 and 66.5 microM, in the presence of 20 microM, ADP, ATP or atractyloside, respectively. 5. ZDV-3P did not displace [3H]-ATP from its mitochondrial binding site(s) whereas ADP and atractyloside did, suggesting that ZDV-3P and [3H]-ATP do not share the same binding sites. 6. ZDV-3P did not affect either mitochondrial respiration or ATP synthesis but inhibited Ca2+-dependent mitochondrial swelling. It was concluded that mitochondrial toxic effects observed during the chronic administration of ZDV cannot be related to its active metabolite (ZDV-3P).

In vitro mitochondrial test to assess haemodialyser biocompatibility.

BACKGROUND: This paper describes an in vitro mitochondrial test to assess the biocompatibility of haemodialysers. METHODS: We tested on isolated liver mitochondria the effect of solutions obtained by an aqueous rinse of different haemodialysers (cuprophane, cellulose acetate, Hemophan, polyacrylonitrile, polymethylmethacrylate, polysulphone, polyamide). Moreover, to determine the penetration into the cell and the cytotoxicity of these solutions from haemodialysers, we examined the effect of rinse solutions on HT29-D4 cells. RESULTS: Our results showed that rinse solutions from haemodialysers decrease the mitochondrial ATP synthesis. Cuprophane has the most marked effect, and the synthetic membranes exhibited only mild effects. Rinse solutions penetrated the cell and were cytotoxic by acting on mitochondria in the cell. In this respect, cellulosic membranes were the most toxic. CONCLUSION: Taken together our findings lead to a classification of haemodialyser membranes which is identical to one based on criteria such as activation of complement (cuprophane > other cellulosics > synthetics). Moreover isolated mitochondria make it possible to differentiate among the synthetic membranes. Isolated mitochondria thus appear to be a good in vitro test to assess the biocompatibility of haemodialysers.

Comparison of the effects of cyclosporine A and trimetazidine on Ca(2+)-dependent mitochondrial swelling.

Cyclosporine A (CsA) is a known potent inhibitor of pro-oxidant-induced mitochondrial swelling. In the present study we show that CsA's effect is only transient when the liver mitochondrial swelling in induced by Ca2+ plus tert-butylhydroperoxide (t-BH). After an initial inhibition, swelling is worsened by CsA as evidenced by an extent of mitochondrial swelling that exceeds that of the control. Unlike CsA, trimetazidine (TMZ), an anti-ischemic drug decreases both the extent and the rate of the swelling with an IC50 value of 214 +/- 24 microM. Its inhibition effect on the initial swelling rate mimicks that of CsA but the mechanism may be independent. During long-term swelling. TMZ counteracts the worsening effect of CsA. The inhibition of swelling induced by TMZ is assessed by the fact that TMZ significantly increases the EC50 of Ca(2+)-induced mitochondrial swelling (46.6 +/- 6.0 to 85 +/- 10 microM, P < 0.01), without affecting its cooperativity. Apparently, TMZ seems to behave like trifluoperazine (TFP), a phospholipase A2 inhibitor that, under our experimental conditions, inhibits the mitochondrial swelling induced by Ca2+ and t-BH with an IC50 value of 25 +/- 10 microM. Both drugs are able to protect mitochondria from both phases (early and late) of the swelling, especially the late, which is enhanced in the presence of CsA. TFP and other phospholipase A2 inhibitors were able to displace [3H]TMZ from its mitochondrial binding sites whereas CsA was ineffective. We suggest that TMZ, like TFP, inhibits the CsA insensitive mechanism involved in the swelling process which is responsible for the worsening effect observed in the presence of CsA when the swelling is generated by Ca2+ and t-BH.

Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients.

AIMS: In renal allograft recipients, trimetazidine (Vastarel) was proposed to be associated with the classic immunosuppressant treatments because it displays anti-ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun, and trimetazidine. METHODS: Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40 mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin-2 and soluble interleukin-2 receptor levels were measured. RESULTS: The data showed that neither cyclosporin A blood pharmacokinetic parameters, Cmax, tmax, AUC, nor the concentrations of interleukin-2 and soluble interleukin-2 receptors were significantly modified. CONCLUSIONS: Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.

Trimetazidine reverses calcium accumulation and impairment of phosphorylation induced by cyclosporine A in isolated rat liver mitochondria.

When applied to rat liver mitochondria in contact with Ca++, cyclosporine A (CsA) induced both an accumulation of this ion and a decrease in oxidative phosphorylation. Trimetazidine (TMZ) reversed both phenomena in a dose-dependent manner. These two effects were demonstrated in separate experiments. A decrease in oxidative phosphorylation was observed with succinate as substrate. V3 and P/O (ratio corresponds to the number of ADP molecules added in the medium per oxygen atom consumed during phosphorylation and represents the yield of ATP synthesis) were simultaneously decreased by CsA (1 microM) and restored by TMZ. Ca++ accumulation in mitochondria was observed when it was added to the mitochondrial suspension; its uptake was followed by a new equilibrium. CsA prolonged its duration, whereas TMZ reduced it in a dose-dependent manner. The same phenomenon was observed when ADP was used instead of CsA. Ca++ efflux from mitochondria could be induced by TMZ without the addition of CsA. It was immediate and always partial and followed by a reuptake process only observed at concentrations of TMZ of >1 microM. Compared with ruthenium red, which blocks Ca++ uniporter, TMZ seemed to act on Ca++ efflux mechanisms. Interestingly, low TMZ doses promote a Ca++ efflux process without activating reentry mechanism, which may explain the correction of deleterious effect of CsA on V3 and P/O. As nephrotoxicity observed in humans after CsA chronic administration is considered to be related, at least in part, to an alteration of Ca++ intracellular homeostasis, TMZ seems to be a candidate for alleviation of CsA nephrotoxic effects in humans.

Lack of pharmacodynamic interaction between trimetazidine and cyclosporin A in human lymphoproliferative and mouse delayed hypersensitivity response models.

The hypothesis of an interaction between trimetazidine and the immunosuppressive effect of cyclosporin A was investigated in two models: a) ex vivo, the lymphoproliferative response of normal human lymphocytes to phytohemagglutinin and a murine monoclonal antibody against the CD3 T-lymphocyte membrane complex; b) in vivo, the delayed hypersensitivity response model in mouse. The uptake of methyl-3H-thymidine was measured in both models. For the lymphoproliferative response, statistical analysis showed that there was a significant inhibitory effect of cyclosporin A on cell proliferation (P < 0.001) and confidence intervals obtained by ANOVA showed the equivalence of the results when trimetazidine was combined with cyclosporin A (all CI95% < or = 10). In the delayed hypersensitivity model, cyclosporin A was also found to be very effective in inhibiting the immune response (P < 0.001), while trimetazidine did not interfere with cyclosporin A's effect. It was concluded that trimetazidine exerted neither an immunostimulatory nor an immunosuppressive effect in the two models, suggesting of the absence of interaction between trimetazidine and cyclosporin A's effectiveness when both drugs are given in combination.

Is the beneficial effect of calcium channel blockers against cyclosporine A toxicity related to a restoration of ATP synthesis?

ATP synthesis inhibited by Cyclosporine A is restored by calcium channel blockers: nifedipine, verapamil, bepridil, diltiazem. ATP synthesis was estimated using liver mitochondria by measuring the rate of respiration during state 3 and a measure of the yield of ATP synthesis, the P/O ratio. The study of calcium fluxes through mitochondrial membrane indicates that calcium channel blockers counteract the mitochondrial calcium storage induced by cyclosporine A. If the restoration of ATP synthesis observed in vitro also occurred in vivo, the increase in ATP pool might contribute to a better functioning of the Ca2+ extrusion pumps of the cells, thereby maintaining the cytosolic calcium concentration (Cai), in the normal range. The nephrotoxicity of cyclosporine A appears to be due to a vasoconstrictive effect related to an increased Cai. This result may account for the reduction of clinical cyclosporine A toxicity by calcium channel blockers. Verapamil appears to be the most efficient in restoring ATP synthesis.

Calcium anti-ionophoretic effect of some calcium channel blockers in rat liver mitochondria.

Beyond their classical action on calcium channels, some calcium channel blockers also exhibit a calcium anti-ionophoretic effect. We studied this effect on respiratory control and Ca2+ fluxes in a mitochondrial model to compare calcium antagonists chosen among three clinical classes: vascular, cardiac, and mixed effects. Synthetic calcium ionophore A23187 decreases respiratory control and modifies Ca2+ fluxes. We show that calcium antagonists partially restore the parameters altered by A23187. By calculating the percentage of restoration, we found that vascular drugs exhibit a strong anti-ionophoretic effect, cardiac drugs exert no significant effect, and mixed calcium antagonists exert an intermediate effect. Thus, it appears possible to link the intensity of calcium anti-ionophoretic effect with the clinical interest of a calcium antagonist.

Protective effect of some calcium antagonists against mitochondrial calcium injury.

Ischaemia induces an increase in calcium cytosolic concentration, leading to a mitochondrial Ca2+ overload. As Ca2+ uptake and storage into mitochondria are the alternative route to oxidative phosphorylation, the Ca2+ overload induces a decrease in ATP synthesis. We have tested in vitro the ability of certain calcium antagonists to restore the ATP synthesis inhibited by mitochondrial calcium overload. Our results showed that diltiazem and bepridil, clinically used as antiischaemic agents, each can restore the ATP synthesis. It is suggested that our in-vitro results might serve to explain the antiischaemic properties of some calcium antagonists.

1H-NMR study of suloctidil-A23187 calcium ionophore interaction.

Suloctidil is a molecule with calcium antagonist properties, whose anti-ionophoretic effect has previously been reported. In the presence of A23187 calcium ionophore free acid (A+), the NMR spectra of suloctidil (S +/-) are modified at the level of H-1 protons and to a lesser degree in the CH3-3 and aromatic regions. Experiments with one of the enantiomers of suloctidil and decoupling investigations led us to postulate the existence of diastereoisomers S+/A+, S-/A+ in the suloctidil +/-/A23187 + mixture. Moreover our results allow the hypothesis that suloctidil and calcium compete for the same binding site of the ionophore molecule.

The restoration of ATP synthesis may explain the protective effect of calcium antagonists against cyclosporine A nephrotoxicity.

Cyclosporine A at pharmacological doses decreases the rate and yield of ATP synthesis in rat mitochondria. This action seems to be due to the mitochondrial calcium storage induced by the drug. If such an effect occurs in vivo, the ATP deficit will affect calcium extrusion pumps, so triggering vasoconstriction which is the major side effect of Cyclosporine A. Calcium antagonists (Nifedipine and Verapamil) at least partially correct this effect on ATP synthesis: this finding may be related with the beneficial clinical effect conferred on Cyclosporine A toxicity by calcium antagonists. This effect of calcium antagonists may be due to an interaction with Cyclosporine A at the level of mitochondrial calcium efflux.

Counteraction by nicardipine of the ionophoretic effect of gliclazide: a mitochondrial study.

Using mitochondria, we demonstrate that gliclazide exhibits a calcium ionophoretic activity. Indeed, gliclazide induces a decrease in the respiratory control of mitochondria; this effect is increased by addition of Ca2+ and corrected by ruthenium red, all characteristics of a calcium ionophoretic compound. Our results, on a biological membrane, confirm previous findings in vitro. Moreover, we show that nicardipine counteracts the action of gliclazide. Besides the effect on ATP-stimulated K+ channels, the ionophoretic effect of gliclazide may play a role in its hypoglycaemic effect, thus this counteracting action of nicardipine might induce drug interaction during the concomitant clinical administration of gliclazide and nicardipine.