Sacrospinous colpopexy in the management of uterovaginal prolapse.

OBJECTIVE: To investigate the morbidity and results of vaginal hysterectomy with concomitant sacrospinous colpopexy for uterovaginal prolapse. STUDY DESIGN: An observational study was carried out from June 17, 1986, to September 22, 1992. Patients were selected if it was thought that the cardinal-uterosacral ligaments could not be relied upon for vaginal vault support. RESULT: During the study period, 265 vaginal hysterectomies were performed. Forty-five (17%) were with concomitant sacrospinous colpopexy. The mean patient age was 54 years. There was one incidental cystotomy during hysterectomy, and two patients required transfusion. Postoperatively, eight patients were treated for soft tissue infection, one developed new-onset urinary incontinence, and no apparent nerve injuries were diagnosed. The mean day of discharge was 4.4. Six patients were lost to follow-up after the early postoperative period. The mean follow-up for the remaining patients was 29 months (12-66). One patient required subsequent vaginal repair for recurrent cystocele and enterocele. Four patients had persistent stress urinary incontinence. CONCLUSION: Sacrospinous colpopexy at the time of vaginal hysterectomy is reasonably safe and effective for reestablishing upper vaginal support.

Effect of propaquizafop and its free-acid derivative on lauric acid hydroxylation and peroxisomal beta-oxidation in primary cultured rat, mouse, guinea pig and marmoset hepatocytes.

The effects of the phenoxyisopropionic acid derivative propaquizafop and its free-acid derivative on microsomal lauric acid hydroxylase and peroxisomal fatty acyl-CoA beta-oxidation have been investigated in primary cultured hepatocytes obtained from various species and compared with those induced by bezafibrate. The hepatocyte cultures were incubated with these compounds for 48 hr at concentrations between 0.1-100mum. No signs of cytotoxicity were observed as shown by the lack of lactate dehydrogenase (LDH) release into the culture medium. Lauric acid 12-hydroxylase was found to be strongly induced after treatment of rat and mouse hepatocytes with all three compounds, but remained largely unaffected in guinea pig and marmoset hepatocytes. Concomitantly, peroxisomal fatty acyl-CoA beta-oxidation was found to be induced in rat but not in mouse hepatocytes after treatment for 48 hr. However, clearly increased beta-oxidation activities could also be observed in mouse hepatocytes after a 72-hr incubation period. In contrast, only marginally increased beta-oxidation activities were recorded, if at all, in guinea pig and marmoset hepatocytes. The results demonstrate that the effects of propaquizafop and its free-acid derivative in hepatocytes from four species are very similar to those produced by the known peroxisome proliferator (PP) bezafibrate. This is in accordance with the known difference in susceptibility of various species to PP, for example, rats and mice being most responsive whereas guinea pigs and primates including humans are far less responsive or even unresponsive.

Modulation of cocaine metabolism in primary rat hepatocyte cultures: effects on irreversible binding and protein biosynthesis.

To study mechanisms of cocaine-induced hepatotoxicity, short-term-cultured rat hepatocytes were exposed to cocaine or norcocaine at 10(-6) to 10(-4) M. Induction in vivo (with Aroclor 1254) or inhibition in vitro (with SKF-525A) of cytochrome P450 modulated the rate of oxidative biotransformation of cocaine to norcocaine and to other metabolites in vitro. The quantitative changes in the metabolic conversion of cocaine were paralleled by the amount of radiolabeled cocaine equivalents irreversibly bound to hepatocellular protein. Furthermore, induction of cytochrome P450-mediated cocaine or norcocaine metabolism was associated with inhibition of protein biosynthesis in cultured hepatocytes, whereas this effect was restored to normal when the oxidative metabolism was blocked by SKF-525A. Glutathione depletion with buthionine sulfoximine both increased the covalent binding of cocaine to hepatic macromolecules and augmented the inhibitory effect on protein biosynthesis. The integrity of the hepatocellular plasma membrane was not affected (no effect on lactate dehydrogenase leakage). The results indicate that in rat hepatocytes (a) a high proportion of intracellular cocaine is converted to a reactive metabolite which irreversibly binds to protein, and (b) irreversible binding of cocaine to hepatic protein is associated with impairment of hepatocellular function and could play a role in cocaine-mediated hepatotoxicity.

Determination of cocaine and norcocaine in plasma and cell cultures using high-performance liquid chromatography.

A new simple high-performance liquid chromatographic (HPLC) method was developed for the determination of cocaine and norcocaine. Cocaine and norcocaine in biological samples were buffered to pH 9.0, extracted with diethyl ether and reextracted in a 0.1% aqueous solution of tetramethylammonium hydrogen sulfate (TMAHS) with a theoretical yield of extraction of 100%. The HPLC elution of cocaine and norcocaine was performed using a Spherisorb RP-18, 100 mm x 4.6 mm I.D., 5 microns particle size column with a mobile phase containing acetonitrile-0.1% TMAHS aqueous solution (60:40). The compounds were entirely separated, and a reliable limit of quantitation was set at 20 ng/ml when extracted from 0.5 ml of plasma. No interference with 26 other drugs was found. Cocaine and norcocaine stability studies showed that their half-lives in human plasma incubated at 37 degrees C were 50.8 and 43.2 min, respectively. In contrast, plasma from dogs or rats exhibited only weak or no enzymatic esterase activity towards cocaine and norcocaine resulting in less rapid degradation. Hydrolysis could be efficiently inhibited with sodium fluoride and prevented by storage of the sample at -20 degrees C. The highly sensitive assay also allowed the assessment of the oxidative metabolism pathway of cocaine to norcocaine in primary rat hepatocyte cultures.

Effect of enzyme induction on Sandimmun (cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo.

This study was designed to examine the relationship between the extent of Sandimmun (cyclosporin A, SIM) metabolism and SIM-induced hepatotoxicity both in vivo and in primary cultures of rat hepatocytes. Firstly, SIM (50 mg/kg p.o.) was administered daily to male Wistar rats for 10 days with or without co-administration of Aroclor 1254. SIM-induced hepatotoxicity appeared after 4 days of treatment and was enhanced after 10 administrations of SIM. Total plasma proteins were decreased and hyperbilirubinemia as well as increased levels of plasma bile salts were prominent. Aroclor 1254 stimulated total hepatic cytochrome P-450 3.7-fold, and markedly increased the rate of SIM metabolism and plasma elimination as determined by both HPLC and RIA techniques. However, this induction did not change the degree of SIM-induced hepatotoxicity. Secondly, short-term cultures of hepatocytes obtained from normal rats and from rats pretreated with either Aroclor 1254 or dexamethasone, a specific inducer of the cytochrome P-450 III gene family responsible for the formation of the primary SIM metabolites M1, M17 and M21, were incubated with various concentrations of SIM for up to 17 hr. At 1 microM SIM, both inducers greatly increased the rate of SIM metabolism in vitro, producing, however, different metabolite patterns. In the hepatocyte cultures, SIM inhibited the incorporation of amino acids into proteins. In addition, a small fraction of [3H]-labeled SIM was covalently bound to hepatocellular macromolecules. Although the fraction of covalently bound SIM was markedly increased in cells from dexamethasone-treated rats, the degree of inhibition of hepatocellular protein synthesis was not changed in cells from induced rats. In contrast to SIM-induced nephrotoxicity, these results suggest that increased rates of SIM biotransformation by inducers of drug metabolism are not associated with an attenuation of hepatotoxicity both in vivo and in vitro.

Management of vaginal vault prolapse: retrospective comparison of abdominal versus vaginal approach.

Twenty-two cases of vaginal vault prolapse were managed by our service over the five-year period ending 12/31/86. Eleven cases were repaired by a transvaginal sacrospinous colpopexy and 11 by a transabdominal suspension. There were no differences in demographic data or preoperative symptoms between these groups. The vaginal procedure required less operative time, had less blood loss, averaged fewer hospital days and overall was more economical. The complication rates and follow-up results of the two techniques were comparable. The abdominal procedure is considered preferable for patients with specific indications for an abdominal approach. The vaginal procedure appears to be more appropriate when the abdominal approach is not otherwise indicated. The experience of the surgeon and individualization of the patient are important factors in choosing the best approach for the repair.

In vitro toxicity assessment of cyclosporin A and its analogs in a primary rat hepatocyte culture model.

The cytotoxicity of cyclosporin A (CsA), a widely used immunosuppressant drug, was evaluated in primary cultures of rat hepatocytes. Furthermore, the concentration-dependent (10(-7) to 10(-5) M) cytotoxic effects of the cyclosporin analogs, CsG, CsH, CsF, and of a major metabolite of CsA, CsA/M17, were assessed in an attempt to classify the different cyclosporin analogs according to their in vitro hepatotoxic potential. All compounds invariably inhibited the net release of taurocholate (de novo synthesized from cholate added to the extracellular medium). This sensitive functional marker did not discriminate between the structural analogs. In addition, all compounds inhibited, to various extents, the biosynthesis and secretion of proteins without affecting the uptake rate of the nonmetabolizable amino acid, alpha-aminoisobutyric acid. These functional changes occurred in the absence of overt irreversible cell damage (no leakage of lactic dehydrogenase up to 10(-5) M cyclosporin during 17 hr of incubation). The relative toxic potential of the drug congeners (CsG greater than CsA greater than CsH = CsF = CsA/M17) correlated well with the degree of their accumulation in the hepatocytes during exposure to equimolar drug concentrations.

Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes.

The relative cytotoxic effects of ten psychotropic drugs were assessed in rat hepatocyte monolayer cultures. Clear concentration-related toxicity was seen in the narrow range of 10(-5) M to 5 X 10(-5) M. The four cytotoxicity endpoints chosen were: release of the cytosolic enzyme, lactate dehydrogenase, and impairment of biosynthesis and secretion of proteins, bile acids and glycerolipids. LDH leakage and inhibition of protein secretion into the culture medium proved to be the parameters which allowed the best differentiation between the test compounds. The inhibition of glycerolipid secretion was the most sensitive test in relation to concentration and time of exposure. Based on the effects of these endpoints, the following ranking of relative in vitro toxicity, using equimolar drug concentrations, could be established: clomipramine greater than imipramine = thioridazine greater than chlorpromazine greater than amitriptyline = fluperlapine greater than haloperidol greater than promazine greater than clozapine much greater than sulpiride. This ranking order of in vitro cytotoxicity correlated well with the potential of the drugs to impair liver function in man. Only clozapine had to be classified as a false negative. There was, however, no correlation between the cytotoxicity and the intracellular accumulation of the test drugs. Furthermore, the comparison of the data obtained with psychotropics with the data from five other amphiphilic cationic drugs was consistent with the widely accepted concept of a direct toxic interaction of the drugs with cytomembranes. This nonspecific toxicity of the membrane-active drugs was further corroborated by a positive correlation between their potential to induce LDH leakage in hepatocytes and their ability to induce hemolysis in red cells. In conclusion, the results obtained in our study strongly suggest that it is possible to assess the relative cytotoxicity of psychotropic drugs in rat hepatocyte cultures. It is proposed that this in vitro system provides a useful tool to evaluate new drugs at an early stage of their development, and to identify the most promising candidates within a class of structurally related compounds. In addition, it allows information to be obtained on possible mechanisms of cytotoxicity.

Psychotropic drugs as inhibitors of glycerolipid biosynthesis and secretion in primary rat hepatocyte cultures.

Glycerolipid synthesis and secretion in rat hepatocyte monolayer cultures have been studied as possible endpoints in cytotoxicity assays. Ten psychotropic drugs of different structural classes were incubated with the hepatocytes at concentrations ranging from 10(-6)m to 5 x 10(-5)m and their effects on the incorporation of [(3)H]glycerol into glycerolipids and on the subsequent lipid secretion into the medium were measured. After 2-hr exposures to eight of the ten drugs, glycerolipid secretion was inhibited as a function of the drug concentration. The integrity of the plasma membrane, however, was still preserved, as no leakage of the cytosolic enzyme, lactate dehydrogenase, occurred. The incorporation of [(3)H]glycerol into the total cell-associated glycerolipid fraction was much less affected by the drugs than was the medium-associated fraction. In this model, the tricyclic antidepressants, imipramine, clomipramine and amitriptyline caused a marked inhibition of in vitro glycerolipid secretion. Chlorpromazine, thioridazine, fluperlapine, haloperidol and promazine were of intermediate potency, and clozapine and sulpiride had no inhibitory effect on glycerolipid secretion. A significant inhibition of glycerolipid secretion was also seen after exposure to low concentrations (10(-5)m) of the non-psychotropic drugs, amiodarone, perhexiline and chloroquine, indicating that the cationic amphiphilic nature of all of the drugs studied accounted for the toxic effect. The results suggest that the assessment of the inhibitory effect on glycerolipid secretion is a sensitive endpoint for cytotoxicity which, in combination with other in vitro tests (e.g. determination of protein and bile acid biosynthesis and secretion, and enzyme leakage), allows a ranking of the relative toxicity of psychotropic drugs.

Cost analysis of a mucoadhesive foam versus conventional treatment for postepisiotomy patients.

The cost of treating postepisiotomy pain and edema with foam containing 1% hydrocortisone acetate and 1% pramoxine hydrochloride and a spray with 20% benzocaine was compared in 200 postpartum patients. Treatment with foam was demonstrated to be more effective than benzocaine spray with greater pain relief and reduction of edema as shown by lower patient need of supplemental pain-relief measures. Treatment with foam was also determined to be less expensive than benzocaine spray when the cost of the supplemental pain-relief measures for benzocaine-treated patients were assessed. Methods used to determine actual hospital costs are presented, and supplemental pain relief treatments are discussed. Use of this type of cost analysis may be useful to the P & T Committee when determining actual cost-effectiveness of different treatment modalities.

Surfactant "apoproteins" in human amniotic fluid: an enzyme-linked immunosorbent assay for the prenatal assessment of lung maturity.

We have developed an enzyme-linked immunosorbent assay for the quantitation of human lung surfactant high--molecular weight proteins and used this assay to evaluate changes in surfactant "apoprotein" content of amniotic fluid during the last trimester of pregnancy. The amount of surfactant apoprotein in human amniotic fluid increased with advancing gestational age and correlated well with other parameters of fetal lung maturity, the lecithin:sphingomyelin ratio, and the presence of phosphatidylglycerol. The findings suggest that this test, which is relatively simple to perform, may prove useful as an additional clinical parameter for assessing fetal lung maturity and predicting more accurately fetuses at risk of developing hyaline membrane disease.

Endodermal sinus tumor: report of a case associated with pregnancy.

The case of a 15-year-old black primigravida with an 18-week intrauterine gestation and concurrent endodermal sinus tumor is presented. Rationale for therapy is discussed.

Hemoglobin and Escherichia coli, a lethal intraperitoneal combination.

Intraperitoneal injection into mice of approximately 8 x 10(6) washed cells of Escherichia coli suspended in a lysate of washed human red blood cells or an aqueous solution of crystalline hemoglobin was lethal. E. coli suspended in washed intact erythrocytes, whole blood, plasma, or saline was innocuous. Fractionation of non-hemoglobin proteins from hemoglobin in lysates showed that only hemoglobin promoted a lethal infection. Overwhelming intraperitoneal growth of E. coli was attained in about 12 hr in lethal infections. The polymorphonuclear leukocytic response was ineffective against this rapid growth. The lethal mechanism is hypothesized to center on a unique role for free hemoglobin in inhibiting peritoneal absorption and stimulating an intraperitoneal exudate which supports luxuriant bacterial growth. Death is attributed to a lethal intoxication from bacterial endotoxins. This role for hemoglobin involves neither enhanced bacterial virulence nor lowered host resistance, and it would be of importance not only in peritonitis but also in problems where hemolysis and infection coexist.