In vitro Metabolism of Bumetanide

A new metabolite of the diuretic drug bumetanide, the 4-[(4-hydroxy)-phenoxy] analog (7), was identified in incubation mixtures of rat liver microsomes. Phenobarbital and clofibrate pretreatment to induce microsomal enzymes changed the relative amounts of the six metabolites formed. Compound 7was the most prevalent metabolite after clofibrate pretreatment.     

Intralesional ethanol in the treatment of unresectable liver cancer

Percutaneous ethanol injection (PEI) under ultrasonography guidance has been widely tried in not advanced hepatocellular carcinoma (HCC). Ten years after the introduction of PEI, some conclusions of its indications can be drawn. In our series, 210 cirrhotic patients were treated; 141 with multisession PEI in an outpatient clinic, 57 with single session PEI under general anesthesia, and 12 with both. The 1-, 3-, and 5-year survival rates (by Kaplan-Meier method) were 93%, 65%, and 41% for Child class A patients with single HCC 5 cm, and 88%, 47%, and 33% for patients with multiple HCC up to five lesions 5 cm. In these patients the local recurrence rate was 15% and the new lesion rate at the 5-year follow-up was 74%. One death due to hemorrhage from esophageal varices in a Child class C patient treated by single session PEI occurred. The large number of cirrhotic patients enrolled in ultrasonography screening programs has created a large demand for effective, safe, repeatable, low-cost treatment that can be offered at many centers. PEI meets all these requirements. PEI is proposed as the treatment of choice for the mentioned patients, excluding candidates for liver transplantation and surgical resection according to the predictive adverse factors currently in use. Single session technique widened the indications of traditional PEI to larger lesions.

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Resumen La inyección percutánea de etanol (IPE) bajo guía ultrasonográfica ha sido ampliamente ensayada en carcinoma hepatocelular (CHC) no avanzado. Transcurridos diez años luego luego de la introducción de la IPE, se pueden sacar conclusiones pertinentes a su indicación: En nuestra serie, se trataron 200 pacientes cirróticos, 141 de ellos con IPE en múltiples sesiones en forma ambulatoria, 57 con una sesión única de IPE bajo anestesia generaly y 12 con ambas modalidades. Las tasas de sobrevida a 1, 3 y 5 años (por el método de Kaplan-Meier) fueron 93%, 65%, 41% en los pacientes en clase Child-A con CHC único de 5 cm, y 88%, 47% 33% en CHC múltiple de hasta 5 lesiones de 5 cm. En estos pacientes la tasa de recurrencia local fue 15% y la tasa de nuevas lesiones a los 5 años de seguimiento fue de 54%. Se presentó una muerte por hemorragia de várices esofágicas en un paciente en clase Child-C tratado con una sesión única de IPE. El gran número de pacientes cirróticos incorporados a programas de tamizaje con ultrasonido ha creado una gran demanda por tratamientos eficaces, seguros, reproducibles y de bajo costo. El IPE llena todos estos requerimientos. Se propone el IPE como el tratamiento de escogencia para los pacientes arriba mencionados, haciendo exclusión de los candidatos para transplante hepático y para resección quirúrgica de acuerdo con los factores adversos de pronóstico actualmente en uso. La técnica de une sesión única ha ampliado las significaciones tradicionales del IPE para ser aplicada a lesiones de mayor tamaño.

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Résumé L'alcoolisation par injection percutanée (APC) sous échographie est utilisée pour traiter des carcinomes hépatocellulaires (CHC) peu volumineux. Dix ans après l'introduction de la technique d'APC, on peut tirer des conclusions quant à es indications. Dans notre expérience, 210 patients cirrhotiques ont été traités: 141 ont été traités par APC en ambulatoire, 57 en «séance unique» sous anesthésie et 12 par les deux. La survie à 1, 3 et 5 ans (méthode de Kaplan-Meier) était respectivement de 93, de 65 et de 41 % pour les patients ayant une lésion unique 5 cm, classés Child A, et de 88, de 47 et de 33% chez les patients ayant des lésions multiples mais inférieures au nombre de 5, toujours 5 cm. Chez ces patients, le taux de récidive locale était de 15% et le taux de nouvelles lésions à 5 ans, de 74%. Il y a eu un décès par hémorragie en rapport avec une rupture de varices oesophagiennes chez un patient Child C traité en une seule séance d'APC. Le nombre croissant de patients actuellement soumis, à une surveillance par échographie va de paire avec un traitement efficace, sûr, de coût réduit, et facilement disponible dans de nombreux centres. L'APC répond à toutes ces conditions. L'APC peut être proposée comme traitement de choix pour des patients répondant aux critères suscités, en excluant les candidats à la transplantation ou ceux qui peuvent être traités chirurgicalement. Les indications de la technique préconisée ici, en une seule séance, s'élargissent actuellement à des lésions plus volumineuses.

     

Ovarian tissue grafting: Lessons learnt from our experience with 55 grafts

Purpose

Uncertainties remain regarding the clinical efficacy of ovarian tissue cryopreservation and grafting. We report a retrospective analysis of reproductive outcomes and lessons learnt following 55 ovarian tissue transplant procedures at our center from 2006 to 2019.

Methods

We analyzed variables related to graft success such as tissue volume, follicular density, total follicular volume, and age on the duration of graft function.

Results

Follicular density and total follicular volume correlate positively with duration of graft function. All clinical pregnancies in our cohort occurred in women who were aged 35 or less at the time of ovarian tissue cryopreservation.

Conclusion

Graft success, as determined by eventual pregnancy and the longevity of graft function, may be impacted by factors including age at cryopreservation, follicular density, and total follicular volume.

     

Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma.

PURPOSE: Fenretinide (4HPR), a synthetic retinoid, induces apoptosis in neuroblastoma cells. A Phase I study in children with neuroblastoma was designed to determine maximum tolerated dose, toxicity, and pharmacokinetics. EXPERIMENTAL DESIGN: Fifty-four patients received oral 4HPR, once daily, for 28 days, followed by a 7-day interruption, for up to 6 courses. The starting dose was 100 mg/m(2)/day. At least 3 patients were entered at each escalating 4HPR dose level. Pharmacokinetic sampling was performed on days 1 and 28 of the first course. RESULTS: Fifty-four patients, of whom 53 were evaluable, received doses between 100 and 4000 mg/m(2)/day for a total of 168 courses. Additional dose escalation was precluded by capsule number intake. A total of 34 of 53 evaluable patients showed manageable, reversible toxicities, which were not dose related. One dose-limiting toxicity (nyctalopia grade 3) occurred after the 1000 mg/m(2)/day dose. Twelve patients showed grade 2 toxicity: skin xerosis (6 cases); nyctalopia (3 cases); hepatic toxicity (1 case); diarrhea (1 case); and headache (1 case). Stable disease was observed in 41 patients for a median period of 23 months (range 2-35+). After first administration, average 4HPR peak plasma levels ranged from 0.6 to 6 micro M (after 100 and 4000 mg/m(2)/day, respectively) and increased 2-fold (to 1.3 and 12.9 micro M, respectively) after the 28-day treatment. 4HPR half-life increased from 17 h after the first administration to 25 h after the 28(th) administration. Incidence of grade 2-3 toxicity was 0 of 12 (0%), 7 of 22 (31%), and 4 of 8 (50%) with peak 4HPR concentrations <3 micro M, 3-10 micro M, and >10 micro M, respectively. After repeated treatment, retinol levels decreased from 20 to 10% of pretreatment levels after all of the doses. CONCLUSIONS: In children, 4HPR administration up to 4000 mg/m(2)/day over 28 days, followed by a 7-day interruption, results in manageable toxicity and in drug plasma concentrations comparable with those that induce apoptosis in neuroblastoma cell lines.     

Assessment of chitosan derivatives as buccal and vaginal penetration enhancers.

The aim of the present work was to evaluate the mucoadhesive and penetration enhancement properties via the buccal and vaginal mucosae of four different chitosan derivatives: 5-methyl-pyrrolidinone chitosan (MPC), two low molecular weight chitosans (DC1 and DC2) and a partially reacetylated chitosan (RC). Chitosan HCl was used as a reference. Polymer solutions (4% w/w) were prepared in media simulating the buccal (pH 6.4 buffer or water) and the vaginal (pH 5.0 buffer) environments and subjected to rheological characterization. Acyclovir was added to the polymer solutions at 5% (w/w) concentration. The mucoadhesive properties of the polymer solutions were measured using excised porcine cheek or vaginal mucosa and mucin dispersions to simulate the buccal or vaginal environments, respectively. Drug permeation and penetration tests were carried out using porcine cheek and vaginal mucosae as model membranes. Acyclovir aqueous suspensions prepared in pH 6.4 and 5.0 buffers were used as blanks. Drug release measurements were also carried out in the same conditions employed for the permeation and penetration tests. Methyl-pyrrolidinone chitosan shows the best mucoadhesive and penetration enhancement properties in both buccal and vaginal environments. The capability to enhance the permeation/penetration of acyclovir was decreased by partial depolymerization of chitosan and disappeared after partial reacetylation.     

Infection with IBV DMV/1639 at a Young Age Leads to Increased Incidence of Cystic Oviduct Formation Associated with False Layer Syndrome

Infectious bronchitis virus (IBV) is an avian coronavirus that causes respiratory disease but can affect the reproductive tract of laying-type chickens. If infection occurs in pullets, false layer syndrome, which is characterized by the development of large, fluid-filled cystic oviducts, can occur. Recently, IBV strain DMV/1639 has been detected in parts of Canada and the U.S., where false layer syndrome has occurred, though it is not clear if IBV is the sole cause or if age at infection is an influencing variable. Our study investigates the role and timing of IBV infection on the development of false layer syndrome, using the IBV types DMV/1639 and Massachusetts (Mass). Six groups of 120 SPF chickens were challenged at either three, seven, or fourteen days of age, using either DMV/1639 or Mass IBV. Cystic oviducts were seen in all the challenged groups, and the pullets challenged at 14 days of age had fewer cystic oviducts than pullets challenged at 3 or 7 days of age. The highest percentage of severe histology lesion scores were seen in the 3-day challenge groups. The data collected in this experiment confirm that IBV DMV/1639 causes cystic oviducts and indicate that age at infection plays a role in the pathogenesis of false layer syndrome.