[Acute pyelonephritis]. / Vignette diagnostique de l'étudiantLa pyélonéphrite aiguë.

The present review details the recommendations for the management of acute pyelonephritis in adults. Acute pyelonephritis corresponds to the infection of the upper urinary tract and is particularly common in women between the age of 15 and 65 years. Symptoms usually include fever, chills, flank pain, nausea and vomiting. There are different types of pyelonephritis, and their management may differ upon the patient's comorbidities and the pathogenic agent. The first step in the management of a patient with suspected acute pyelonephritis focuses on the need for hospitalization. Bacteriological samples should always be collected before the initiation of antibiotics. The antibiotic therapy will then be adapted according to the profile of the infecting pathogen.

Cette vignette reprend les recommandations de prise en charge de la pyélonéphrite aiguë (PNA) de l'adulte. La PNA est une infection urinaire haute, particulièrement fréquente chez la femme entre 15 et 65 ans. La symptomatologie typique associe fièvre, frissons, douleur au niveau de la loge rénale, nausées et vomissements. Il existe différents types de PNA dont la prise en charge peut varier selon les comorbidités du patient ou le type de bactéries. Devant toute PNA, la première étape est d'évaluer la nécessité d'une hospitalisation. Les prélèvements à visée bactériologique doivent toujours précéder l'initiation de l'antibiothérapie, dont le spectre sera adapté en fonction de la sensibilité antibiotique du germe mis en évidence.

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1.

BACKGROUND: ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells. METHODS: Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines. RESULTS: Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions. CONCLUSION: ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

Pharmacokinetics and tolerability of a novel long-acting glucagon-like peptide-1 analog, CJC-1131, in healthy and diabetic subjects.

OBJECTIVE: The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated. METHODS: CJC-1131 was subcutaneously injected in 8 groups (1.5 - 20.5 microg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 - 12 microg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3. RESULTS: CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in Cmax. The half-life of CJC-1131 varied from 8.9 - 14.7 days in healthy subjects and from 9.1 - 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 microg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients. CONCLUSIONS: Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.

Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2.

BACKGROUND AND PURPOSE: Paclitaxel is highly efficacious in the treatment of breast, head and neck, non-small cell lung cancers and ovarian carcinoma. For malignant gliomas, paclitaxel is prevented from reaching its target by the presence of the efflux pump P-glycoprotein (P-gp) at the blood-brain barrier. We investigated the utilization of a new drug delivery system to increase brain delivery of paclitaxel. EXPERIMENTAL APPROACH: Paclitaxel molecules were conjugated to a brain peptide vector, Angiopep-2, to provide a paclitaxel-Angiopep-2 conjugate named ANG1005. We determined the brain uptake capacity, intracellular effects and antitumour properties of ANG1005 in vitro against human tumour cell lines and in vivo in human xenografts. We then determined ANG1005 activity on brain tumours with intracerebral human tumour models in nude mice. KEY RESULTS: We show by in situ brain perfusion that ANG1005 enters the brain to a greater extent than paclitaxel and bypasses the P-gp. ANG1005 has an antineoplastic potency similar to that of paclitaxel against human cancer cell lines. We also demonstrate that ANG1005 caused a more potent inhibition of human tumour xenografts than paclitaxel. Finally, ANG1005 administration led to a significant increase in the survival of mice with intracerebral implantation of U87 MG glioblastoma cells or NCI-H460 lung carcinoma cells. CONCLUSIONS AND IMPLICATIONS: These results demonstrate the antitumour potential of a new drug, ANG1005, and establish that conjugation of anticancer agents with the Angiopep-2 peptide vector could increase their efficacy in the treatment of brain cancer.

Prolonged action of a chimeric interleukin-2 receptor (CD25) monoclonal antibody used in cadaveric renal transplantation.

A high affinity chimeric CD25 mAb (chRFT5: SDZ CHI 621) blocking interleukin-2 binding to the interleukin-2 receptor alpha-chain was evaluated in a phase I/II study in human renal cadaveric transplantation. The chRFT5 was well tolerated with no immediate adverse effects during 6 spaced infusions (from before transplantation to day 24) in 24 patients escalating from 2.5- to 25-mg dosages. The chRFT5 had a long terminal half-life with a mean of 13.1 days. There was good correlation between the detection of chRFT5 in the serum by radioimmunoassay, the coating and suppression of CD25 on T cells, and antibody activity in patient serum samples. The chRFT5 activity persisted in vivo for up to 120 days. No antibody response to the chRFT5 was detected in any of the patients, even though two patients who required treatment with antithymocyte globulin or OKT3 developed xenogeneic antiglobulin responses while chRFT5 was still present in vivo. There was a 33% incidence of rejection and the first rejection episode always occurred during chRFT5 therapy. Patients who did not reject during therapy did not reject during the first year following transplantation. Equal numbers of patients received dual and triple immunosuppressive therapy together with chRFT5. Posttransplant lymphoproliferative disorder developed in 2 patients, both on triple therapy, at 9 months after transplantation. The disorder did not develop in any patient receiving dual therapy, and no further cases have been observed to a minimum of 2 years' follow-up. No other viral, fungal, or bacterial infectious complications were prevalent in patients treated with chRFT5.

Utilization of erythropoietin in the treatment of the anemia due to chronic renal failure.

Administration of recombinant erythropoietin constitutes a revolution in treatment of the anemia of chronic dialysis patients. Such treatment has been anxiously awaited. Its realization has been possible thanks to the spectacular progress allowed by the newly developed techniques of recombinant genetics. Correction of this type of anemia can be obtained rapidly and permanently if treatment is continued without interruption. It is followed by a remarkable transformation of the patient's physical and psychic status. The occurrence of certain side effects (e.g., elevation of blood pressure and an increased tendency toward vascular thrombosis), however, requires increased awareness in the follow-up of patients at risk and adaptation of erythropoietin administration to individual needs.

Pancrease gastroresistance: in vitro evaluation of pH-determined dissolution.

In order to avoid inactivation in the stomach, pancreatic enzymes have been prepared as pH-sensitive, enteric-coated microspheres (Pancrease). An in vitro study was performed to evaluate the pH-related dissolution of Pancrease and to confirm its resistance to gastric acidity. Two assay methods were used with three different batches of Pancrease: (a) Enzyme absorbency at 280 nm was measured at unit pH intervals from pH 1 to pH 8 and at 0.5 pH intervals from the start of dissolution to pH 8. (b) Proteolytic activity was measured at pH 6.8. Significant enzyme dissolution started at pH 5.5 and was maximal at pH 6.0. At pH 6.8, the pH of simulated intestinal fluid, dissolution was complete in less than 15 min. At pH 5.0, no dissolution occurred within the first 10 min and only 13% dissolution was observed after 2 h. At pH 7.0, 100% dissolution was seen within 10 min. Results of the two assay methods were comparable with all three enzyme batches assayed. This study confirmed the gastroresistance of Pancrease. Because of the enteric coating of Pancrease, liberation of enzymes occurs in the duodenum and jejunum, providing maximal enzymatic efficacy in exocrine pancreatic insufficiency.

Efficacy of pancrease: crossover comparative study versus eurobiol in cystic fibrosis.

An open crossover study in patients with documented cystic fibrosis (CF) compared the efficacy and acceptability of Pancrease (Cilag, PC), consisting of pH-sensitive, enteric-coated microspheres, with those of Eurobiol, consisting of lyophilized total pancreas. Eleven patients, age 6-17 years, were hospitalized for study. A hypercaloric, normal fat diet as well as previous antibiotic, vitamin, and other CF therapy were maintained during the 2-week study period. During the first study week, eight patients were given four divided doses of either Pancrease, 8 capsules daily, and two patients were given Eurobiol, 2 bottles daily. One patient received six Pancrease capsules or 1.5 bottles of Eurobiol daily. Patients were switched to the alternate drug for the second study week. Stools were collected for analysis over the final 3 days of each week. Steatorrhea (mean +/- 1 SD) with Pancrease was 11.8 +/- 6.6 g/24 h and with Eurobiol was 17.9 +/- 11.7 g/24 h. The coefficient of lipid absorption was 74.1 +/- 13.3% for Pancrease and 58.6 +/- 22.5% for Eurobiol (p less than 0.02). The decrease in steatorrhea and increase in lipid absorption with Pancrease compared to Eurobiol were 33.9% and 26.5%, respectively. All patients considered the acceptability of Pancrease superior to that of Eurobiol. No adverse effects were seen with either drug.

[Clinical and biological justifications for the use of Triella]. / Justifications cliniques et biologiques de l'emploi de Triella.

PIP: The principal preclinical studies of the biological properties of norethisterone and the clinical research leading up to development of the low dose triphasic oral contraceptive (OC) Triella are described. Triella mimics the natural cycles of women, allowing effective contraception with a small dose of estrogen and progesterone and excellent cycle control. Preclinical studies demonstrated that norethisterone is an active progestin whose luteo-mimetic and antiovulatory activity are equivalent to those of other progestins. Unlike levonorgestrel, norethisterone shows no notable androgenic activity in experiments with rats and does not modify serum levels of SHBG in rabbits. These findings support the conclusion that norethisterone effectively inhibits ovulation without androgenic secondary effects. The increased intermenstrual bleeding experienced by early users of low-dose formulations necessitated new protocols for evaluation. Each user noted on a daily calendar whether the pill was taken or forgotten and whether "bleeding" requiring sanitary protection or "staining" not requiring protection had occurred on that day. A formulation combining 35 mcg of ethinyl estradiol (EE) and .5 mg norethisterone was effective but caused frequent intermenstrual bleeding, especially during the 2nd phase of cycles and in the 1st cycles of use. Research was then directed toward finding a multiphasic mode of administration to reduce the norethisterone dose to the lowest possible level that would be effective and still permit good cycle control. Several biphasic combinations showed bleeding in the middle of the cycle. The Triella formulation therefore contains 3 levels of norethisterone for the 21 days of treatment: .5 mg for the first 7 days, .75 mg for the following 7 days, and 1 mg for the last 7 days. The EE dose is constant at 35 mcg/daily for the 21 treatment days. Midcycle bleeding was eliminated and the frequency of late cycle bleeding was minimized. Tolerance to Triella equalled that of Ortho-novum 1/35 despite its much smaller total dose. Later studies showed that intermenstrual bleeding in the early cycles of Triella use later diminished.^ieng

Membrane expansion as a mechanism explaining the antisickling action of ticlopidine observed in vitro.

Ticlopidine, a platelet antiaggregant, has shown some efficacity in a clinical trial in patients with sickle cell disease. We have studied this agent in vitro to evaluate its effects on sickle erythrocyte. Ticlopidine effects sickling in vitro not by direct interaction with hemoglobin, but via strong binding to the red cell membrane. The density of the whole cell population is decreased when cells are treated with 0.1 mM ticlopidine, which is higher than the concentrations of 1 microM potentially achievable in vivo. Since hemoglobin concentration influences the delay time for gelling, its decrease in the red cell could have a beneficial effect. Such a partial inhibition of the polymerization is shown by oxygen equilibrium studies at various ionic strengths.

[Triella: a French multicenter double blind clinical study]. / Triella--etude clinique multicentrique francaise menee en double aveugle.

PIP: Following a brief review of the progressive improvements in oral contraceptive (OC) formulations and a description of the multicenter international study of Triella, this article describes a French multicenter double-blind study which compared the triphasic OC Triella with the widely used biphasic pill Adepal. Triella combines a constant dose of 35 mcg ethinyl estradiol (EE) with norethisterone doses of .5 mg for 7 days, .75 mg for 7 days, and 1 mg for 7 days. 91 women used Triella for a total of 463 cycles and 87 used Adepal for 412 cycles. There were no statistically significant differences in the age, height, weight, blood pressure or previous OC usage of the 2 groups. Average menstrual cycle length and duration of menstruation were both shortened after OC use, from 30.16 to 27.6 days and 4.74 to 3.65 days with Triella and from 30.49 to 27.6 days and 4.85 to 3.59 days with Adepal. Some diminution of menstrual flow was also observed. Spotting or staining was observed during 14.0% of days in the 1st cycle and 2.0% in the 6th cycle with Triella and during 11.9% of days in the 1st cycle and 3.9% in the 6th cycle with Adepal. Before treatment, during the 1st cycle, and during the 6th cycle respectively, 48.4%, 9.9%, and 4.8% of women using Triella and 65.5%, 11.4%, and 8.9% using Adepal experienced dysmenorrhea, while 45.1%, 12.1%, and 6.3% using Triella and 57.5%, 13.8%, and 10.7% using Adepal experienced premenstrual syndrome. There were no statistically significant changes in weight. Mean blood pressure did not show any tendency to increase with Triella after a temporary rise in the 1st 2 cycles, which was not statistically significant. Average blood pressure with Adepal increased from 118.6/70.9 before treatment to 121.4/71.6 in the 6th cycle. 3.3% of Triella users and 9.2% of Adepal users had blood pressure increases to 140/90 or above. Among cycles of Triella and Adepal use respectively, 6.9% and 8.3% had breast problems, 6.2% and 5.6% had digestive problems, 6.9% and 3.6% had abdominopelvic problems, 5.4% and 4.9% had headaches, 3.2% and 4.6% had leucorrhea, 1.9% and 3.6% had psychic problems, .9% and 1.5% had vascular problems, and .6% and .7% had skin problems. All side effects had a tendency to decline with use. No new anomalies were detected in the final gynecological examination, except a case of mastosis in an Adepal user. 20 Triella users and 23 Adepal users were evaluated before treatment and at the 3rd, 6th, and 12th cycle for triglycerides, fasting and postprandial insulin and glucose tolerance, and total cholesterol. There were no significant changes, although there were nonsignificant postprandial elevations in glucose and insulin with both formulations. There were slight declines in total cholesterol with both OCs. No pregnancies occurred in either group.^ieng

In vitro study of ticlopidine, as a model of antisickling action of platelet antiaggregant.

The in vitro antisickling effect of ticlopidine may be explained by the action of the drug on the membrane. The drug molecule increases slightly the volume of the cell, decreases the mean intra-erythrocytic hemoglobin concentration and therefore affects the delay time for hemoglobin S polymerization.