[Study impacto: Descriptive analyzis of pharmacist's clinical practice in onco-hematology]. / Étude impacto : analyse descriptive des pratiques de pharmacie clinique en cancérologie.

Pharmaceutical analyses of chemotherapy prescriptions by hospital pharmacists are activities codified by regulation and rules (bon usage). The involvement of the pharmacists in clinical pharmacy activities in the oncology setting is not clearly identified, justifying the development of a mapping of these activities from a questionnaire addressed to the professionals. One hundred and seven centers have participated to this study at the national level (overall participation rate of 32.4%). More than 95% of them used a computerized ordering system and three quarter of them submit the introduction of new compounds to an analysis by the drug therapeutic committee. Prescription analysis allowed detecting around 2% of errors from the current prescription. Clinical pharmacist participates to tumor boards of onco-hematology (RCP) at a level of 46% for senior pharmacist and 42% for junior pharmacist. This involvement in the RCP allowed anticipating protocol's modification and temporary used authorization. Ninety-two percent of the senior pharmacists estimate that they highlight the risk of no reimbursement for prescription out of the guideline during RCP, resulting to a modification of the prescription for 40% of them. This level of intervention is lower with respectively 64% and 10% for the juniors. This study underlines the expert value of the clinical pharmacist dedicated to oncology setting in pre and post analysis prescriptions. It could be targeted by a prospective analysis of both clinical and pharmacoeconomics impact of these interventions.

The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing.

SUMMARY: The present study shows no adverse effects of the anti-diabetic drug metformin on bone mass and fracture healing in rodents but demonstrates that metformin is not osteogenic in vivo, as previously proposed. INTRODUCTION: In view of the increased incidence of fractures in patients with type 2 diabetes mellitus (T2DM), we investigated the effects of metformin, a widely used T2DM therapy, on bone mass and fracture healing in vivo using two different rodent models and modes of metformin administration. METHODS: We first subjected 12-week-old female C57BL/6 mice to ovariectomy (OVX). Four weeks after OVX, mice received either saline or metformin administered by gavage (100 mg/kg/daily). After 4 weeks of treatment, bone micro-architecture and cellular activity were determined in tibia by micro-CT and bone histomorphometry. In another experiment, female Wistar rats aged 3 months were given only water or metformin for 8 weeks via the drinking water (2 mg/ml). After 4 weeks of treatment, a mid-diaphyseal osteotomy was performed in the left femur. Rats were sacrificed 4 weeks after osteotomy and bone architecture analysed by micro-CT in the right tibia while fracture healing and callus volume were determined in the left femur by X-ray analysis and micro-CT, respectively. RESULTS: In both models, our results show no significant differences in cortical and trabecular bone architecture in metformin-treated rodents compared to saline. Metformin had no effect on bone resorption but reduced bone formation rate in trabecular bone. Mean X-ray scores assessed on control and metformin fractures showed no significant differences of healing between the groups. Fracture callus volume and mineral content after 4 weeks were similar in both groups. CONCLUSIONS: Our results indicate that metformin has no effect on bone mass in vivo or fracture healing in rodents.

Guidelines for the practical stability studies of anticancer drugs: a European consensus conference.

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles' formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

[Cyclosporine 2% eye drops preparation]. / Préparation d'un collyre de ciclosporine à 2%

PURPOSE: Cyclosporine administration is very effective in the case of immunological diseases of the cornea, conjunctive or uvea. Moreover, it is widely used in the case of high-risk rejection corneal transplantation. We present a preparation of cyclosporine 2% eye drops. METHODS: Cyclosporine 2% eye drops are prepared following a particular formulation including one part commercially available cyclosporine oral solution (Sandimmun) diluted in four parts of sterile castor oil. Manufacturing procedures maintain the sterile state of the preparation with a laminar airflow hood placed in a particulate controlled room, with pharmacists, technicians and clerical personnel wearing sterile clothes. Physical and chemical monitoring during and after manufacture for each batch guarantees the process and minimizes the risk of batch rejection. Chemical analysis of cyclosporine is conducted using a validated stability-indicating high-performance liquid chromatographic assay (reverse-phase). Blood dosages taken after the first administration at the 24th hour (after administration of the 6th drop) check for systemic integration. RESULTS: Cyclosporine 2% eye drops are fairly stable: 12 months after manufacturing, concentrations result in levels not statistically different from concentrations measured the day of preparation. After a daily regimen of six drops in the eye, cyclosporine 2% eye drops have a very low systemic bioavailability, because the blood concentrations only reach the detection limit of the fluorescence polarization immunoassay used for cyclosporine drug monitoring. This explains the absence of systemic toxicity. CONCLUSION: Cyclosporine 2% eye drops can be available in the hospital pharmacy. The eye drops are stable at room temperature and can be delivered up to 12 months after manufacture. No local adverse effects have been noted, probably in relation with the very low concentration of ethanol in the ocular preparation.

[Plasma assay of methadone enantiomers with high performance liquid chromatography]. / Dosage plasmatique des énantiomères de la méthadone par chromatographie liquide à haute performance.

6-Dimethylamino-4,4-diphenylheptane-3-one (methadone) is a synthetic opioid. Presence of an assymetrical carbon in its structure explains existence of two enantiomers. Levogyral enantiomer or R-methadone exhibits an 25 fold superior analgesic activity to the dextrogyral enantiomer S-methadone. In order to run separately a plasma assay of these two enantiomers, a chromatographic chiral separation method coupled with an ultraviolet detection has been performed. It allows selective assay of each enantiomer. This method, although an analytical interference with d-propoxyphene, is sensitive, reproductible, specific and shows a convenient resolution for the analysis of both the stereospecific and racemic forms. This method can be applied for pharmacokinetic study of the drug in patients treated by methadone.

Effects of dipeptide administration on hypoglycaemic counterregulation in type 1 diabetes.

OBJECTIVES: To investigate if a dipeptide made of glutamine and alanine is able to contribute to the recovery from insulin-induced hypoglycaemia in type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifteen adult type 1 patients were randomly assigned to study group (n=7): intravenous infusion of 20 g Dipeptiven in normal saline (i.e., 8 g alanine and 13 g glutamine), or control group (n=8): same infusion, normal saline only. A 150 min gradual hypoglycaemic hyperinsulinemic clamp was administered after 2 h of infusion. Counterregularory hormones, symptoms, and cognitive function (4 choice reaction test) were regularly measured during the study. RESULTS: Blood glucose and glucose infusion rates were similar in the 2 groups. Circulating levels of alanine and glutamine peaked at 90 min and remained elevated throughout the test. This was associated with significant differences in: glucagonemia 107 +/- 20 vs 58 +/- 8 pg/ml, and neuroglycopenic symptoms scores: 7 +/- 3 vs 18 +/- 13, at t 150 min, in study and control group, p<0.05. Dysautonomic symptoms, cognitive tests as well as epinephrine, norepinephrine, cortisol and growth hormone were similar between groups. CONCLUSION: Intravenous infusion of a dipeptide made of alanine and glutamine is capable to reactivate glucagon secretion during insulin-induced hypoglycaemia and to reduce hypoglycaemic symptoms.

Comparison of risks from percutaneous central venous catheters and peripheral lines in infants of extremely low birth weight: a cohort controlled study of infants < 1000 g.

OBJECTIVE: To evaluate in infants of < 1000 g (extremely low birth weight; ELBW) the success rate of insertion of percutaneous central venous catheters (PCVC) and their duration; and the short- and long-term complications, i.e. mechanical and infectious, when compared to a control group of infants of the same age treated only with peripheral venous access. STUDY DESIGN: A cohort of 44 ELBW infants managed with PCVC (study group) was compared to a cohort of 44 infants managed only with peripheral venous access (control group). The two groups were matched for birth weight, gestational age and gender, and were comparable for severity of illness (CRIB scores). RESULTS: The success rate of PCVC insertion was 74% with the right axillary vein being the most frequently used site. The mean duration of PCVC treatment was 28 +/- 13 days. The reasons for removal of the catheter were: cessation of the total parenteral nutrition administration in 75% of the cases and occlusion in 25%. There were three infectious episodes for a total of 1138 catheter days in the PCVC group vs. 12 episodes for a total of 1114 days (p = 0.03) in the control group. Three infants died in the study group and 11 infants died in the control group (p = 0.05) of infants of ELBW. CONCLUSION: Insertion of PCVC is successful in the vast majority of cases and carries a lower risk of infection than multiple insertions of peripheral lines in infants of ELBW. It prevents repeat and painful introductions of intravenous needles.

Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin.

OBJECTIVES: To evaluate the effectiveness of a hydrogel implant containing the gonadotropin-releasing hormone (GnRH) agonist histrelin in suppressing testosterone production in men with prostate cancer and to determine the effective dose (one, two, or four implants). METHODS: Forty-two men with prostate cancer and indications for androgen ablation were treated with one, two, or four implants. In two of the clinics, comprising 27 subjects, the treatment period was 12 months, with replacement with the same number of implants at 12-month intervals. In a third clinic, which treated 15 subjects, the implants were left in place for up to 30 months. The total experience was 605 treatment months. RESULTS: The histrelin levels were detected in serum proportional to the number of implants placed. The response, however, was similar among all three dose levels, with testosterone and luteinizing hormone essentially completely suppressed. Serum testosterone levels decreased from 21.9 +/- 17.6 nmol/L to 0.93 +/- 1.57 nmol/L within 1 month and were maintained at 0.55 +/- 0.24 nmol/L at 6 months and 0.60 +/- 0.28 nmol/L after 12 months of treatment. Of the 38 assessable patients, 35 (92%) had castrate levels of testosterone within 4 weeks of the initial implant placement. All patients followed for up for 12 months after placement of the initial set of implants maintained suppression of testosterone production while the implant was in place. CONCLUSIONS: The histrelin hydrogel implant provided adequate and reliable delivery of the potent GnRH agonist histrelin during at least 1 year using a single implant in men with prostate cancer. No apparent advantages were found in using more than one implant, and the question of the possible effectiveness of even lower doses remains open. This treatment modality appears to be both safe and effective.

Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic Type 2 diabetic patients with oral drug failure: a cross-over study.

AIMS: We have evaluated the local tolerance and the metabolic efficacy of a lyophilized nasal insulin preparation in 10 severely hyperglycaemic Type 2 diabetic patients. METHODS: The study included two 4-month randomized periods: (A) three preprandial doses of nasal insulin secondarily combined with one evening subcutaneous NPH if the desired glycaemic control was not achieved; (B) two NPH injections daily. We assessed: (i) diabetes control on monthly HbA1c levels and occurrence of hypoglycaemic events; (ii) local tolerance on clinical symptoms, rhinoscopy, nasal muco-ciliary clearance and nasal biopsies; (iii) insulin absorption at months 0 and 4. RESULTS: One patient was withdrawn because of cough and dizziness after each nasal application. HbA1c was not significantly different at month 4 (9.4 +/- 0.5% vs. 8.8 +/- 0.2%, A vs. B). Blood glucose control remained only fair in the majority of our patients. Nasal insulin was able to replace the daytime fraction of the subcutaneous insulin with a 18% efficacy. Side-effects included transient nasal hyperactivity (pruritus, sneezing and rhinorrhoea) and chronic persistence of nasal crusts. Plasma insulin profiles were not significantly different between months 0 and 4. CONCLUSIONS: The utilization of nasal insulin (with or without NPH) was associated with similar diabetes control compared with NPH twice daily. Nasal insulin alone was able to achieve an adequate glycaemic control in three of the 10 patients.

The relationship between introduction of American society of clinical oncology guidelines and the use of colony-stimulating factors in clinical practice in a Paris university hospital.

BACKGROUND: Clinical practice guidelines are issued periodically by professional medical societies or committees to assist practitioners in clinical decision making. However, it is unclear whether such guidelines have any lasting impact on clinical practice. OBJECTIVE: The purpose of this study was to assess the impact of the American Society of Clinical Oncology (ASCO) guidelines regarding use of hematopoietic colony-stimulating factors (CSF) on cancer care in a university hospital in Paris. METHODS: The study was performed at Hjpital Tenon, an 830-bed university hospital in Paris, in 1996 and 1997, both before and after the ASCO guidelines were implemented. The guidelines were first disseminated as a continuing medical education program and then actively implemented using a CSF prescription order form summarizing the guidelines. This form had to be used during the patient consultation and was sent to the Hjpital Tenon pharmacy for CSF dispensation. Even if CSF use did not comply with the ASCO guidelines, the pharmacy filled the prescription. Seven other university hospitals in Paris, where the ASCO guidelines were not actively implemented, comprised the control group. The main outcome measure was the proportion of prescriptions in compliance with the 1996 update of the ASCO guidelines. Secondary outcome measures were the proportions of prescriptions in compliance with ASCO guidelines regarding primary prophylactic, secondary prophylactic, and therapeutic CSF administration. RESULTS: Before implementation of the ASCO guidelines, CSF use in compliance with the guidelines was 39% (41/105) at the study site and 31% (16/51) at the control sites (P > 0.05). Six months after dissemination and implementation of the guidelines, the proportion of CSF prescriptions complying with ASCO guidelines increased significantly versus baseline (P = 0.003) in the study group, to 61% (50/82). However, even after the guidelines were implemented, compliance with guidelines on primary prophylactic CSF administration did not change significantly versus before implementation in the study group (12% [5/41] before implementation vs 6% [2/33] after implementation; P > 0.05). CONCLUSIONS: The results suggest an association between the active implementation strategy (continuing medical education and CSF prescription reminder form) and physician compliance with the ASCO guidelines. Implementation of the ASCO guidelines appears to have had some impact on medical practice.

Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance.

OBJECTIVE: Nasal insulin administration is a potential route for intensive insulin management, less invasive and more rapid than subcutaneous injections. Previous studies have shown poor bioavailability (less than 15%) with nasal insulin administration with various absorption enhancers. The aim of the study was to evaluate in type 1 diabetic patients, the metabolic efficacy and local tolerance of a new gelified sprayed nasal insulin containing glychocolate and methylcellulose as absorption promoters. MATERIAL AND METHODS: The study was conducted in 16 type 1 diabetic patients (HbA1c 8.6+/-0.2%) in a cross-over trial including 2 six month randomized periods: a) NPH twice daily + 3 pre-prandial nasal insulin doses + nasal supplementation in case of unexpected hyperglycaemia; b) NPH twice daily + 3 pre-prandial regular insulin injections. End points were HbA1c levels, hypoglycaemic episodes and tolerance evaluated at month 0, 2, 6 and 8 on clinical symptoms and objective nasal assessments. RESULTS: Four patients were withdrawn because of nasal burning (3 cases) and persistent sinusitis (1 case), and one patient had purulent sinusitis at the month 6 examination. At month 6, HbA1c levels were comparable (8.3 +/- 0.1 vs 8.6 +/- 0.1%, m +/- SEM, NS) for nasal and subcutaneous period respectively. The number of hypoglycaemic events was identical during the 2 periods (88 episodes). Nasal tolerance with the gelified form was better than with the already reported lyophilized form but, when present, symptoms were more marked, suggesting a potentiating additional role of methylcellulose excipient on nasal intolerance. CONCLUSIONS: 1) Gelified nasal insulin is as efficient as subcutaneous regular insulin in type 1 diabetic patients. 2) Other galenic forms should be investigated to improve nasal tolerance and bioavailability.

[Analysis of the medico-economic literature comparing primary angioplasty and thrombolysis in the management of acute myocardial infarction]. / Analyse de la littérature médico-économique comparant angioplastie primaire et thrombolyse dans la prise en charge de l'infarctus aigu du myocarde.

OBJECTIVE: To assess the generalizability of the medico-economic analysis comparing primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction. METHOD: A systematic analysis of published studies was performed by two independent reviewers, in accordance with guidelines promulgated by health economic experts. RESULTS: Eleven articles, which concerned seven studies, were selected. Respectively, four evaluations were carried out in U.S. and three other in European countries (France, Netherland and Austria). There were three randomized trials, two observational studies and two decision trees. The costs were respectively ranged 2042 to 83,708 1999 US dollars for thrombolytic therapy and 3289 to 83,477 1999 US dollars for angioplasty. In two randomized trials and one decisional tree, the primary coronary angioplasty was both more effective and less costly than the thrombolysis therapy. One observational study concluded that thrombolytic therapy was less costly than primary angioplasty despite comparable effectiveness. Two analysis could not conclude of a difference between the alternatives, because of lack of statistical power. DISCUSSION: Published medico-economic analysis remain of a little interest for the French health care system because of lack of transparency in presentation of results. The dominance of the primary angioplasty was sensitive to time required for patient's transfer (ideally less than an hour), to the presence of redundant laboratories in an area and to the presence of an experienced staff for 24 h a day.

Effects of androgen on androgen receptor expression in rat testicular and epididymal cells: a quantitative immunohistochemical study.

Androgen is essential for maintenance of spermatogenesis in the testis and for maturation of spermatozoa in the epididymis. The effects of androgen are mediated through its receptor (AR), the levels of which are, in turn, regulated by androgen. Previous studies have shown that AR concentrations in Leydig and Sertoli cells are differentially regulated during development. The aim of the present study was to determine if cell-type-specific regulation of AR by androgen occurs in testicular and epididymal cells during adulthood. Adult male rats were treated with the LHRH-antagonist Azaline B (100 g/day) by osmotic pump for 1, 2, 3, 4, or 8 wk to suppress endogenous androgen, with identical numbers of intact control animals at each time period. An androgen replacement group was simultaneously treated with the antagonist and a synthetic androgen, 7 alpha-methyl-19-nortestosterone (MENT), during the final 4 wk of the experiment. Levels of nuclear AR protein in specific cell types were quantified by immunohistochemistry in conjunction with computer-assisted image analysis. Levels of AR in testicular cells declined sharply after treatment with the LHRH antagonist. In Sertoli cells, nuclear AR levels decreased to 8% of control (P < 0. 01) after 4 wk treatment; and to 12% and 17% of control (P < 0.01) in Leydig and myoid cells, respectively. Androgen replacement resulted in complete recovery of nuclear AR levels in Sertoli cells (93%, P > 0.05) but in only partial recovery in myoid (69%, P < 0. 01) and Leydig cells (56%, P < 0.01). In the epididymis, tubular epithelial cells and stromal cells differed in their responses to the LHRH antagonist. After 1 wk, nuclear AR levels in caput stromal cells decreased dramatically to 34% of control (P < 0.01) and in cauda stromal cells to 43% (P < 0.01). In contrast, the decline of AR levels in epididymal epithelial cells was not as dramatic as that in stromal cells. After 1 wk, the decline in the caput and cauda was to 87% and 76% of control, respectively. After 8 wk, nuclear AR levels in stromal cells further declined to 1.1% in caput and 1.4% in cauda, whereas in the epithelial cells, a smaller decline in nuclear AR was noted (to 30% in the caput and 45% in the cauda). After androgen replacement with MENT, nuclear AR levels recovered to more than 90% of control in both epididymal cell types. These results indicate that AR levels in the nuclei of adult Sertoli cells depend mainly on the level of androgen, whereas in the adult Leydig and myoid cells, the androgen dependency is more limited. The results also indicate that in the epididymis, stromal cells are more sensitive than epithelial cells to the regulation of AR levels by androgen.

Anordiol produces pregnancy loss in the rat--via the embryo or via the uterus?

Anordiol, the dihydroxylated metabolite of anordrin, is an antiestrogen with estrogenic activity that is known to inhibit fertility. The following study was conducted to determine the mechanism of this antifertility effect. Anordiol was administered orally to rats, prior to implantation, on Day 2 of pregnancy. Control animals were treated with the vehicle only. The effectiveness of the agent in terminating pregnancy was determined on Day 14 of pregnancy. Anordiol was 100% effective in abolishing pregnancy at a dose of 0.6 mg/Kg. Administration of smaller doses resulted in a decreased number of implanting embryos, in a dose-dependent manner. An additional dose of anordiol on Day 3 of pregnancy yielded similar results. To determine whether pregnancy impairment by anordiol is exerted via the embryo or via the uterus, reciprocal embryo transfers were performed. Day 5 blastocysts were transferred into the uteri of pseudopregnant rats. In one set of experiments, the donor rats were treated with anordiol, and in the second set the recipient rats were treated. The results indicate that the effects of anordiol administration are exerted via the embryo as well as the uterus.

Multicenter study of the impact of prescription guidelines on the use of colony stimulating factors.

The aim of this work was to assess the impact of circulating guidelines for correct prescription practices of colony stimulating factors (CSF). Two hospital groups were compared, a 'guidelines' group (seven teaching hospitals) that circulated the guidelines and a control group (eight teaching hospitals) that did not. In addition, two periods were compared before and after distribution of the guidelines: from 17 February to 2 March 1996 and from 17 February to 2 March 1997. The assessment involved compliance with the guidelines for the following parameters: indications, dose regimen, time to start of CSF therapy and duration of CSF therapy between the control and guideline groups and also between the two periods. The population included 404 patients analyzed (209 in 1996 and 195 in 1997) for the indication of post-chemotherapy neutropenia. Total compliance in the first period (all four items) was 44.2% in the control group and 50.8% in the guideline group (nonsignificant), and during the second period was 31.9 and 59.6% in the two groups (p<0.001). During the first period, the differences in compliance with the guidelines for indication, dose regimen, time to start of treatment and duration between the groups were not significant. In the second period, this difference became significant and in favor of the guideline group for dose regimen (p = 0.009) and treatment duration (p = 0.02). The results of this study show the need to continuously define prescription reference systems according to available data, and to circulate them widely to improve the quality of health care and to control expenses.

Distinct subsets of dendritic cells resembling dermal DCs can be generated in vitro from monocytes, in the presence of different serum supplements.

We recently demonstrated that dendritic cells (DCs) can be generated from monocytes in the presence of high concentrations of human serum (HS), provided the extra-cellular pH is maintained at plasma values. Because monocyte-derived DCs (Mo-DCs) can also be generated in the presence of fetal calf serum (FCS) or serum-free medium, we have investigated whether these different culture supplements influence DC generation. With this aim, purified monocytes were cultured with GM-CSF plus IL-4 for 6 days and were further exposed to TNF-alpha for 2 additional days, in the presence of HS, autologous plasma (AP), FCS, or X-VIVO 20, a serum-free medium. Our results show that good yields of functionally mature DCs can reproducibly be obtained in the presence of HS or AP, as assessed by CD83 and CD86 up-regulation, dextran-FITC uptake, allogeneic MLR assays and the induction of an autologous response. Interestingly, the effect of serum on DC generation was probably not only quantitative, but also qualitative, since (i) the majority of HS- or AP-cultured DCs expressed CD83 with very weak levels of CD1a, whereas CD83+ DCs cultured in FCS or X-VIVO were mostly CD1a++; (ii) HS- and AP-cultured DCs were much more granular and heterogeneous than FCS- or X-VIVO-cultured DCs, and (iii) the presence of Birbeck-like granules was preferentially observed in HS- or AP-cultured DCs, as assessed by electron microscopy. That these different cells resemble dermal DCs (DDCs) was further supported by the observations that most of the cells displayed intracytoplasmic FXIIIa in the absence of Lag antigen, and expressed E-cadherin at very low levels. Altogether, our results indicate that starting from the same monocytic population, different subsets of DCs can be generated, depending on the culture conditions. Thus, HS or AP favors the generation of fully mature DCs that resemble activated dermal DCs, whereas FCS, or X-VIVO preferentially leads to the generation of less mature CD1a++ dermal-like DCs.

Synthesis and biological activity of a new progestogen, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3, 20-dione acetate.

The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches.