The rationale of opportunistic bilateral salpingectomies (OBS) during benign gynaecological and obstetric surgery: a consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG).

Ovarian cancer (OC), is a disease difficult to diagnose in an early stage implicating a poor prognosis. The 5-year overall survival in Belgium has not changed in the last 18 years and remains 44 %. There is no effective screening method (secondary prevention) to detect ovarian cancer at an early stage. Primary prevention of ovarian cancer came in the picture through the paradigm shift that the fallopian tube is often the origin of ovarian cancer and not the ovary itself. Opportunistic bilateral salpingectomy (OBS) during benign gynaecological and obstetric surgery might have the potential to reduce the risk of ovarian cancer by as much as 65 %. Bilateral risk-reducing salpingectomy during a benign procedure is feasible, safe, appears to have no impact on the ovarian function and seems to be cost effective. The key question is whether we should wait for a RCT or implement OBS directly in our daily practice. Guidelines regarding OBS within our societies are therefore urgently needed. Our recommendation is to inform all women without a child wish, undergoing a benign gynaecological or obstetrical surgical procedure about the pro's and the con's of OBS and advise a bilateral salpingectomy. Furthermore, there is an urgent need for a prospective registry of OBS. The present article is the consensus text of the Flemish Society of Obstetrics and Gynaecology (VVOG) regarding OBS.

DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression.

Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

Focus on cannabinoids and synthetic cannabinoids.

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids.

ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.

The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance.

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network.

Glioblastoma multiforme (GBM) is the most common form of primary brain tumor in adults, often characterized by poor survival. Glioma-initiating cells (GiCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. GiCs are known to be involved in tumor growth and recurrence, and in resistance to conventional treatments. One strategy to efficiently target GiCs in GBM consists in suppressing their stemness and consequently their tumorigenic properties. In this study, we show that the miR-302-367 cluster is strongly induced during serum-mediated stemness suppression. Stable miR-302-367 cluster expression is sufficient to suppress the stemness signature, self-renewal, and cell infiltration within a host brain tissue, through inhibition of the CXCR4 pathway. Furthermore, inhibition of CXCR4 leads to the disruption of the sonic hedgehog (SHH)-GLI-NANOG network, which is involved in self-renewal and expression of the embryonic stem cell-like signature. In conclusion, we demonstrated that the miR-302-367 cluster is able to efficiently trigger a cascade of inhibitory events leading to the disruption of GiCs stem-like and tumorigenic properties.

An information campaign on aminoglycosides use during septic shock failed to improve the quality of care.

BACKGROUND: Septic shock remains a major cause of death in intensive care units (ICU) and an inappropriate antibiotic regimen worsens the prognosis. The aim of the study was to assess the impact of an information campaign on modalities of prescription of aminoglycosides in septic shock. STUDY DESIGN: A prospective observational study. METHODS: Consecutive septic shock patients admitted to the surgical ICU over a 2-year period were included. An information campaign allowed to differentiate between a pre- (P1) and a post- (P2) interventional period. The campaign clarified the rules and requirements for pharmacological monitoring of aminoglycosides. The main objective was to increase the rate of prescription of peak serum aminoglycoside following the first intravenous injection. RESULTS: One hundred and forty-eight patients (P1=76 and P2=72) were finally included into the study. Similar clinical characteristics were observed during both periods. The rate of prescription of peak serum aminoglycoside following the first injection was performed in 49% (P1) versus 65% (P2), P=0.09. The length of stay in ICU was 16 days [extremes: 1-74] (P1) versus 17 days [extremes: 1-133] (P2) (P=0.84). Inhospital mortality was 28% (P1) versus 26% (P2), P=0.86. CONCLUSIONS: An information campaign describing the modalities of prescription of aminoglycosides in septic shock failed to improve medical practices and patient outcomes. A mobile team of antibiotics could be useful in daily practice.

PET and SPECT imaging of the NMDA receptor system: an overview of radiotracer development.

Imaging the N-methyl-D-aspartate receptors (NMDARs) in the living human brain by positron emission tomography (PET) or single photon emission computed tomography (SPECT) would provide useful information on the role of these receptors in ischemia and in various neurological disorders such as degenerative diseases, epilepsy or schizophrenia. To assess NMDAR radiotracer development and to propose perspectives, we overviewed the PET and SPECT candidate radioligands developed until now. Labelled molecules of interest were classified in three groups according to their binding site: intrachannel pore site blockers, glycine site inhibitors and NR2B selective subunit antagonists.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Cyclosporine monitoring in peripheral blood mononuclear cells: feasibility and interest. A prospective study on 20 renal transplant recipients.

Cyclosporine (CsA) has potent immunosuppressive properties, reflecting its ability to block the transcription of cytokine genes (mainly interleukin 2) in CD4+ T lymphocytes, markedly improving transplantation outcomes in the past 20 years. CsA pharmacokinetic variability and renal toxicity require whole blood (WB) monitoring by 4-hour area under the drug concentration curves (AUC0-4) or 2-hour postdose concentration (C2) monitoring. Nevertheless, graft rejection can occur despite target blood levels, suggesting that WB monitoring does not guarantee optimal immunosuppression. For a decade, pharmacologists and clinicians have worked to optimize CsA doses; some authors, inspired by its mechanism of action, have proposed therapeutic drug monitoring using peripheral blood mononuclear cells (PBMC; lymphocytes and monocytes). The aim of this study was to assess the feasibility and interest of CsA monitoring in PBMC ([CsA]PBMC). We also measured in vitro distribution of CsA in CD4+ and CD4- subsets.

[Fortified antibiotic (vancomycin, amikacin and ceftazidime) eye drop stability assessment at -20 degrees C]. / Stabilité à -20 degrés C des collyres antibiotiques renforcés (amikacine, ceftazidime, vancomycine).

INTRODUCTION: Fortified antibiotic ophthalmic solutions are regularly administered as an immediate treatment for bacterial keratitis. Fortified antibiotics used to be self-prepared by nurses. To solve this problem, pharmacy staff studied the stability of three 5% solutions of vancomycin, amikacin, and ceftazidime prepared in aseptic conditions from parenteral antibiotic solutions. MATERIAL AND METHODS: Solutions were frozen at -20 degrees C. Each solution were examined before storage and over a 75-day period. Ceftazidime and amikacin were diluted in 0.9% sodium chloride and vancomycin in 5% dextrose. Over a 75-day period, physical and pharmacological (absorbance spectra) properties and the sterility of each stock solution were studied. RESULTS: The pH of amikacin (6.51), ceftazidime (6.47), and vancomycin (3.77) remained stable during the 75-day period. Osmolarities also remained stable (367, 488, and 351 mOsm/L, respectively). There were no significant differences in the concentration, osmolarity, and pH of the three antibiotic solutions before storage and after 75 days of freezing. Over a 75-day period, the stability of amikacin, ceftazidime, and vancomycin remained constant; no contamination was detected before storage and after 75 days. CONCLUSION: Topical fortified antibiotic solutions can be stored for 75 days at -20 degrees C (15 days quarantine). After this time, these eye-drops should be stored at 4 degrees C and should be discarded after 3 days.

Pharmacokinetics of mycophenolic acid in kidney transplant patients receiving sirolimus versus cyclosporine.

INTRODUCTION: Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients. METHODS: We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5. RESULTS: While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively. CONCLUSIONS: These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.

Short-term pharmacokinetics and brain distribution of mecamylamine as a preliminary to carbon-11 labeling for nicotinic receptor investigation.

As a preliminary to development and evaluation of labeled mecamylamine as a potential in vivo imaging ligand for human central nicotinic receptors (nAchRs), this work was intended to determine whether the pharmacokinetic properties of mecamylamine are suitable for experimental studies using (11)C-radiolabeled mecamylamine preliminary to positron emission tomography (PET) in humans. An original gas chromatographic method for rapid and simple determination of mecamylamine in biological samples was developed and validated (within run precision, 3.8-5.2%; between assay variation, 5.3-6.9%; assay accuracy, 5.6-11.8%). The results of the pharmacokinetic investigation in the rat demonstrated a very fast clearance of mecamylamine from blood [half-life, 1.2 h; clearance (CL), 1.2 L/kg/h) concomitant with an uptake that was higher in kidney, intermediate in lung, and lower in heart, liver, and brain. Brain tissue kinetics of mecamylamine showed a similar pattern for all the regions, with a rapid increase followed by a plateau after 15 min. This plateau differed according to the region of the brain; it was higher in colliculi, hippocampus, and cortex (area of high density of nAchRs) than in cerebellum or white matter (area with a limited population of nAchRs). No other lipophilic metabolites that were able to disturb the specific binding to nAchRs were identified during the investigation. Thus, mecamylamine shows peculiar qualities making it a good candidate for carbon-11 labeling for experimental studies in view of final PET imaging.

Pharmacokinetics of antifungal agents in onychomycoses.

Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.

Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of Rat.

We have measured the pharmacokinetics of three retinoids, all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain [especially white matter (WM) and gray matter (GM)] to help select retinoids for treating human malignant glioma. All-trans retinoic acid permeated well into the WM, giving peak concentration in WM of 25.7 microg/g, 6 to 7 times higher than the peak serum concentration. There was less 13-cis retinoic acid in WM: area under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) serum = 18.00 microg ml(-1) h/32.67 microg ml(-1) h. The ratio WM/GM was over 1 for these two compounds, but the half-lives were short in the serum and cerebral tissue (0.57-1.02 h). Fenretinide had different pharmacokinetics: the peak concentrations were in serum (1.7 microg/ml) and WM (1.2 microg/ml)-low, but the AUC(0-->infinity) was large (25.55 microg ml(-1) in serum and 57.53 microg ml(-1) in WM) due to its long elimination half-life (13.78 h in serum and 17.77 h in WM). These findings provide information that may be used to select a retinoid and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.

Benzodiazepines: toxic serum concentrations in positive enzyme immunoassay responses.

A total of 588 blood specimens collected in an emergency unit were screened for benzodiazepines (BZDs) using enzyme-multiplied immunoassay and gas chromatography. Two-hundred eighty-five samples were positive for BZDs, and 303 samples that were negative by EMIT included 20 samples with BZDs detectable by gas-liquid chromatography. A total of 15 BZDs were identified, and the most frequently occurring were nordiazepam, bromazepam, diazepam, and alprazolam. Individual BZDs were found in 74% of cases, but some samples contained two, three, or even four BZDs. There is a risk of missing intoxication by BZDs with low therapeutic range and/or low cross-reactivity (alprazolam, bromazepam, flunitrazepam). There is a risk of misinterpreting a positive result for some BZDs with high therapeutic range and/or high cross-reactivity (nordiazepam), which may reflect a pharmacologically ineffective concentration. A semiquantitative analysis is inappropriate even when the identity of BZD is known. Immunoassays are the only methods presently available for use in emergencies, but physicians must be clearly informed of their limitations and interpret results with caution.

Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN

A comprehensive investigation of plasma and brain regional pharmacokinetics of imipramine and its metabolites during and after chronic administration in the rat.

The relationship between the serum imipramine concentration and its antidepressant effects remain undefined despite > 30 years of clinical investigation. No study to date has assessed the kinetic relationships between the concentrations of imipramine and its metabolites in plasma and in various brain structures. In this study, we examine the pharmacokinetics of imipramine (IMI) and its desmethylated and hydroxylated metabolites in rats given IMI chronically (20 mg/kg, intraperitoneally twice a day for 14 days). The concentrations in serum, cerebrospinal fluid, and six brain structures were measured by high-performance liquid chromatography at 13 different times from 0.5 to 120 h after the end of treatment. The concentrations of IMI, desipramine (DMI), and didesmethylimipramine (DDMI) in brain tissue were much higher than in the serum; concentrations were maximal at 1-2 h in the serum and the brain, which is indicative of the rapid metabolism of IMI with immediate and massive entry of the metabolites into the brain. The elimination halflives of desmethylated compounds increased with the degree of desmethylation, and DDMI was still present in brain tissue 96 h after the end of treatment. These results suggest that DDMI should be taken into account in clinical investigations of the effects of serum concentrations of IMI. The hydroxylated metabolites 2-OH imipramine (2-OH IMI) and 2-OH desipramine (2-OH DMI) were detected in serum, but not in cerebral tissue. The 10-OH metabolites were detected in both serum and brain, but the antidepressant action of these metabolites have not been clearly established. Finally, there were significant differences in the distributions of IMI and several of its metabolites in brain structures. Such differences may have clinical relevance if they also occur in humans.

Bile and blood ratios of cyclosporin and its metabolites in patients on continuous infusion during the first three weeks after liver transplantation.

Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 µg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.