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The history of Formula conferences was summarized with a particular focus on Formula I and Formula IX (the first and last conferences of the series). The foundation of formulation during the middle of the 1980s by people from academia and industry in the fields of chemistry and chemical engineering was briefly overviewed. The current trends in formulation as well as in product engineering were listed.

The dextran-covered poly (lactic acid) (PLA) polymeric nanoparticles were prepared by a nanoprecipitation process for the encapsulation of monocaprin (MC) or monolaurin (ML). The concentration of PLA/MC or ML was varied to evaluate the best condition for preparation. The miscibility of various PLA/MC or ML blends was studied using differential scanning calorimetry. The result showed that at concentrations of 50/50 wt/wt, the PLA/ML blend was partly miscible and the nanoparticle suspension produced large amounts of macroscopic aggregates after nanoprecipitation. Conversely, the miscibility of PLA/MC blends progressively increased with increasing amounts of PLA. Therefore, the best concentration to encapsulate the MC was the PLA/MC 90/10 (wt/wt), according to the miscibility results.

The output power of backward wave oscillators and carcinotrons decrease considerably at high frequencies. This drop in power can be due to the increase in losses and manufacturing defects in their delay lines. In this study, we present measurement methods and setups developed for the characterization of delay-line performance. The developed methods were validated on two scaled-down models of a TH4229 carcinotron operating in frequency bandwidths around 10 and 100 GHz. Measurements of losses and dispersion diagrams were made using two different wave couplings with propagating waveguides and radiating horn antennas. Electromagnetic simulations were performed using finite-difference time-domain (FDTD) code. For both delay lines, the results obtained from measurements with different couplings presented a very good level of consistency with simulations. The measured losses, normalized per delay line elementary cell, were 0.04 and 0.12 dB/cell at 9.5 and 95 GHz, respectively. Accordingly, the normalized ohmic losses were extrapolated at THz frequencies and at 0.95 THz, 0.38 dB/cell was obtained. As a first approximation, only the skin-effect ohmic losses were considered. The ability to characterize delay lines using radiating coupling was demonstrated.

Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax(Cend) of 1.95 mgL of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmaxwith achieved Cmax. The mean±SD Cmaxachieved was 1.93±0.16 mgL. No statistically significant difference was observed between experimental and target values (P>0.05, ttest), and Cendachievement was done with an overall 6.6 precision, a performance to be compared with the initial 54 interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r20.84, P0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r20.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (20, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60 higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Dextran, a neutral bacterial polysaccharide, is chemically modified by reaction with an aromatic epoxide (phenylglycidylether). The reaction conditions are either homogeneous, using dimethylsulfoxide as a common solvent, or heterogeneous, dispersing the epoxide into an aqueous solution of dextran. The grafting yield is much higher in homogeneous conditions. The viscometric characteristics of the amphiphilic polysaccharides are examined in water and in dimethylsulfoxide. These properties clearly depend on both the degree of substitution and the reaction conditions at a given degree of substitution. Highly modified dextrans (with more than 30% hydroxyl substituted) exhibit characteristic solubility in organic liquids that are non-solvents for the unmodified dextran. Changing the degree of hydrophobic substitution of the amphiphilic polysaccharide, direct and inverse submicronic emulsions are prepared. The stability of direct and inverse emulsions is analysed by following the evolution of the droplet size. Ostwald ripening is the major ageing process for both emulsions.Dextran, a neutral bacterial polysaccharide, is chemically modified by reaction with an aromatic epoxide (phenylglycidylether). The reaction conditions are either homogeneous, using dimethylsulfoxide as a common solvent, or heterogeneous, dispersing the epoxide into an aqueous solution of dextran. The grafting yield is much higher in homogeneous conditions. The viscometric characteristics of the amphiphilic polysaccharides are examined in water and in dimethylsulfoxide. These properties clearly depend on both the degree of substitution and the reaction conditions at a given degree of substitution. Highly modified dextrans (with more than 30% hydroxyl substituted) exhibit characteristic solubility in organic liquids that are non-solvents for the unmodified dextran. Changing the degree of hydrophobic substitution of the amphiphilic polysaccharide, direct and inverse submicronic emulsions are prepared. The stability of direct and inverse emulsions is analysed by following the evolution of the droplet size. Ostwald ripening is the major ageing process for both emulsions.

Summary: Amphiphilic polysaccharides are obtained by hydrophobic modification of a neutral bacterial polysaccharide, dextran. By reacting the polysaccharide with aliphatic epoxides (epoxyoctane and epoxydodecane) in dimethyl sulfoxide, a series of amphiphilic polymers is obtained which covers a large range of structural parameters (length of the polysaccharide, number and nature of hydrocarbon moieties). The solution behavior of dextran derivatives is first characterized by viscometric measurements in dilute and semi-dilute domains. The effects of molecular parameters on polymer viscosity behavior are evidenced and discussed. Information on the state of aggregation of polymers is obtained by the use of static and dynamic light scattering. The presence of aggregates in the dilute domain is clearly evidenced and their structural characteristics are estimated (size, molecular weight and number of aggregation). The aggregates are shown to account for the viscometric results in the examined concentration range, relating their chemical parameters (hydrodynamic radius and molecular weight) to the macroscopic behavior of the solutions.

A 15.57 meter core was extracted from the West-Termit endoreic depression at the present-day Sahara/Sahel boundary (NW of Lake Chad Basin, Ténéré, Republic of Niger). Three formations were identified representing widely contrasting paleoclimates; they are attributed to the end of the Lateglacial period, the Younger Dryas period of maximum aridity, and the early Holocene period of maximum humidity. A range of methods was used to analyze the sedimentology of these essentially siliciclastic formations, including the quantum model of Folk (1971). The proportion of eolian deposits could thus be identified and quantified. Six eolian stocks are distinguished by analogy with present-day regional eolian dynamics. They reflect different dynamics (deflation, accumulation by saltation, and suspension deposits from a nearby or remote area). Their co-occurrence or alternatively their absence serve as markers of varying degrees of aridity (seasonal or permanent, local or regional, slight or intense). Whereas paleoclimatic studies are usually based primarily, if not exclusively, either directly (paleolimnology) or indirectly (paleobiology) on the presence of water, we widen and reverse the scale of reference by using aridity to define a climatic situation. Thus, the uninterrupted input of fine dust during the early Holocene period of maximum humidity calls into question the often suggested idea of a “green Sahara”.

Antineoplastic agent etoposide (VP16) displays narrow therapeutic index and erratic pharmacokinetics, and dose individualization is a convenient way for overcoming the interpatient variability, so as to maintain the drug exposure within a therapeutic range. The authors proposed a population-based Bayesian methodology to adjust routinely VP16 dosage when given as a 5-day infusion. The mean VP16 pharmacokinetic parameters of the reference population calculated from 14 patients following the two-stage method were CL 1.92 ± 0.512 L/h and t1/26.7 ± 2 hours. The reference population was next used prospectively for Bayesian dose individualization for 25 patients (47 courses) undergoing 5-day infusions of VP16. Resulting steady-state concentrations proved to be successfully adjusted to the target values in 77 of the courses. Therefore, the method presented here meets the requirements for routine therapeutic drug monitoring of VP16, a major anticancer drug extensively used in clinical oncology.

The free-radical polymerization of acrylamide initiated by a redox system (hydrogen peroxide/β-diketone) catalyzed by horseradish peroxidase is studied with emphasis on the control of the molecular weight of the polymer. The case where 2,4-pentanedione (Acac) is used as the β-diketone is particularly examined. It is shown that the concentration of Acac and that of the enzyme readily control the molecular weight of the polymer. The concentration of hydrogen peroxide does not influence the molecular weight to a significant extent except at extreme values for which enzyme degradation or side reactions interfere with the normal enzymatic cycle. The variations of the molecular weight induced by changes in the chemical structure of the β-diketone are attributed to the reactivity toward the enzymatic cycle. The experimental results are rationalized by the use of classical kinetic equations for free-radical polymerization and including the specific expressions of enzymatic catalysis. The tendencies indicated by the theoretical expressions account for the evolutions given by the experimental results.

The relationship between ritonavir plasma concentration, efficacy, and tolerance was evaluated in 31 children with advanced HIV infection who were receiving a triple therapy with ritonavir as protease inhibitor. Median CD4lymphocyte count and median viral load before the initiation of ritonavir-containing combination therapy were 1320 cells/mL and 5 log10 copies/mL, respectively. Ritonavir was given at a dose ranging from 300 to 450 mg/m2twice daily. The median follow-up of triple therapy was 19 months. Response was defined as a drop of viremia of more than 1 log. Plasma drug levels were determined twice during the observation period after at least 4 weeks and after 3 months of combined treatment. Samples were collected before (residual) and 2 hours (T2) after drug intake. Cholesterol, triglycerides, alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase were assessed at the same time. The median values of ritonavir residual and T2 levels were 1.64 mg/L and 5.9 mg/L at observation 1 and 3.35 mg/L and 6.29 mg/L at observation 2, respectively. According to virologic response, median residual concentrations of ritonavir were 3.17, 2.52, and 1.04 mg/L for the complete, the partial, and the no-response groups. The authors observed a wide intersubject variability of ritonavir concentrations with an increase in residual levels between the two observation periods. Residual levels were correlated with virologic response whereas there was no direct association between T2 levels and long-term response. Patients with complete or partial response displayed statistically significantly higher residual concentrations than the no-response group. No correlation could be demonstrated between elevated plasma drug concentrations and abnormal cholesterol or triglycerides values. These results emphasize the importance of a sustained high ritonavir concentration to achieve optimal treatment efficacy. Furthermore, these results prove the clinical benefit of therapeutic drug monitoring and could potentially improve patient evaluation in terms of treatment efficacy, compliance, and viral resistance.

new family of thermoassociative graft copolymers has been recently synthesised using a two-step procedure. Schematically, their structure combines a weak polyelectrolyte backbone (poly(sodium acrylate), PAA) and thermosensitive side chains containing mainly N-isopropylacrylamide (NIPA). Taking advantage of this well controlled synthesis we have selectively varied the primary structure of the copolymers concerning the grafting extent, the length of the backbone, and the hydrophilic-lipophilic balance of the side chains by incorporating either hydrophilic or hydrophobic comonomers. The thermoassociative properties of the resulting copolymers were studied in semi-dilute solutions by rheology. It was clearly evidenced that the association temperature of the copolymers is selectively controlled in pure water (in the 0–100°C range) by the chemical composition of the side chains. Moreover, the magnitude of the thermothickening effect is directly related to the modification extent while the absolute value of the viscosity is modulated by the length of the PAA backbone. Very sharp transitions were also evidenced by developing specific attractive interactions between the PNIPA grafts and the PAA backbone dependent on the pH of the solutions. In all the cases we demonstrate that the associative behaviour is well correlated to the thermodynamic properties of the precursors. A good knowledge of their phase diagrams in aqueous solution is therefore a very strong guideline for designing copolymers with responsive properties.

New thermoassociative polymers were developed on the basis of the self-aggregation behaviour induced by heating of the `poly(N-isopropylacrylamide) (PNIPA)/water' binary system. The preparation of the graft copolymers involves a 2-step method with (1) the synthesis of amino end functionalised oligo-NIPA by radical polymerisation initiated with a convenient redox system based on thiol and (2) a `grafting onto' reaction of the PNIPA chains on a poly(acrylic acid) backbone. In semi-dilute aqueous solution, the resulting graft copolymers exhibit a large viscosity enhancement upon heating as soon as the temperature exceeds the lower critical solution temperature (LCST) of the PNIPA side chains. The influence of various physicochemical parameters (copolymer concentration, shear rate) and structural characteristics (side chains length) on the thermothickening behaviour are examined and interpreted using the concept of thermally induced physical network.

La comparaison des données chromosomiques des gorilles, des chimpanzés et de l'homme, intégrée dans lecadre paléogéographique et paléoclimatique du Néogène africain, suggère que l'ancêtre commun était polytypique, constitué par trois “sous-espèces” dont l'une des composantes était un Australopithèque archäique. L'individualisation des lignées aurait été facilitée par les fluctuations climatiques du Mio-Pliocène pulvérisant son aire de répartition. Ce modèle de spéciation allopatrique, qui aboutit à une trifurcation, explique la présence de caractères dérivés communs, d'une part entre Pan-Homoet d'autre part entre Gorilla-Pan.

In an open, clinical trial comprising a total of 21 depressed in-patients (6 men and 15 women) citalopram was administered in doses of 20–60 mg once daily for a period of at least 3 weeks. Fourteen of the patients were treated for 4 weeks, and 6 of these patients were treated for another 2 weeks.

The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PFCLfor a patient with median covariates values was similar in both BE/ MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PFCLby both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL,respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CLin the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CLin the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CLfor actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL(decrease of CL for weight <65 kg) whereas the BE/MLR analysis predicted an increase of CLin patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.

Bayesian estimation (BE) of pharmacokinetic parameters enables the clinician to adjust the dosage of high-dose methotrexate (HDMTX) to correct the inter- and intraindividual variation of concentrations that are responsible for severe toxicity. In this study of 672 HDMTX infusions, we validated an approach that consisted of reaching as nearly as possible a theoretical concentration of 5.10-4Mor 10-3Mat the end of an 8-h infusion by adjusting, when necessary, the dosage at the 6th h. The BE of the clearance was compared with that obtained by maximum likelihood estimation (MLE), which was used as reference. BE performance was evaluated by calculating the bias and precision that indicated an overestimation of clearances obtained by BE compared with the higher clearance of the MLE in the group of patients receiving the higher dose (15 and 37.9). Linear regression analysis of clearance obtained by BE and MLE showed a correlation (p < 0.0001) in both groups of patients with a closer link in those with the lower dose. However, in current clinical practice the important point is to obtain MTX concentration that is as close as possible to the desired concentration. Adjustments were evaluated by comparing the obtained concentrations with the desired theoretical concentration. There was no bias and precision was satisfactory in both groups of patients (15 and 12, respectively, for 5.10-4Mand 10-3M). This method makes it possible to limit the inter- and intraindividual variations of concentrations. As a result, severe complications were essentially nonexistent and were never life threatening.

Cigarette smoking is a worldwide health problem and is the greatest risk factor for lung cancer. By activating procarcinogens, hepatic and extrahepatic cytochromes P450 can participate in lung carcinogenesis. Tobacco smoke contains numerous cytochrome P450 inducers, substrates, and inhibitors. In the present study we investigated, in male NMRI mice, the effects of cigarette smoke on hepatic and pulmonary cytochrome P450 expression and their possible role in the induction of DNA lesions such as DNA single strand breaks (SSB). Hepatic and pulmonary mouse cytochrome P450 isozymes involved in carcinogenesis (Cyp1a, 2b, 2e, 3a) were differently induced by cigarette smoke. Cyp2e1 mRNA was dramatically enhanced (12.7-fold increase) while Cyp2b10 mRNA remained unchanged and Cyp1a1 was decreased or not detected. Cyp3a protein and mRNA were not detected in lung, suggesting that this isozyme is not expressed in mouse pulmonary tissue. The SSB of DNA increased in lung and liver treated mice. In contrast no modification was observed in lymphocytes that barely expressed cytochromes P450. Cimetidine and propylene glycol reduced SSB of DNA induced by smoking in liver and lung cells. The inhibition (−70%) observed in lung following treatment by propylene glycol, a CYP2E1 inhibitor, suggested that this isozyme is at least in part involved in pulmonary DNA damage induced by tobacco smoke. The high concentration of CYP2E1 function and regulation in mammals suggests that this protein could be involved in pulmonary carcinogenesis in human smokers.

The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive inhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibition of dextromethorphan-O-demethylation: lomustine (Ki=7.7 µM), doxorubicin (Ki=75 µM), vinorelbine (Ki=22 µM), and vinblastine (Ki=42 µM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.

Poly(N-isopropylacrylamide) (PNIPAM) and poly(acrylic acid) (PAA) were synthesized by aqueous radical polymerization initiated by the redox couple ammonium persulfate/sodium metabisulfite. PNIPAM was also synthesized by using a similar redox system: ammonium persulfate/2-aminoethanethiol hydrochloride (AET), the reducing agent being in this case a well known chain transfer agent. The final products were characterized by size exclusion chromatography. The influence on the weight-average molar mass (Mw) of several factors, such as monomer concentration and ionic strength of the reaction solution, were investigated. It was found that the concentration of ammonium persulfate does not practically affect the Mw of the products for both polymers investigated and independently of the reducing agent used. On the contrary, for constant monomer concentration, Mw is inversely proportional to the concentration of the reducing agent, either sodium metabisulfite or AET. This behaviour, combined with similar observations concerning the synthesis of polyacrylamide and other redox initiator systems containing metabisulfite as reducing agent, proves the special role of this reducing agent in the aqueous radical polymerizations.

Summary:

Abstract: Three white-rot basidiomycetes, Bjerkandera adusta, Ischnoderma benzoinum and Dichomitus squalens, were cultivated on a liquid medium supplemented with l-phenylalanine, a precursor for benzaldehyde (bitter almond aroma) and benzyl alcohol. Remarkable amounts of benzaldehyde (587 mg l−1) were found in cultures of B. adusta. Immobilization of this fungus on polyurethane foam cubes allowed an 8.3-fold increase of the production of benzaldehyde and a 15-fold increase of the productivity as compared with non-immobilized cells. Aryl-alcohol oxidase activity was only detected in B. adusta. This activity was also significantly enhanced in immobilized cells, suggesting that it plays an important role in benzaldehyde biosynthesis. Conversely, consistent amounts of benzyl alcohol (340 mg l−1 for B. adusta and I. benzoinum and 100 mg l−1 for D. squalens) were produced by the three fungi when immobilized. Laccase activity was found only in the strains I. benzoinum and D. squalens. This activity was markedly enhanced in free cells cultures. Immobilization of the fungi did not promote benzyl alcohol production by comparison with free cell cultures (500 mg l−1).

Several HPLC methods for quantification of acitretin and its 13‐cisisomer in biological fluids have been described. Only limited data are available on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin. With a new optimized mobile phase [methanol: acetonitrile (7:3, v/v), purified water with 1.5% (v/v) acetic acid, mixed in a 85:15 ratio (v/v)] and a new internal standard (arotinoid ethyl sulfone), a limit of quantification of 1 ng/g tissue was reached. Nine male volunteers were given an oral daily dose of 50 mg acitretin for up to 28 days. Blood and skin samples (punch and shave biopsies, suction blister skin, and fluid) were taken at various time points during and after treatment. Drug concentration and metabolism in plasma and skin samples appeared to be linked in that thetrans‐isomer concentration was always higher than thecis‐isomer concentration during dosing and 3 h after the last dose. However, 7 and 14 days after the last dose in plasma and in all tissue samples (except the shave biopsy), the all‐trans‐acitretin concentration rapidly decreased and approached the detection limit. In the shave biopsy, the all‐trans‐acitretin concentration remained higher than the 13‐cis‐acitretin concentration. Furthermore, the elimination of two isomers from the shave biopsy was delayed. Our HPLC method has provided a suitable tool for pharmacokinetic and drug monitoring studies of all‐trans‐acitretin and 13‐cis‐acitretin that can be performed by any laboratory with a darkroom and abasic isocraticHPLC system.

A novel type of interferometer was designed and tested experimentally. It combines the advantages of the spatial path separation used in the two-wave polarized Jamin interferometer and the high sensitivity that characterizes the multiwave Fabry–Perot interferometer. Furthermore, when it is sandwiched between crossed polarizers it shows a sensitivity to intracavity anisotropies that is proportional to the square of the Fabry–Perot interferometer’s finesse.

Ciprofloxacin distribution was assessed in cerebral tissues in 14 patients undergoing craniotomy. The study objective was to determine the brain tissue/serum concentration ratio of ciprofloxacin. Patients received a single intravenous (iv) 200 mg dose of ciprofloxacin. Mean (+/- S.D.) tissue/serum concentration ratios were (mg/kg): parietal fat during opening 1.40 +/- 1.05, during closure 1.34 +/- 1.17, in the dura mater 2.26 +/- 1.36, in skull bone during opening 0.44 +/- 0.29, during closure 0.97 +/- 1.57 and in brain tissue 0.88 +/- 0.99. Mean (+/- S.D.) concentrations of ciprofloxacin in brain tissue were 0.87 +/- 0.08 mg/kg, suggesting that a dose >200 mg iv ciprofloxacin is required to ensure therapeutic concentrations in brain tissue.

Thrombosis of the renal artery to a single functioning kidney is a known cause of anuric acute renal failure in atherosclerotic hypertensive patients. In the present report, recovery of renal function rapidly occurred following transluminal recanalization of the occluded artery with a 7F catheter after a 5-week period of anuria. The most interesting feature was that improvement of renal artery permeability was observed following a minimal interventional procedure.

Let $ P$ the Mahler measure of $ P$ on the disk $ \left\vert z \right\vert \leqslant 1)$ $ M(P) = \inf \left\Vert {PQ} \right\Vert$ with complex coefficients satisfying .

This paper presents how to specify an ADC to digitalize the analog video of the uncooled infrared readout circuit. In a first part the main features will be discussed to select the right resolution, SNR, THD and ENOB of the converter. In a second part the characteristics more specifically sensitive for an ADC integrated in the readout circuit will be presented: architecture, power consumption, electrical dynamic range, crosstalk issues. Indeed, the increasing demand for integrated functions in uncooled readout circuits leads to on-chip ADC design as interface between the internal analog core and the digital processing electronic. In addition this IP could be seen as an inescapable link to integrate also NUC, BPR or all other processing functions on-chip. However specifying an on-chip ADC dedicated to focal plane array raises many questions about its architecture and its performance requirements. We show two architectural approaches are needed to cover the different sensor features in term of array size and frame speed. Finally we will conclude with a trade-off between external or internal approach taking into account the application of the camera, the cost and the ADC state of art.