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The aim of this study was to compare salivary miconazole pharmacokinetics following once daily application of bioadhesive tablets (50 or 100 mg), vs the current treatment with a gel (3 times a day, 375 mg day(-1)).A three way cross over study was carried out in 18 healthy subjects (nine males, nine females) with a 1 week washout period between each treatment. Plasma and salivary pharmacokinetics of miconazole were assessed over a 24-h period.In all subjects the tablets gave higher and more prolonged salivary miconazole concentrations than the gel. Thus salivary miconazole AUC(0,24 h) was 37.2 times greater for the 100 mg tablet (90% confidence interval [CI] 22.9, 60.5) and 18.9 times greater for the 50 mg tablet (CI 11.7, 30.6) compared with the gel. Similarly, Cmax was 17.2 times greater (CI 11.8, 25.2) and 7.8 times greater (CI 5.3, 11.4) for the 100 mg tablet and 50 mg tablet, respectively. Comparison of the 100 mg and 50 mg tablets gave ratios of 2.2 and 2.0 for Cmax and AUC(0,24 h), respectively (CI 1.5, 3.2 and 1.2, 3.2). The mean time that salivary miconazole concentrations were above 0.4 micro g ml(-1) (the concentration reached 3 h after application of the oral gel according to published data) or above 1.0 microg ml(-1) (the MIC of some Candida species) was greater for both bioadhesive tablets than for the oral gel (10-14 h vs 1.5 h and 7 h vs 0.6 h). Only 19 plasma samples from eight subjects had concentrations of miconazole above 0.4 micro g ml(-1). Ten of these were taken from five subjects after administration of the gel and nine from three subjects after administration of the tablets.These data strongly support the further development of miconazole bioadhesive tablets as a sustained release formulation leading to improved antifungal exposure in the buccal cavity. A single daily application should improve compliance, whereas the low systemic absorption of miconazole will alleviate concerns regarding drug interactions and adverse effects.

Antes de escribir este trabajo el primer problema fue establecer una definición precisa de la expresión «no invasiva». Según el diccionario, se puede ver que la «invasión» es una entrada violenta en un país o en el cuerpo. Es así como normalmente se deben presentar los métodos in vitro para el estudio de las nuevas formas de administración. Sin embargo, no es eso lo que la gente espera. Se considera las técnicas no invasivas como «técnicas no violentas, no traumatizantes», porque se hacen en seres humanos sanos a quienes se administran las formas farmacéuticas cuyo destino es estudiado directamente in situ. Estas técnicas no presentan peligro para el voluntario, no son violentas y además tienen una gran sensibilidad ya que durante el trabajo se puede tomar muchas muestras, y emplear dispositivos para facilitar la observación directa. Antes de escribir este trabajo el primer problema fue establecer una definición precisa de la expresión «no invasiva». Según el diccionario, se puede ver que la «invasión» es una entrada violenta en un país o en el cuerpo. Es así como normalmente se deben presentar los métodos in vitro para el estudio de las nuevas formas de administración. Sin embargo, no es eso lo que la gente espera. Se considera las técnicas no invasivas como «técnicas no violentas, no traumatizantes», porque se hacen en seres humanos sanos a quienes se administran las formas farmacéuticas cuyo destino es estudiado directamente in situ. Estas técnicas no presentan peligro para el voluntario, no son violentas y además tienen una gran sensibilidad ya que durante el trabajo se puede tomar muchas muestras, y emplear dispositivos para facilitar la observación directa.

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration-time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the Cmax of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found.

The in vitro diffusion of progesterone from a gel formulation using the European Pharmacopoeia method for transdermal dosage forms is described. The membranes used were the dorsal and ventral portions of the shed skin of three different species of snake. Considerable differences are apparent between the dorsal and ventral sites and between the different species of snake. The dorsal area shows better permeability for progesterone and the permeability order for the different species is python>cobra>viper. These differences may be due to the thickness of the skin and the hinge:scale ratio. The results indicate that shed snake skin is not a model membrane for human skin.

Several studies have been devoted to cross-linked sodium chondroitin sulphate (SCS), in the context of numerous strategies attempting to target the colon for the absorption or the therapeutic action of a drug. SCS, a glycosaminoglycan presenting a specific degradation in the colon, is in fact soluble in water and its use as drug carrier at such a distance from the digestive tube necessitates its hydrophobisation. One method described in the literature consists in manufacturing a three-dimensional network by cross-linking with bifunctional compounds. However, all the structural characterisations carried out on the products resulting from the catalysed treatments of SCS with diaminoalkanes demonstrate that there are no cross-linking bridges between the polymer chains. Moreover, treated SCS-based tablets containing theophylline as model drug lead in vitro to dissolution profiles which are identical to those obtained with the non-treated SCS. We were therefore unable to find the announced results using the method described.

A novel method is described that simplifies in vitro dissolution tests of programmerelease drug dosage forms. It is based on a single solid reagent that affords immediate stepped-pH conditions using a single unitization to model the physiological gradient. Six pharmaceutical products were tested using two methods; the paddle method and the through flow cell method. The dissolution efficiencies obtained with the proposed reagent were identical to those obtained with classical buffers used in dissolution tests. Varying dissolution parameters (paddle rotation rate, flow rate in the through flow cell, use of surfactants) gave closely similar results for the two pH stepping methods but with the added advantage of a single medium.

Synopsis A gelling process for glycerides (synthetic or natural) by a cellulose derivative has been developed to obtain transparent oleogels of different consistencies. The present work examines the rheological behaviour of these oleogels. The study was carried out with a Trombomat Viscosity Follower. This measurement system allowed the determination of the gelling time and viscosity changes as a function of temperature. Resume La gelification de glycerides (naturels ou de synthese) a l'aide d'un derive cellulosique permet la fabrication de gels huileux transparents. L'objectif de ce travail est d'observer le comportement rheologique de ces oleogels. Toute cette etude a ete realisee a l'aide d'un suiveur de viscosite Trombomat. Ce dispositif original a permis de determiner les temps de gelification et les modifications de la viscosite en fonction de la temperature.

The work reported here describes the improvement of an industrial production of tablets formed by direct compression. This formulation contained 50% active substance of plant origin as a nonhygroscopic powder. The first step was to evaluate a number of direct compression excipients in preformulation tests and then make up a basic formulation providing tablets with correct characteristics. The second step was the optimization of the initial formulation using a two-level factorial experimental design. This enabled the best formulations to be selected objectively.

The characteristics of poly (2-hydroxyethyl methacrylate) matrices for the controlled release of drugs have been investigated using methotrexate (MTX) as a model drug. Radiation-induced polymerization of hydrophilic monomers (HEMA and related compounds) at low temperature (-78°C) was performed to immobilize MTX in the polymer matrix. The effect of the drug loading and diflerent amounts of cross-linking agent on the in vitro drug release was studied in this work. The diffusion of MTX from the hydrogel matrices was proportional to the square root of the time, according to the equation proposed by Higuchi (1).

A capillary gas chromatographic method with mass-selective detection was developed for the determination of oxeladin in human plasma. Plasma samples (1 mL) were alkalinized and extracted using 5mL of hexane: isoamyl alcohol (99:1). The method was demonstrated to be sensitive (limit of quantitation at 1 ng/mL), linear between 1 and 150 mg/mL, accurate and precise enough (mean error and mean coefficient of variation at the limit of quantitation were 2.3 and 13.3%, respectively) to support pharmacokinetic evaluation of the drug at doses down to 30 mg.

In a French region where farmer's lung (FL) is common, we determined the prevalence of FL precipitins in dairy farmers and analyzed the relation between the presence of FL precipitins and the clinical probability of the disease. All the exposed dairy farmers of both sexes (n = 2555) from five districts of the Doubs department were asked to respond to a medical and professional questionnaire. A total of 1763 (69%) farmers agreed to participate. Precipitins tests were conducted in 551 (31%) farmers who showed any respiratory symptom and in a random sample of 100 asymptomatic farmers. Serum for each farmer was analyzed by both double diffusion and immunoelectrophoresis against Micropolyspora faeni (MF) and extracts of moldy hay (HE) from Doubs. The 651 farmers were then divided into four groups (G 1–4) with a decreasing probability of FL (G1: typical FL symptoms; G4: asymptomatic farmers). The estimated prevalence of precipitins in the whole population was as follows: 1) by double diffusion, against HE: 83%, against MF: 27%; 2) by immunoelectrophoresis, against HE: 26%, against MF: 19%. There was a close “linear” relation between the prevalence of precipitins detected by immunoelectrophoresis against HE and the symptoms: 51% in G1, 36% in G2, 29% in G3, and 13% in G4. Precipitins detected by immunoelectrophoresis were also related to exposure and geography (more immunization in tableland area than in plain or mountain area). Presence of precipitins detected by double diffusion was not related to symptoms, exposure, or geography. This study shows that the prevalence of precipitins is high in the exposed dairy farmers of Doubs, and suggests that immunoelectrophoresis (with the antigens used) is a more effective method for the diagnosis of FL than double diffusion.

Matrix or monolithic systems can be considered to date as the easiest and least expensive means of controlling drug release. The principle of these dosage forms is based on the uniform dispersion of the active ingredient in an inert solid polymeric excipient. This excipient forms a skeleton in which the drug is trapped and released by erosion and/or diffusion.The aim of this work is to show the progress in the formulation of these dosage forms, their conception, design, and resulting biopharmaceutical properties. The first part is related to the classical matrix study according to the kind of excipient used. A more or less arbitrary classification can be considered: plastic, lipidic, and hydrophilic matrices. The various excipients used, the mechanisms allowing the drug to be released, and the formulation parameters influencing these dosage forms in in vitro/in vivo are also presented.The second part is dedicated to the new matrix systems. Their technology and conception derive directly from the experienc...

A specific and sensitive method has been developed for the determination of phloroglucinol in plasma; it involves an optimized procedure for blood sampling designed to minimize the in vitro oxidation of the molecule, and gas chromatography-mass spectrometry after silylation of the compound. The method allowed a reliable determination of phloroglucinol in plasma. The precision and accuracy of the assay, reported as coefficients of variation, were below 15%. Using a plasma sample of 0.25 ml, the limit of quantitation was 5 ng/ml with a precision of 17.4%, which is sensitive enough for pharmacokinetic studies. Stability studies under different conditions revealed that ascorbic acid limits the degradation of phloroglucinol in plasma during storage at freezer temperatures.

Synopsis A new gelification process of vegetable oils was developed using a cellulose derivative in order to obtain transparent oleogels (anhydrous gels based on fatty components) of different consistencies. The study of their structure has been carried out by infra-red spectroscopy, differential thermal analysis and X-ray diffractometry. All these physical tests have demonstrated the gel structure of the formulations. Finally, a rheological study was run to elucidate their specific properties and their stability during storage.

A high-performance liquid chromatographic method for the simultaneous determination of phenylephrine and tropicamide in human aqueous humor was developed. After centrifugation, an aliquot of the supernatant was injected onto the column and the eluent was monitored at 280 nm then 254 nm after 5 min. Separation was performed on a CN column with 0.01 M Pic B8 (octane sulfonic acid)-acetonitrile (65:35, v/v) as mobile phase. The standard curves were linear in the detection range. The precision of the method (expressed by relative standard deviation) and the accuracy (mean error in per cent) were

The sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.

In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.

This document is a part of the heritage of the public library of Clermont-Ferrand. It has been realized in 1656 by Germain Perdrix, official printer of the King, as a copy of the original printed in Paris. This document gathers some papers written during the lives of Kings Louis XIII and Louis XIV. The most important paper (published on January 20, 1637) specifies the conditions of admission to be Master in Apothecary as well as the rules of this profession.

This study compares the pharmacokinetics and bioinversion of two chemical forms of ibuprofen administered intravenously or orally. Dogs were given the free acid form of the S(+) isomer p.o. or i.v., or the racemate, as the free acid or sodium salt, p.o., in a cross-over design. The main kinetic parameters were calculated and formation and bioinversion curves plotted. The values of Cmax, Tmax and AUC were higher for the S(+) isomer. The percentage bioinversion averaged between 35–70% according to the form. This study proposes a new index for the calculation of bioinversion, independently of any i.v. administration, and confirms its self-limiting nature.

A high-performance liquid chromatographic method for the simultaneous determination of phenylephrine and tropicamide in human aqueous humor was developed. After centrifugation, an aliquot of the supernatant was injected onto the column and the eluent was monitored at 280 nm then 254 nm after 5 min. Separation was performed on a CN column with 0.01 M Pic B8 (octane sulfonic acid)-acetonitrile (65:35, v/v) as mobile phase. The standard curves were linear in the detection range. The precision of the method (expressed by relative standard deviation) and the accuracy (mean error in per cent) were5% for both intra- and interassays.

A simple and sensitive HPLC method for determination of metronidazole in human plasma has been developed. A step of freezing the protein precipitate allowed an efficient separation of aqueous and organic phases minimizing the noise level and improved therefore the limit of quantitation (10 ng ml(-1) using 1 ml of plasma sample). The separation of compounds was performed on a RP 18 column with acetonitrile-aqueous 0.01 M phosphate solution (15:85, v/v) as mobile phase. Detection was performed by UV absorbance at 318 nm. Metronidazole was well resolved from the plasma constituents and internal standard. An excellent linearity was observed between peak-height ratios plasma concentrations over a concentration range of 0.01 to 10 microg ml(-1). Within-day and between-day precision (expressed by relative standard deviation) and accuracy (mean error in per cent) did not exceed 4% between 1 and 10 microg ml(-1) and 8.3 and 7.2% respectively for the limit of quantitation. The method is suitable for bioavailability and pharmacokinetic studies in humans.

Seventeen diabetic patients (5 males and 12 females) treated with long-term metformin therapy received their morning dose after an overnight fast or after one of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the maximum concentrations (tmax) were calculated for the major biological parameters (glycemia, C-peptide, insulin and glucagon levels). None of the diets were bioequivalent to the fasting condition and only the low carbohydrate diet gave comparable results. A strong relationship was found between the carbohydrate intake (in g) and the AUC of the various markers except glucagon.

Percutaneous absorption has now been largely demonstrated and is defined as the passage of a molecule applied to the skin from the external environment to the blood. This phenomenon takes place in two main steps: penetration and actual absorption. Percutaneous absorption avoids the first-pass effect to which orally and rectally administered molecules are submitted, although these molecules can be metabolized in the skin, but to a much lesser degree that by hepatic metabolism. Transdermal devices present many advantage compared to forms administered by other routes: improved patient compliance, easy self-administration, prolonged plasma plateau levels. However, it depends on the skin type and, in the case of allergic reactions, other classical forms designed for the cutaneous route, such as ointments or gels. There are two types of transdermal device: so-called matricial forms, which are semi-solid or solid preparations in which the active ingredient(s) can be dispersed or dissolved; reservoir systems, in which one of the walls is a membrane, placed directly on the skin. In the case of the nitroglycerin, plasma curves are essentially identical regardless of the type of device used. The active ingredients currently available on the market in the form of transdermal devices are scopolamine, nitroglycerin, 17-beta-oestradiol, nicotine, and, for the future, forms containing fentanyl, timolol, ephedrine ... are currently being developed.

The application of the Montreal convention which not only plans to remove CFCs from pressurized preparations but to stop also the production, will affect companies. However, for pharmaceutical use, antiasthmatic drugs are considered as essential and at the moment the use of CFCs is allowed. But if the production stops, a reformulation will be necessary. Three solutions are conceivable: The first one is to replace CFC 11, 12 and 114 with the old well known propellants as butane, isobutane, propane but they are not very compatible with pulmonary use. The second one is the use of new official substitutes as 134a (tetrafluorethane) or R227 (heptafluoropropane). The former is immediately available and can be used because its take of toxicity has been demonstrate by an international consortium, IPACT as well as the absence of action on ozone but a light "greenhouse effect" is expected. However, the simple substitution of CFCs for those two propellants is not easy due to their physical-chemical properties which are different from the old CFCs. This reformulation is so delicate that pharmaceutical companies have chosen a third solution: precompression pumps or clever devices which can deliver directly the pure drug in powder form. The other preparations to be used for dermatological or cosmetological uses have been reformulated since a long time with original and special presentation (bags in can or volatile solvents).

The sustained release properties of an indomethacin hard-gelatin capsule formulated with saturated polyglycolysed glycerides (Gelucire) were demonstrated in vivo. Indomethacin was selected as a model drug with very poor solubility in water and acidic media. It is known to exhibit high intersubject variability because of enterohepatic circulation. The formulation, which in vitro showed an erosion-controlled release, was compared in six human volunteers in the fed state by using a randomized cross-over design, to a standard multiple-unit diffusion-controlled pellet capsule. Close action period values (time duration with plasma levels higher than 0.5 micrograms/ml) were found for the test and the reference formulation (5.2 and 5.7 h). The time to reach peak t(max) appeared slightly shorter for the test preparation (1.75 h) than for the reference formulation (2.67 h), but the difference was not statistically significant because of the high intersubject variability (non-parametric Wilcoxon matched pair test). Again, due to the small number of subjects entered in the study (insufficient for a real bioequivalence study) equivalence could not be accepted in terms of extent and rate of absorption based on the decision procedures involving the 90% confidence interval and the two one-sided t-tests. The mean maximum plasma concentrations Cmax were 3.35 and 2.82 micrograms/ml for the test and the reference formulation respectively, with the corresponding values of the area under the plasma concentration-time curve AUC amounting to 10.14 and 11.38 micrograms h/ml. However, a simulation on 24 subjects (3 repetitions of the same data) would lead to bioequivalence of the two preparations. As for other corrosion-controlled forms, drug release from the proposed Gelucire formulation was very sensitive to hydrodynamic conditions, leading to poor in vitro-in vivo correlation, when comparison is made with a reference formulation characterized by a diffusion-controlled release. Finally, it was concluded that erosion-controlled release formulations are especially suitable for drugs, such as indomethacin, that have low solubility in water or acidic media. More generally, sustained release hard gelatin capsules with thermosetting excipients is very versatile and their preparation is very straightforward.

The effect of food on the bioavailability of the antidiabetic drug metformin (Glucophage, Lipha Laboratories) was investigated in patients at steady-state. Seventeen diabetic patients (5 males and 12 females) treated with a long-term metformin therapy received their morning dose after an overnight fasting or after each of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the Cmax (Tmax) were calculated. Compared to fasting conditions, AUC and Cmax for metformin were bioequivalent after the four types of breakfast except the low fat (high carbohydrate) diet which had results slightly reduced (90% CI = [0.76-0.90]). The intraindividual variability was calculated and found to be lower than the interindividual variability.

A highly specific and precise method using gas chromatography-mass spectrometry was developed for the measurement of isosorbide 5-mononitrate in plasma using isomannide mononitrate as internal standard. With regard to the numerous analytical problems encountered when organic mononitrates were determined in plasma, such as thermal instability and adsorption, compounds were silylated before gas chromatography. In order to increase the specificity of the assay, two specific ions of the isosorbide 5-monitrate were simultaneously recorded. The accuracy of the assay was tested day to day with quality specimens spiked blind to the analyst.

This study is concerned by the determination of the toxicity of an Olea europaea L.aqueous leaf extract after repeated administrations. Female and male rats were given 37.5, 75, 150, 300, 600 and 1200 mg/Kg/24h of the extract for 60 days. The results show that the drug studied induces an increase of weight growth, an hypotension, an hypoglycaemia and an hypouricaemia in treated animals.

This study shows that diazepam (20 mg/Kg) and clonazepam (2 mg/Kg) administered intraperitoneally to 36 hour-fasted rabbits induce a significant (p0.05) hyperglycaemia 30 min. after administration. It also shows that the hyperglycaemic action of these benzodiazepines is significantly potentiated by nifedipine (10 mg/Kg) and inhibited by adenosine (1 mg/Kg), caffeine (40 mg/Kg) and propranolol (20 mg/Kg). The most pronounced inhibitory effect was that exerted by propranolol (p0.05). It is suggested that diazepam and clonazepam induced hyperglycaemia may be due to the release of hyperglycaemic hormones including adrenaline responsible for an increase of 3' 5' cAMP since the action of these benzodiazepines is inhibited by propranolol.

Six acyloxymethyl esters of Furosemide were synthesized and the structures were determined by chemical and spectroscopic methods. Lipophilicity parameters were analysed by high performance liquid chromatography (HPLC). Hydrolysis performances in human plasma and intestinal fluids anticipate their properties as absorption prodrugs of Furosemide. A bioavailability study carried out with 8 male Wistar rats with one of the synthesized prodrug (acetyloxymethyl 4-chloro-N-furfuryl-5-sulfamoylanthranilate) showed a greater absorption in relation to Furosemide. The percentages of mean urinary recovery of Furosemide for the prodrug and for the standard solution of the drug were 20.84 and 14.36 respectively. The doses were 10 mg/Kg in Furosemide. The analytical determinations of Furosemide in biological fluids were done by HPLC.

Stabilized, bedridden, inactive trauma patients on enteral nutrition via continuous, constant rate tube feeding (2 different formulas) were given a single dose of cefroxadine p.o. There were no differences in the pharmacokinetic parameters between the groups on different enteral nutrition. These patients were compared to cefroxadine absorption in ambulatory healthy subjects after a standardized meal (bolus-fed). The mean residence time was significantly longer in the patients, and the extent of absorption was slightly reduced with one enteral nutrition formulation and significantly reduced with the other. The other pharmacokinetic parameters were not significantly different. The difference is believed to be caused by reduction in splanchnic blood flow in the immobilized patients, weakening of migrating motor complex due to tube feeding and the lower temperature (4 degrees C) of enteral nutrition.

Female and male rats were given 300 and 600 mg/kg/24 h of a Garlic bulb aqueous extract for 21 days. The results showed that garlic extract causes toxic effects affecting weight growth, biologic parameters and histologic structures.

The aim was to study a new method of dissolution in vitro, the “Bio-Dis” apparatus, and to compare it with the classical rotating bottle method. Several theophylline controlled-release drug dosage forms were studied. Dissolution testing was performed in increasing pH in standard conditions and after treatment with peanut oil in order to simulate high fat meals and to correlate the in vitro percent dissolved with the in vivo results obtained. The in vivo study was carried out on three groups of healthy volunteers receiving each dosage form in a randomized order just before a high fat breakfast or in the fasting state. The in vitro percent dissolved obtained was compared with those published results obtained with rotating bottles. A linear relationship was established between these results. From the in vivo absorbed percentages calculated according to the Wagner-Nelson method, a linear relation was found between the in vivo percent absorbed and the in vitro percent dissolved in the different conditions. The relationships observed are similar for all the forms under both conditions. The “Bio-Dis” offers advantages over the rotating bottle method. The study reported allows this dissolution apparatus to be proposed as an alternative to the rotating bottle apparatus.

The drug release of salbutamol from a controlled release (osmotic pump) tablet was determined in vitro by four different dissolution apparatuses. From published in vivo data, percent of drug absorbed and percent of drug released in vivo were estimated. The highest correlation was obtained between percentage released in vitro versus percentage released in vivo using polynomial regression.

The aim of this work is to study the toxicity of Valeriana officinalis and Crataegus oxyacantha after reiterated administrations. The study has been carried on the rat which received 300 and 600 mg/kg/24 h of the drugs for 30 days. During the period of the treatment, animals weight and blood pressure have been measured. On the end of the treatment the animals have been sacrificed. The principal organs have been weighed and in blood samples collected hematological and biochemical parameters have been determined. This work is concerned by pharmacological properties which are related to the two plants. The influence of the drugs on the behaviour, the pain, the intestinal peristalsis and strychnine convulsions are reported.

Sick building syndrome is the name given to a set of varied symptoms experienced by a number of people working predominantly in hermetically sealed and air-conditioned buildings. The syndrome, which is probably multifactorial, can be diagnosed only after eliminating all other building-related-illnesses since it is not, as a rule, accompanied by any organic lesion or discernible physical sign. The symptomatology includes different classes of symptoms: - Respiratory manifestations - Ocular manifestations - Cutaneous manifestations - Odour and taste complaints - Neuropsychic manifestations Diagnosis of sick building syndrome (SBS) should be confirmed once all other building related illnesses have been eliminated: infectious disease, allergic manifestations, humidifier fever or allergic rhinitis. A considerable number of factors are supposed to provoke SBS: physical factors, chemical factors, psychological factors. But the most important are biological factors. They include dusts and various particle...

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.

Synopsis Benzoyl peroxide has been used for over 20 years to treat youthful acne. The aim of this study is to determine its release rate from the vehicle that allows it to reach and treat the skin (topical availability) and its ability to pass through the skin and reach the general circulation (bioavailability), in order to bring about good topical availability, linked to bioavailability or, an 'abioavailability'. Three preparations containing 10% of benzoyl peroxide were administered to the back of shaven New Zealand rabbits. At day 0, day 5, day 12, day 19, day 26 and day 33, the topical effects were measured by cutaneous temperature, degree of erythema and the benzoic acid plasma record card, which shows blood sample results of the metabolism of the drug. The results obtained show that the topical availability of benzoyl peroxide coincides with a decrease in cutaneous temperature, after application in various dosage forms, in spite of the appearance of a marked erythema. The bioavailability is demonstrated by plasma benzoic acid evaluation. Before administration, benzoic acid levels are low but increase half an hour after administration, to reach a maximal level at 3 h. Benzoyl peroxide metabolizes quickly and does not seem to be able to cross the skin without being changed.

The in vitro study of transdermal therapeutic systems is of first importance to ensure a good quality control of such drug dosage forms. As several national Pharmacopoeias have published different in vitro methods, the authors aimed at comparing two of them. The first method described in the French Pharmacopoeia is a cell, consisting of a reservoir which contains a central chamber designed to receive the transdermal therapeutic system and a lid which fits onto the reservoir in order to centre the transdermal therapeutic system and delimit the area of diffusion. The second method described in the USP is a hollow cylinder mounted on the end of a steel rod like a paddle; the transdennal therapeutic systems are stuck on the outside of the cylinder, horizontally. In both cases the transdennal therapeutic systems are placed with the diffusion membrane outward, in direct contact with the medium (degassed distilled water). The transdermal therapeutic systems studied are composed of a reservoir one of the walls of which is a membrane of surface area 10 cm 2 when containing 25 mg of trinitrine, or 20 cm 2 when containing 50 mg of trinitrine. Released trinitrine was assayed using a HPLC technique. In spite of some small differences in the technique used (e.g. temperature 30° C or 32° C), the release of trinitrine is linear (zero-order) and the results are correlated by an equation of type y = ax + b and thus validated.