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Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a 'single-pot process' using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests.

Background: Globularia alypum L. (Globulariaceae) is a shrub growing in the Mediterranean basin and known to be used as a popular medicine for its several pharmacological properties against rheumatism, gout, typhoid, intermittent fever, and diabetes., Materials and Methods: The acute and chronic toxicities of a G. alypum L. aqueous leaf extract were studied in animals. Acute toxicity was performed in male and female mice whereas chronic toxicity was realized in male and female rats that orally received the drug at the doses of 300 and 600 mg/kg/24 h for 30 days., Results: Acute toxicity showed that the extract, administered by the oral route, does not induce any mortality even for a dose of 10,000 mg/kg. Administered by the intra-peritoneal route to female and male mice, the LD(50) of the extract was found to be of 2750 and 2550 mg/kg, respectively. A chronic toxicity study showed that, compared to the control groups that only received the vehicle (water), the drugs affects weight growth (effects more pronounced in female than in male rats), some organs weight after autopsy, hematological and biochemical parameters and histology of some principal organs (lungs: histological grades I to II pulmonary hypertension (PHT), respiratory distress syndrome (ARDS), and lymphoid hyperplasia; esophagus: thinning down of esophageal wall, atrophic muscular coat). The most important finding of the study was the recorded active spermatogenesis induced by the reiterated administrations of the drug that was confirmed by reducing the administered dose and the period of treatment (100 mg/kg/24 h for 15 days)., Conclusion: It is suggested that the G. alypum L. leaf extract contains active substances with androgenic properties that could be used in human therapy.

Pellets and spheres are manufactured in the pharmaceutical industry by various processes which are not always easily automated. In this paper, a 'single pot process' is described using rotary fluid bed granulation with lipid fillers. This technology is based on wet granulation of powder components, continuously suspended in a fluidized air with a tangentially sprayed liquid solution. After a previous work devoted to selection of matrix filler, this work focuses on lipid component: hydrogenated castor oil, used as matrix filler associated with theophylline as tracer. Spheres manufactured can be introduced either directly into a hard gelatine capsule or compressed as tablets. The influence of the formulation and process parameters on the sphere manufacture in terms of feasibility is studied with in vitro tests. Spraying time and weight of liquid sprayed are found to be the most relevant parameters that governed the final quality of the sphere.

Background: Garlic plays an important role in complementary and alternative medicine. Most people believe in and use herbal products even when they have not been as thoroughly researched as garlic. Garlic is also known for its beneficial effects on the cardiovascular system., Materials and Methods: The relaxant effect of Allium sativum L. bulb aqueous extract (ASBAE) containing 0.06%-0.10% of allicin was studied on isolated smooth muscle of trachea of rats precontracted using acetylcholine (10(-5) M)., Results: It was found that ASBAE induced a dose-dependent relaxation with recorded EC (50) values of 71.87 ± 5.90 µg/mL (n = 7). Pretreatments with mepyramine (10(-7) M), methysergide (10(-7) M), caffeine (10(-6) M), theophylline (10(-6) M), nifedipine (10(-6) M), and dipyridamole (10(-6) M) did not alter ASBAE concentration-response curves. In turn, concentration-response curves to ASBAE were significantly shifted toward right in the presence of aspirin (3.10(-3) M), indomethacin (10(-6) M), prazosin (10(-6) M), and propranolol (10(-7) M)., Conclusion: It is suggested that the recorded relaxation results are due to the release of prostaglandins E (1) and E (2) consecutively to α- and β-adrenoreceptor stimulation.

In Europe, the concept of biopharmaceutics was first introduced at the end of the 70s by various highly informed young Europeans who took into full account the publications and studies carried out by the first generation of explorers in this area in the United States such as John Wagner, Gerhard Levy, and W.A. Ritschel, amongst others. Their primary aim was to develop bioavailability studies for the registration of generics or new dosage forms. They then worked on setting up a new system for drug dissolution in vitro, including in vitro and in vivo correlations to better define the formulations. All this research led to the publication of numerous reports on different congresses, the most important of these being the European Congress of Biopharmaceutics and Pharmacokinetics, which is held once every two years in a European country and includes a large number of participants with an attendance ranging from 300 to 500 persons. During this same period, books were published in French and other European languages such as English, German and Spanish, with the result that updated information was efficiently circulated throughout all European countries. In the near future, the introduction of the biopharmaceutical classification as well as new in vitro models will certainly make a positive contribution to the further development of research in this area.

Aims: 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))., Methods: 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., Results: 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., Conclusions: 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., (Copyright 2004 Blackwell Publishing Ltd)

An impairment of respiratory function has been demonstrated in dairy farmers. The objective of this study was to evaluate the relationship of allergy to respiratory function in dairy farmers in a longitudinal study conducted in the Doubs (France). A cohort of male dairy farmers constituted in 1990 was re-evalued in 1995. Subjects completed a medical and occupational questionnaire, and a spirometry test in both 1990 and 1995, in 1995 they were also subjected to immunological tests. Relationships between immunological variables and respiratory function were studied by a multiple linear regression model adjusted for age, smoking status, respiratory symptoms, altitude and occupational exposure. Amongst the 394 subjects of the initial cohort, 330 were included in the longitudinal study and 320 had immunological tests. Log immunoglobulin (Ig) E was negatively correlated with the 1995 respiratory function parameters (p<0.05 for forced expiratory volume in one second (FEV1) and FEV1/vital capacity (VC). Immunoglobulin (Ig) G response to Aspergillus fumigatus detected by enzyme-linked immunosorbent assay (ELISA) was negatively correlated to 1995 respiratory function parameters (VC: p<0.01; FEV1: p<0.001; FEV1/VC: p<0.01). There was a positive relationship between IgG antibodies against Aspergillus fumigatus and the mean annual decline in FEV1 (p<0.01) and FEV1/VC (p<0.01). To conclude, allergy may play a role in the impairment of respiratory function in dairy farmers of the Doubs and sensitization to Aspergillus fumigatus seems to constitute an independent risk factor for the development of airflow obstruction in this occupational setting.

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) were <5% 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.

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.

In order to assess the extent and the rate of absorption in bioavailability studies, area under the curve (AUC), experimental maximum concentration (Cmax) and experimental time to reach Cmax (Tmax), are used. But when slow-release formulations are considered, the drug concentration-time curves usually show multiple peaks, and it is difficult to compute a Cmax and Tmax value. In case a Cmax value is computed, important variability in this parameter results in high values in the residual variance of the ANOVA test. So in order to decrease the high variability, average parameters: average concentration (Cav), average maximum concentration (Cmax,av) and Cmax,av x 100/Cav (%Cmax,av), are proposed. These new parameters were applied in a bioavailability study of slow-release amitriptyline formulation.

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.

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.

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 different barriers that slow the penetration of active ingredients administered by the ocular route are described, and some novel dosage forms designed for this route are discussed. Both precorneal and corneal factors considerably restrict ocular penetration. The low bioavailability of classical ophthalmic dosage forms can be improved by several approaches, particularly by increasing the time the active ingredients remain in contact with the eye tissues. The new dosage forms are reviewed according to their type and their drug release mechanisms. The characteristics, advantages, and limitations of each are outlined. The potential of these dosage forms can be expected to enhance development. They offer prolonged effectiveness, reproducibility, fewer unwanted side effects, and improved tolerance.

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).

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.

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.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

This study shows that diazepam (20 mg/Kg) and clonazepam (2 mg/Kg) administered intraperitoneally to 36 hour-fasted rabbits induce a significant (p < 0.05) 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 (p < 0.05). 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.

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.

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.

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.

In the very near future, the CFC manufacturers are going to be obliged to stop their production as a result of the "Montreal protocole on substances that deplete the ozone layer". The replacement of these propellants by other fluorinated ones will be possible as soon as their lack of toxicity has been demonstrated. Other substitution substances like haliphatic hydrocarbons (butane, propane) or compressed air generated by the device system itself or the user himself are also under development. The pulverisation can also be obtained by the pressure of a classical propellant onto an aluminum or plastic bag. The dispersion is achieved by means of a regulator which is positioned into the valve. The hand-operated spray pumps with or without compression will also allow the obtention of very small particles though the delivered doses are reduced. However, as few of the new devices have metered valves, they are not yet suitable for pulmonary administration.

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.

A randomized cross over study was carried out in 12 healthy volunteers to investigate simultaneously the pharmacokinetics and the effects on urinary volume and electrolyte excretion after administration of single doses of 40 mg frusemide and a combination tablet containing both 40 mg frusemide and 5 mg amiloride. From a statistical analysis of plasma levels of frusemide and amiloride measured by HPLC methodology, no significant difference between the reference drug alone, frusemide, and the combination tablets was observed in mean peak plasma levels, mean times to peak or mean areas under the plasma concentration-time curves (AUC). Frusemide and the combination tablet both produced a rapid and powerful diuresis in the 0-2 hours postdose period and did not differ significantly in urine output at any time point. However a difference in natriuretic activity was observed between frusemide and the combination with the latter producing a significantly greater sodium excretion in the 0 to 2 hours period (p less than 0.05). Potassium retaining activity throughout the 24 hours was marked after the administration of the combination, the potassium excretion being significantly less (p less than 0.05) than either control of frusemide alone. There was also a significant correlation between plasma levels of frusemide and the time course of urine and electrolyte excretion in healthy subjects.

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.

Peroral absorption of cefroxadine given to 7 24-h fasted trauma patients by nasogastric tube within the first day of admission was compared to that obtained in fasted healthy volunteers. The trauma patients exhibited significantly lower Cmax and reduced AUC. Even though rate and extent of bioavailability cannot be determined from these two different population groups since the total clearance must be assumed to be different in patients and healthy subjects, a reduced bioavailability is assumed based on pathophysiologic reflections.