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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.

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.

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.

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.

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 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.

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.

The results of a survey conducted in a company employing 1850 persons working in air-conditioned premises are reported. One hundred and five persons were examined, including 790 who mostly complained of respiratory disorders and 20 controls. Regular check-ups during the last two years have failed to reveal any serious disease. The most frequent complaints were rhinitis and tracheitis, especially among female employees. No alveolitis was observed. The finding of Bacillus subtilis in samples of ambient air and air-conditioner filters in conjunction with the presence of precipitating antibodies against crude extracts from these samples, suggested that the respiratory disorders might have been due to this microorganism. A multifactorial analysis demonstrated a statistically significant correlation between clinical symptoms and immunological disorders. The air-conditioner disease, therefore, may present as a benign condition.

The aim of this study is to compare the bioavailability of acetylsalicylic acid administered rectally in suppositories form and orally in tablets form to the rabbit. Acetylsalicylic acid was given to 8 males rabbits rectally and orally in a balanced crossover design with 15 days of interval between each study. In blood samples, acetylsalicylic acid is determined by Trinder's method. It has been established that the rectal route has a faster absorption than the oral route however it displayed a more intense first pass effect than that of the oral route.

A double blind study of thiophene carboxylate in 32 chronic bronchitis patients, show an improvement of clinical and respiratory condition in the treated group. However, there is no increase in volume of expectoration and no fluidizing. The product acts as mucoregulator, the reorganization of fibrillary mucus allowing a better efficiency of mucociliary apparatus.

The authors report 2 cases of hypersensitivity pneumopathy associated with haematological abnormalities: benign lymphoproliferative syndrome in one case, and malignant lymphadenopathy with fatal outcome in the other case. Such cases, now observed with increasing frequency, can be regarded either as chance associations of 2 types of disease, or as the results of immune disorders with repercussions on the blood.

Bidimensional electrophoresis is of most interest for the diagnosis of extrinsic allergic alveolitis. In fact, this detecting method is more specific than classical immunoelectrophoresis. Thus patients showing with the classical methods precipitation lines with one or several antigens do not present everytime the corresponding clinical signs. These positive but false reactions cannot in any case appear with bidimensionnal electrophoresis. Generally, the patient showing at least two precipitation lines opposite one antigen in bidimensional electrophoresis always followed by an increase of IgG, does also present the clinical signs of the disease.

In this work, we have studied in the rabbit, bioavailability of acetylsalicylic acid contained respectively in three forms of suppositories which are made as follows: for the first by only acetylsalicyclic acid (0.1 g); for the second by the association: acetylsalicylic acid (0.1 g) and phenobarbital (0.01 g); and for the third by acetylsalicylic acid (0.01 g), ascorbic acid (0.02 g) and thiamine chloride (0.002 g). It has been shown that ascorbic acid and thiamine chloride do not change the bioavailability of acetylsalicylic acid, while phenobarbital decreases it. In this work we have also compared two pharmaceutical forms of suppositories containing acetylsalicylic acid, ascorbic acid and thiamine chloride. In one of the two forms, acetylsalicylic acid is buffered by glycocolle. The study which consisted in giving the two forms to the rabbit rectally was concerned with the effect of glycocolle on the bioavailability of acetylsalicylic acid. It was shown that making glycocolle a buffer to acetylsalicylic acid resulted in an improved absorption as well as a delayed elimination of acetylsalicyclic acid. In this study too, we have evaluated the bioavailability of acetylsalicylic acid which is released from two types of suppositories containing respectively base witepsol W31 and base cocoa butter. In order to study this bioavailability whole suppositories were administered by rectal route to the rabbits after 24 hours of fasting (balanced crossover design with 15 days of interval after each study). Statistical analysis does not reveal any significant difference between the two forms of suppositories.

In order to evaluate the influence of food and time of administration on the absorption of diethylamine chromocarbe, a bioavailability study was performed in 8 volunteers by using a new method of plasmatic drug evaluation. The results obtained indicate that lunch has little effect on diethylamine chromocarbe absorption in comparison with the administration 0.5 h before breakfast. The bioavailability parameters Cmax, tmax, and AUC are not statistically different and the two methods of administration can be considered as bioequivalent. The absorption of diethylamine chromocarbe seems to be reduced when the drug is administered before dinner. This delay on absorption may be due to circadian rhythm of tractus gastrointestinal absorption or to the reduction of physiological activity of volunteers.

Precipitins against avian antigens in sera from patients with extrinsic allergic alveolitis, asymptomatic pigeon and chicken breeders and from control individuals were tested with different antigen extracts in six laboratories by a variety of different methods. Eighty percent of the results coincided in identifying the positive sera from patients and 90% in identifying the controls. It seems possible therefore to exchange results among experienced laboratories with fair confidence.

The in vitro and in vivo dissolution of a sustained release theophylline formulation labeled with 99mTc-diethyltriaminepentaacetic acid (DTPA) has been monitored in six subjects with a scintillation camera. The study was performed in fasting conditions and was repeated after ingestion of a standardized meal. Results showed that the presence of food in the stomach dramatically increased the oesoduodenal transit time of the tablet (74 +/- 27 min vs 352 +/- 77 min, P less than 0.001) but did not modify the biodisponibility of theophylline. This study is another example when scintigraphy can be of definite value in pharmacokinetics.

The aim of the study was to investigate the pharmacokinetic modelling of Cefotaxime (CTX) and its main metabolite Desacetyl Cefotaxime (DCTX) which has a less antibacterial activity than the CTX. After intravenous administration of lg of CTX to 26 patients, the plasma concentrations determined by HPLC showed that the pharmacokinetics of CTX and transformation to DCTX can be described with an open five-compartment model. The implications of this are discussed from the clinical point of view.

Tobacco may act as an allergenic or immunogenic agent, the antigen being present in either leaves or smoke. It is capable of producing immediate hypersensitivity reactions with respiratory disorders or cardiovascular lesions through a mechanism involving interaction between basophils and IgE. It may also induce the production of IgG-type antibodies, the significance of which remains to be elucidated. Finally, tobacco interferes with cell-mediated (alveolar macrophages, lymphocytes) lung defense mechanisms in normal subjects or patients. Any interpretation of some pathological conditions associated with tobacco should take these immunological reactions into account.