Antibiotics and mucous membrane: pharmacokinetic aspects.

The penetration of chemoantibiotic agents across the mucous membrane is affected by several factors, some of which are related to the drug and others to the membrane. Molecular weight can influence the penetration of chemoantibiotic agents into mucous membranes. Liposolubility is another factor which can enhance the penetration of chemoantibiotic agents. Factors related to the membrane can affect diffusion of the antibiotic. Inflammation of the mucous membrane enhances the volume of blood circulating within tissues and, as a consequence, the rate of drug penetration into them. This condition, however, can be counterbalanced by a high binding rate of the drug to tissues. The pH affects the action of antibacterial agents. Acid pH range enhances the antibacterial activity of beta-lactams, an alkaline range that of macrolides. Besides purely physiochemical factors, there are others able to interfere with the diffusion of a chemoantibiotic agent into and through the mucous membranes. The diffusion into bronchial membrane and the penetration through the hematobronchial barrier seems to occur substantially by means of a passive transfer. There is therefore an establishment of a proportionality relationship between the concentrations in the two blood-bronchial fluid compartments. Exceptions to this rule seem to be some drugs like macrolides, even if a real active transfer mechanism has not yet been demonstrated. A precise knowledge of its pharmacokinetic parameters is an indispensable condition for the characterization of a molecule which penetrates the mucous membranes.

Pathogen-host interaction.

Host defense, as it generally applies to humans, refers to the individual's ability to withstand infections. Human host defense mechanisms are numerous, diversified, complex, and often interdependent. The administration of drugs may influence some phases of immunocompetence mechanisms. The effect of several antimicrobial agents on organic defenses has been studied. The parameters considered were chemotaxis, phagocytosis, intracellular killing, superoxide-anion production, antibody production, lymphocyte subset behavior, and natural killer cell activity. Some antibacterial agents inhibit these parameters, whereas others can enhance some of these immune parameters to differing extents. Some antibacterial agents have a neutral effect on these parameters.

Miocamycin distribution in tonsillar and pulmonary tissues after repeated administration.

Twenty patients undergoing tonsillectomy were treated with a peroral administration of 600 mg of miocamycin every 12 hours for 4 days. On the 5th day, after a last administration of a dose of 600 mg the ablation of the tonsils was carried out on groups of 4 subjects, each one at the following times after oral intake of the drug: 2, 4, 6, 8, 12 h. Twenty-nine patients, admitted to hospital to undergo lung resection were treated with peroral administration of miocamycin in accordance with the above mentioned dose scheme. The operation was carried out on groups of 5 subjects, each on the fifth day at the following times after the last administration: 2, 3, 4, 6, 8 and 12 h (4 subjects). Simultaneously blood was withdrawn for the determination of miocamycin in serum. Miocamycin was measured by a microbiological procedure using Sarcina lutea ATCC 9341. The highest levels of miocamycin were observed after 2h in tonsils (3.2 +/- 0.82 mg/kg) and serum (1.3 +/- 0.33 mg/l). After 12h miocamycin proved to be still measurable in the tissue (0.12 +/- 0.05 mg/kg), whereas it was not detected in serum. In pulmonary tissue, the highest levels of miocamycin were likewise identified at the 2nd hour (2.82 +/- 0.59 mg/kg), simultaneously with the highest serum levels (2.3 +/- 0.61 mg/l). At the 12th hour miocamycin could still be dosed in 3 tissue samples, with values between 0.1 and 0.2 mg/kg and was found just at dosing limits in only one serum sample.

Pharmacokinetics of dactimicin in rats.

Dactimicin is a new pseudo-disaccharidic aminoglycosidic antibiotic produced by Dactylosporangium matsuzakiense. The aim of the present research was to evaluate the pharmacokinetics of dactimicin intramuscularly administered, at the dosage of 20 mg/kg, in male Sprague-Dawley rats with an average b.w. of 200-220 g. Dactimicin levels were assessed by using a microbiological method (agar diffusion) employing Bacillus subtilis ATCC 6633 as test organism. Samples were collected immediately before and 0.25, 0.50, 1, 1.15 and 2 h after drug administration. The mean peak serum level, reached after 15 min, was 33.6 micrograms/ml (range 30.3-40 micrograms/ml); T1/2 beta was 0.42 h; extrapolated AUC was 26.8 mg h/l.

Activity and tolerability of domifen bromide in patients affected by acute infectious dental diseases: a double-blind placebo-controlled trial.

Thirty-one patients (21 M and 10 F), affected by acute infectious dental disease, were treated with domifen bromide (A) or placebo (Pl). It was found that A had a beneficial effect on the results of clinical controls and reduced the need for the concomitant use of an antibiotic (p = 0.001 and p = .008 respectively). Furthermore, after two days of treatment with A, there was a significant decrease in pain and inflammation (p less than 0.01). A alone or in combination with an antibiotic elicits a good response, improves the prognosis and reduces the number of days of illness.

Kinetic profile of miocamycin in middle ear fluid and mucosa.

A group of 18 patients, before undergoing otoplastic surgery, was treated with miocamycin 600 mg in a single dose; middle ear tissue samples were collected at 2, 3, 4 and 6 h. A group of 20 patients suffering from secretory otitis media (SOM) was also treated with 600 mg of miocamycin in a single dose; collections of middle ear fluid (MEF) were performed at 1, 2, 4 and 6 h. Blood withdrawals from all patients occurred at the same time intervals. The miocamycin determination was performed by means of a microbiological method employing Sarcina lutea ATCC 9341. The highest serum levels (1.06 +/- 0.13 mg/l) were found at 2 h in the group from which middle ear mucosa had been withdrawn and at 1 h (2.2 +/- 0.5 mg/l) in the group from which the MEF had been collected; at 6 h miocamycin could be determined in both groups, with values ranging from 0.1 to 0.2 mg/l. In middle ear mucosa the miocamycin concentration was 1.52 +/- 0.27 mg/kg at 2 h and 0.2 +/- 0.09 mg/kg at 6 h. In MEF, the miocamycin concentration was 2.1 +/- 0.27 mg/l at 1 h and 0.24 +/- 0.05 mg/l at 6 h. The miocamycin concentration determined at 1 h in MEF was virtually equal to that in serum at the same time. At the following experimental times of withdrawal, the miocamycin concentration in mucosa specimens, as well as in MEF samples, proved to be markedly higher than values simultaneously found in serum.

Pineal gland and polyamines.

The activity of ornithine decarboxylase was assayed in several organs (thymus, testes, prostate gland, liver, kidneys, adenohypophysis, anterior hypothalamus, and adrenals) taken from adult male rats killed at seven day interval up to six weeks after pinealectomy. The absence of the pineal gland particularly influences the ornithine decarboxylase activity in the thymus, in which the level of the enzyme is decreased irreversibly by the fourth week after the operation. In other organs the ornithine decarboxylase activity was often significantly different from that of corresponding shampinealectomized controls at various weeks after the surgical removal of the gland. Moreover, these differences between operated and sham-operated animals are sometimes positive, sometimes negative. Thus, the polyamine biosynthetic pathway in different organs appears to be regulated, directly or indirectly, by a new neuroendocrine centre, the pineal gland, and this pineal gland has thus been shown to be active in adult life in correlating endocrine-enzymatic functions.

Endocrine regulation of thymic biosynthetic polyamine decarboxylases in adult rat.

The activities of ornithine and S-adenosyl-L-methionine decarboxylase were assayed in the thymuses of adult rats killed at 7-day intervals up to 6 wk after either pinealectomy or sham pinealectomy. The absence of the pineal gland markedly influenced the ornithine decarboxylase activity in the thymus, in which the level of the enzyme was decreased permanently by the 4th wk after the operation (P less than 0.05). The time course of the changes in S-adenosyl-L-methionine decarboxylase activity in the thymus during the entire period investigated was also significantly (P less than 0.05) modified by pinealectomy but did not show any stable trend. Adrenalectomy significantly raised (P less than 0.001) for ornithine decarboxylase; P less than 0.01 for S-adenosyl-L-methionine decarboxylase) the basal levels of the thymic biosynthetic polyamine decarboxylases. A pharmacological dose of corticosterone or cortisol produced a rapid and significant decrease in ornithine and S-adenosyl-L-methionine decarboxylase activities (P less than 0.02) in the thymus, whereas the injection of either D-aldosterone or ACTH was ineffective. Therefore, the thymic biosynthetic polyamine decarboxylases that in this organ are known to be located only in the lymphocytes appear to be regulated in opposing ways by the pineal gland and by the adrenal cortex.