Clinical pharmacokinetics of kanamycin in endolymphatic therapy of peritonitis]

The pharmacokinetics of kanamycin in patients with peritonitis was studied after its intramuscular, endolymphatic and lymphotropic administration. Endolymphatic administration of kanamycin provided an increase in its activity in the inflamed tissues of the peritoneum and omentum and markedly prolonged its halflife as compared to those after the routine intramuscular administration of the drug. Lymphotropic administration of kanamycin failed to provide the same effect. Endolymphatic therapy of the patients during the postoperative period provided a decrease in the lethality, development of complications and the terms of the treatment in the hospital. The therapeutic effect of the endolymphatic administration of kanamycin to the patients with peritonitis proved to be high. The more efficient antibiotic therapy of the cases was likely due to favourable shifts in the pharmacokinetics of kanamycin after its endolymphatic administration.     

Resolution of the enantiomers of ibuprofen; comparison study of diastereomeric method and chiral stationary phase method

In this study, an indirect diastereomeric method and a direct method utilizing a chiral stationary phase (CSP) were investigated for the resolution of ibuprofen enantiomers. In the indirect method, ethylchloroformate (ECF) and 2-ethoxy-1-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) were utilized as first-step derivatizing reagents in acetonitrile or toluene. In the direct CSP method, ibuprofen enantiomers were derivatized to p-nitrobenzyl ureides and then resolved on an (R)-(−)-(1-naphthyl)ethylurea CSP column. The derivatization procedure took place in 10 min with an overall inversion efficiency of 90.3%. Racemization was not observed under the derivatization conditions used. The HPLC-CSP method was utilized to study the pharmacokinetics of ibuprofen enantiomers in dog plasma after a single oral administration of 200 mg of ibuprofen racemate.     

Propranolol antagonism to the effect of furosemide on the compostion of endolymph in guinea pigs.

Furosemide, administered intravenously (50 mg/kg) to guinea pigs, caused an increase in the sodium concentration and a decrease in the potassium concentration of endolymph, and a fall in the endolymphatic potential. The furosemide-induced electrolyte changes were prevented by pretreatment of five guinea pigs with propranolol given intravenously (2 mg/kg). The fall in the endolymphatic potential was not prevented by propranolol. Local administration of furosemide to the perilymphatic or endolymphatic space caused a fall in the endolymphatic potential, but had no effect upon the concentrations os sodium and potassium of endolymph. These studies provide additional information suggesting the mutual independence of the endolymphatic potential and sodium and potassium concentration gradients.     

Effect of indirect endolymphatic antibiotic therapy on clinical and immunological indicators in patients with erysipelas of the lower extremities]

Two groups of patients with erysipelas of the lower extremities underwent indirect endolymphatic therapy with bicillin-3 (58 patients) and routine penicillin therapy (79 patients). Comparative clinicoimmunological examinations in the two groups revealed that lymphotropic administration of the antibiotic had a more favourable effect on the disease process, as evidenced by more rapid reverse time courses of erysipelas clinical signs, less frequent incidence of early relapses and normalization of the majority of immunological parameters by the end of the treatment. For estimation of the anti-recurrence efficacy of the antibiotic therapy in the patients with erysipelas, it was recommended to use a specific scale based on the principles of the Wald successive alternative analysis.     

Intralymphatic administration of antibiotics in the complex treatment of suppurative complications in patients with neurosurgical pathology

The efficacy of endolymphatic route of gentamicin and ceporin administration was studied in 89 patients with neurosurgical pathological processes complicated by acute pneumonia (80 patients) and meningoencephalitis (9 patients) usually after ineffective antibiotic therapy according to the routine methods. The antibiotics were used in accordance with the antibiograms of the causative agents isolated from the bronchial tree or CSF. The endolymphatic use of gentamicin or ceporin once a day in doses of 80 mg or 1 g respectively provided rapid sanation and arresting of the inflammatory foci, lowering of the intoxication level, more rapid promotion of the positive time course of the clinico-roentgenological and laboratory indices and decreasing of the recovery periods by 1.5-2 times in 86 per cent of the patients with pneumonia. The endolymphatic administration of gentamicin in a dose of 80 mg twice a day or ceporin in a dose of 1 g twice a day allowed one to maintain the antibiotic therapeutic levels in the cerebrospinal fluid and to obtain satisfactory clinical results in the combined treatment of meningoencephalitis. The endolymphatic administration of the drugs was well tolerated by the patients and no adverse reactions were observed. This route of administration of antibiotics and in particular broad spectrum antibiotics may be recommended for urgent antibacterial therapy of especially severe neurosurgical patients with pyo-inflammatory complications and patients who did not respond to the routine antibiotic therapy.     

Sulfate conjugation in drug metabolism: role of inorganic sulfate

Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC 2.8.2.1) activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.     

Action of nonsteroidal anti-inflammatory agents on fibrinolysis and platelet aggregation

The influence of non-steroidal antiphlogistics (NSA, fluor derivatives of phenylanthranilic acid) on fibrinolysis, platelet function, prostaglandin metabolism and pharmacokinetics of indirect anticoagulants was studied in rats and rabbits in vitro and in vivo. NSA were found to shorten the euglobulin lysis time and to enlarge the lysis zones on fibrin plates. They potentiated the fibrinolytic activity of streptokinase and trypsin. Furthermore, they inhibited platelet aggregation induced by arachidonic acid in rabbits. NSA in combination with inhibitors of thromboxane synthetase potentiated inhibition of aggregation. After oral administration, NSA inhibited formation of thromboxane A2 and prostacyclin in rabbits in a dose-dependent manner. At comparatively low doses, thromboxane A2 synthesis was more effectively inhibited than prostacyclin formation. Due to pharmacokinetic interactions NSA enhanced the anticoagulant effect of indirect anticoagulants and accelerated their distribution and elimination.     

In vitro resistance test of human leprosy bacilli to anti-leprous drugs.

Sensitivity to anti-leprous drugs of M. leprae isolated from an L-type leprosy patient was tested using M--Y 14b liquid medium by direct and indirect methods. The results revealed that the strain, SR61-L74, was almost completely resistant to DDS, and responded only to the long-term administration of Streptomycin and Isoniazid. However, the strain was completely sensitive to rifampicin which had never been administered previously. The subsequent administration of rifampicin resulted in a rapid improvement of the patient's clinical symptoms. It can be concluded that the in vitro method, both direct and indirect, to test the sensitivity of M. leprae to anti-leprous drugs is economic, and accordingly available practically as one of the routine examinations in the laboratory of ordinary leprosaria. This must be very beneficial to the treatment of leprosy patients.     

Role of t lymphocytes in the humoral immune response. II. T cell-mediated regulation of antibody avidity.

The effect of activated T lymphocytes (ATC) on the avidity distribution of PFC in the secondary response was studied in normal mice. The total PFC response was not significantly changed for either direct or indirect PFC by administration of ATC before secondary antigen challenge. However, marked suppression occurred of indirect PFC that secreted high avidity antibody; no suppression was seen of high avidity direct PFC. At the same time, significant stimulation was seen of relative and absolute frequencies of indirect PFC that secreted middle and low avidity antibody. These effects were dependent on Thy 1-bearing, nylon nonadherent cells which demonstrated carrier specificity. In further characterization of these effects, it was found that increasing the number of ATC transferred produced progressive loss of high avidity PFC and compensatory increase in lower avidity PFC. Moreover, in these experiments, suppression of the high avidity response was inducible with the administration of ATC 5 weeks before to 3 days after the secondary immunization. Thus, it is likely that the avidity-modifying effects are dependent on T lymphocytes which influence the late stages of B lymphocyte maturation.     

Clinico-laboratory basis for the endolymphatic use of beta-lactam antibiotics in pulmonology

Clinical efficacy and effect of cefuroxime, claforan and pentrexyl used endolymphatically were studied in 85 patients with acute abscess forming and persisting pneumonia. Previous routine antibiotic therapy in these patients was little effective. Administration of the antibiotics into the peripheral lymph nodes provided blocking of the lymphagenic pathway for the infection due to high levels in the lymphatic system. Endolymphatic use of cefuroxime and claforan resulted in a significant improvement of the functions of the T- and B-immunity systems and the indices of natural resistance. The levels of the autoimmune reactions and sensitization to the bacterial antigens decreased. Endolymphatic use of cefuroxime and claforan once every 3 days provided recovery of 9 2.8 per cent of the patients, the treatment periods being decreased 2.5--3 times. Intravenous administration of the drugs according to the routine schemes, endolymphatic use of pentrexyl (5 g once every 3 days) and endolymphatic administration of cefuroxime in a single dose followed by intravenous therapy was less effective. The efficacy of pentrexyl increased, when it was used endolymphatically in combination with lysozyme. Endolymphatic use of claforan in doses of 2--3 g once every 3 days (3--4 infusions during the treatment course) was most effective.     

Semi-Quantitative vs. Volumetric Determination of Endolymphatic Space in Menière’s Disease Using Endolymphatic Hydrops 3T-HR-MRI after Intravenous Gadolinium Injection

Magnetic resonance imaging enhances the clinical diagnosis of Menière''s disease. This is accomplished by in vivo detection of endolymphatic hydrops, which are graded using different semi-quantitative grading systems. We evaluated an established, semi-quantitative endolymphatic hydrops score and with a quantitative method for volumetric assessment of the endolymphatic size. 11 patients with Menière''s disease and 2 healthy subjects underwent high resolution endolymphatic hydrops 3 Tesla MRI with highly T2 weighted FLAIR and T2DRIVE sequences. The degree of endolymphatic hydrops was rated semi-quantitatively and compared to the results of 3D-volumetry. Moreover, the grade of endolymphatic hydrops was correlated with pure tone audiometry. Semi-quantitative grading and volumetric evaluation of the endolymphatic hydrops are in accordance (r = 0.92) and the grade of endolymphatic hydrops correlates with pure tone audiometry. Patients with a sickness duration of ≥ 30 months showed a significant higher total labyrinth fluid volume (p = 0.03). Fast, semi-quantitative evaluation of endolymphatic hydrops is highly reliable compared to quantitative/volumetric assessment. Endolymphatic space is significantly higher in patients with longer sickness duration.     

The functional morphology of the regional inguinal lymph nodes during the endolymphatic antibiotic therapy of patients with vascular diseases of the lower extremities]

The general structure and cell composition of the inguinal lymph nodes has been analysed at a direct endolymphatic antibiotic therapy, performed with the aim of prophylaxis of suppurative complications, when surgical interventions are performed in the vessels of the lower extremities. Morphokinetics of the lymph nodes depends on duration of the endolymphatic therapy. During early terms it reflects an increase in transport function of the regional inguinal lymph nodes, during late terms it reflects an increase in their immune role. In the lymph nodes, situating on the contralateral side, an analogous reaction is revealed; this appears to demonstrate presence of well developed collaterals between lymph vessels of the lower extremities.     

Adrenocorticotropin administration increases testosterone secretion in adult male rats

It appears that the effect of acute administration of pituitary-adrenal hormones on the pituitary-gonadal axis is species-dependent. However, no information is available with regard to the effect of acute adrenocorticotropin (ACTH) administration on testosterone secretion in rats. The present data indicate that acute ACTH administration can increase serum testosterone levels without modifying luteinizing hormone (LH) levels. Since this rise was not observed in castrated rats, it must be assumed that increased serum testosterone was of gonadal origin. The action of ACTH on testosterone secretion was likely an indirect one since there is no evidence at present for a direct, short-term action of the pituitary-adrenal axis on Leydig cell function.     

Endolymphatic delivery of IL2 in patients with melanoma and lymphoma

During this phase I/II study, enodolymphatic cannulae were placed in the iliac lymphatics under general anaesthesia. IL2 was then infused via this route at escalating doses until the highest tolerated dose was achieved; then, continuous infusion was maintained for 2 to 3 weeks. Seven patients with advanced cancer (3 lymphoma, 4 melanoma), resistant to all other modalities of treatment received such therapy.Most patients tolerated 4 to 5 × 10⁶ u/day of IL2 for 2 to 3 weeks with less toxicity as compared to the equivalent dosage given intravenously. No severe perioperative morbidity was experienced. One melanoma patient had a minor clinical response. Changes in circulating lymphocyte numbers and cytotoxicity demonstrated a systemic effect of endolymphatic IL2 therapy.Conclusions: The endolymphatic administration of IL2 is associated with less toxicity than the intravenous route but still achieves a systemic effect; a lower tumour burden may prove more responsive to this therapy.     

Pharmacokinetics of the interferon inducer PHL-6 and interferon synthesis in target organs under various methods of drug administration]

The pharmacokinetics of PHL-6 and interferon synthesis dynamic in the target organs (tissues) of mice were studied during its and intraperitoneal administration. In the experimental setting, there was a direct correlation between the interferon production in the murine organs with single PHL-6 and distribution of 14C PHL-6. The highest radioactivity with its oral administration was detected in the liver and intestine. Interferon was actively synthesized in the intestine, liver and serum, showing the levels of 20000, 1024-2048 and 512-1024 IU/ml, respectively. The prolonged action of the drug was in good agreement with the low PHL-6 excretion from the body. It was also shown that almost the whole radiation dose 1 (greater than 98%) was excreted with feces and urine after single and chronic administrations of uniformly labeled PHL-6 which proved important clinical drug use.     

Inhibition by colchicine of fibrinogen translocation in hepatocytes

In the rat, 8 h after intraperitoneal administration of colchicine, fibrinogen (detected by antirat fibrinogen antibodies labeled with peroxidase) accumulated in the lumina of the rough endoplasmic reticulum of the hepatocytes; 16 and 24 h after colchicine administration, fibrinogen was detected, respectively, in the lumina of the smooth endoplasmic reticulum and in the Golgi apparatus. The effect of colchicine on the cytoplasmic translocation of fibrinogen could be due to a direct action of the drug on the membranes of the endoplasmic reticulum or could be the indirect result of the disruptive action of the drug on the microtubules.     

Chronopharmacology of roflumilast: a comparative pharmacokinetic study of morning versus evening administration in healthy adults

The human circadian system is known to affect the pharmacokinetics and pharmacodynamics of several classes of respiratory disease medications. The current study involving 16 healthy adults investigated if the time-of-day of dosing of roflumilast, a novel phosphodiesterase-4 inhibitor, affects its pharmacokinetics. The rate of drug absorption (t(max): 1.50 versus 2.00 h) and peak concentration at t(max) (C(max): 3.79 versus 3.06 μg/L) was slightly greater with morning than evening administration, but without clinical significance. The extent of drug absorption (AUC) and drug elimination (t(1/2)) did not differ between the two dosing times. The pharmacokinetics of the active main metabolite, roflumilast N-oxide, also was not affected by the time of drug administration. Finally, the safety and tolerability of roflumilast did not differ between the two different times of administration.     

Pulmonary gemcitabine delivery for treating lung cancer: pharmacokinetics and acute lung injury aspects in animals

Gemcitabine, a nucleoside analogue for treating lung cancer, is clinically administered as an intravenous infusion. To achieve better patient compliance and more direct effect on the lung, we explored a new gemcitabine pulmonary delivery route and evaluated the pharmacokinetics and acute lung injury aspects in animals. Pharmacokinetics of gemcitabine were measured in Sprague-Dawley rats after intravenous (i.v.), intratracheal instillation by tracheotomy (i.t.t.), intratracheal instillation via orotrachea (i.t.o.), and intragastric (i.g.) administration of gemcitabine. Acute lung injury effects of the pulmonary delivery of gemcitabine were performed in Sprague-Dawley rats after i.t.o. and i.v. administration of gemcitabine and i.t.o. administration of lipopolysaccharide (LPS) as a positive control and physiological saline as a blank control. Indicators for acute lung injury that were evaluated included lung morphology, lung histopathology, lung coefficient, lung wet/dry weight ratio, total cell and classification counts in bronchoalveolar lavage cells (BALC), and total protein and TNF-alpha levels in bronchoalveolar lavage fluids (BALF). After i.t.t. or i.t.o. administration, gemcitabine was quickly absorbed, but i.g. administration led to an undetectable plasma gemcitabine concentration. Absolute bioavailability of gemcitabine after i.t.t. and i.t.o. administration was 91% and 65%, respectively. Gemcitabine given as i.t.o. administration did not cause any overt acute lung injury. All indicators for acute lung injury in the i.t.o. group were similar to those in the i.v. group or in the blank control, but significantly different from those in the positive control. In conclusion, the pharmacokinetics and acute lung injury studies suggest that pulmonary gemcitabine delivery would be a new and promising administration route.     

The fate of serotonin released from the intrathyroidal mast cells in albino rat.

After the administration of 500 muC of 3H-5-HT the mast cells were degranulated by 1500 IU of PO B. The grains were found within the follicular cells and in the vicinity and wall of the arterioles. These findings support both the direct and indirect (vascular) mechanism of action exerted by serotonin on the thyroid function.