Showing papers in "Drug Research in 1988"

Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids.

Abstract: The influence of replacing the phenolic hydroxyl by the methoxy group on opioid receptor binding, analgesic and antitussive action was investigated in the corresponding couples morphine-codeine, hydromorphone-hydrocodone and O-desmethyltramadol (L 235)-tramadol. Binding was studied on rat whole brain membranes (without cerebellum) with the radioligands dihydromorphine (mu-site), ethylketocyclazocine (k-site), D-Ala2-D-Leu5-enkephalin (delta-site) and naloxone (no selective binding). Analgesia (tail flick) and antitussive action (NH3-vapour induced cough) was investigated in rats and ED50 values 10 min after i.v. application were calculated to compare efficacy. All free hydroxyl compounds had higher opioid receptor affinities than the corresponding methoxy derivatives and were more active at the mu-site. The methoxy derivatives codeine and tramadol only had low affinities lacking selectivity towards mu-, kappa-, or delta-binding. Hydrocodone in contrast showed strong and mu-selective binding. The hydroxy compounds had higher analgesic activity than the methoxy congeners and analgesia appeared to correlate with mu-binding affinity. Codeine and hydrocodone were weaker antitussives than the corresponding hydroxy compounds, whereas no significant difference was found between O-desmethyltramadol and tramadol. Only in the tramadol group the methoxy substitution increased antitussive potency in relation to analgesic potency.

Immunologic in vivo and in vitro studies on Echinacea extracts

Abstract: Ethanolic extracts of Echinacea purpurea, E pallida and E angustifolia roots were examined for immunological activity in the carbon clearance test with mice and in the granulocyte test In the in vivo experiment all extracts, administered orally, were found to enhance phagocytosis significantly These results correlate with the stimulation of phagocytosis in the in vitro granulocyte test The lipophilic fractions of the extracts appeared to be more active than the polar fractions All extracts were analyzed by HPLC in order to correlate the chemical constituents with the immunological activities

Special pharmacology of the new sulfonylurea glimepiride.

Abstract: Glimepiride (Hoe 490) is a new sulfonylurea. After oral administration of Hoe 490 to rabbits, blood glucose was lowered 3.5 times more than after glibenclamide (HB 419) and after intravenous administration, 2.5 times more. This superiority in efficacy was demonstrated by onset, maximum and duration of action. In rats, intravenous and oral Hoe 490 has a much shorter effect on blood glucose than HB 419, but the initial effect of Hoe 490 orally was up to 6 times and i.v. up to 2 times stronger than that of HB 419. In dogs, oral and intravenous Hoe 490 had a considerably longer blood glucose-lowering effect than HB 419. However, the effect of intravenous Hoe 490 was only half as intense as that of HB 419 in the first hours after treatment and the effect of oral Hoe 490 was initially stronger and thereafter temporarily distinctly weaker than that of HB 419. The more rapid decrease in blood glucose in the dog after oral administration of Hoe 490 was accompanied by a correspondingly earlier and higher plasma insulin increase. In accordance with the less intense initial blood glucose decrease in the dog after intravenous Hoe 490 there was a weaker and slower rise and faster drop of plasma insulin. The long action of oral and intravenous Hoe 490 in the dog can, however, not be sufficiently explained by the plasma insulin values. In the isolated rat pancreas perfused with glucose-free medium, HB 419 released glucagon beside insulin and somatostatin. The threshold concentration for the glucagon secretion was lower as those for the insulin and somatostatin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiulcer activity of an anthocyanidin from Vaccinium myrtillus.

Abstract: The antiulcer effects of 3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-1-benzopyrylium chloride (IdB 1027) were assessed in various experimental models. Given orally, IdB 1027 antagonized gastric ulcerations induced by pylorus ligation, stress, nonsteroidal antiinflammatory drugs, ethanol, reserpine, histamine and duodenal ulceration induced by mercaptamine (cysteamine). Moreover it antagonized chronic gastric ulcers induced by acetic acid. Given intraperitoneally, it was more potent than after oral administration. IdB 1027 did not affect gastric secretion in pylorus-ligated rats and increased gastric mucus in normal animals both in the absence and in the presence of indometacin treatment. Tolerability was very good. These results indicate that IdB 1027 possesses a promising antiulcer activity, probably by potentiating the defensive barriers of the gastrointestinal mucosa.

Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers

Abstract: Pharmacokinetics of recombinant tissue plasminogen activator (rt-PA, large-scale process) were determined based on antigen and activity after infusion of 0.25 mg/kg in 8 healthy volunteers. Plasma antigen was measured using enzyme-linked immunosorbent assay (ELISA) with and without treatment of blood at collection with D-Phe-Pro-Arg-CH2Cl (P PACK); activity was quantified in acidified plasma both on fibrin plates and in a chromogenic assay. Highest rt-PA concentrations were measured in ELISA with P PACK-treated samples, yielding the following pharmacokinetic parameters (2-compartment model, mean +/- S.D.): Cmax = 973 +/- 133 ng/ml, CL = 687 ml/min, dominant half-life t1/2 alpha = 3.3 +/- 0.4 min, t1/2 beta = 26 +/- 12 min, V1 = 3.9 +/- 0.6 l and Vss = 7.2 +/- 1.0 l. The other assays yielded lower rt-PA concentrations, which affected clearance and volume parameters but not t1/2 beta and t1/2 beta. Linear regressions of the fibrin plate and chromogenic assay results vs. ELISA yielded excellent correlations (R greater than 0.96, n = 55-57) but slopes of 0.76 and 0.64, respectively. This indicates that about 25-35% of rt-PA antigen in thawed plasma samples are not detected in activity assays, due at least partially to in vitro binding of rt-PA by proteinase inhibitors.

In vitro stimulation of human granulocytes and lymphocytes by pico- and femtogram quantities of cytostatic agents.

Abstract: The influence of a broad concentration range of naturally occurring naphthoquinones and other cytotoxic or cytostatic agents (azathioprine, colchicine, cyclophosphamide, fluorouracil, methotrexate and vincristine) on human granulocytes and lymphocytes was investigated in a systematic in vitro study. At high concentrations (100 micrograms-10 ng/ml) nearly all substances showed the known cytotoxic or immunosuppressive effects, whereas most of the same compounds displayed immunostimulating activities at very low concentrations (10 ng-10 fg/ml). After a cold shock or heat treatment lymphocytes became more sensitive against these compounds in the active concentration range than untreated cells. These results possibly give an explanation for the antitumour activity of some plant extracts, for which a direct cytotoxicity due to the applied low dose can be excluded.

Pharmacokinetics and metabolism of torasemide in man

Abstract: Torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3- sulfonyl)urea) is a potent new loop diuretic. The pharmacokinetics, absolute bioavailability and metabolic disposition of torasemide have been studied after administration of a standard-release tablet to healthy volunteers. According to a latin square design 9 subjects received in random order single doses of either 20 mg i.v. over 1 h or 20 or 40 mg p.o. On each of the three occasions, torasemide and its metabolites were analysed in plasma and urine up to 24 h. From the results of urinary excretion and plasma AUC, the availability of torasemide from the tablet was 80% to 90%, i.e. nearly complete. The kinetics were linear with dose. The time of peak was reached at 1 h, the elimination half-life varied from 3 h to 4 h. None of the metabolites M1, M3 or M5 found in plasma exhibited a longer half-life. Only a quarter of the low systemic clearance of torasemide (41 ml/min) was accounted for by renal clearance. The distribution volume of 15.5 l was in the order of the extracellular fluid volume. The total amount of torasemide and metabolites recovered in urine was 83%, i.e. 25% torasemide, 11% M1, 3% M3 (both active), and 44% M5 (inactive). Therefore, M1 and M3 probably contribute to the diuretic action of torasemide. Since the renal clearances of the metabolites exceeded that of the parent drug, renal impairment may change their elimination kinetics.

General pharmacology of the novel centrally acting antihypertensive agent moxonidine.

Abstract: Moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, BDF 5895) reduces blood pressure and heart rate in rats with genetic hypertension (SHR/Okamoto) and in rats with renovascular hypertension (Goldblatt 1 k/1 c). The hypotensive action was also confirmed in renal-hypertensive dogs. The hypotensive action is preceded by a reduction in plasma noradrenaline concentration, thus reflecting a reduction in sympathetic activity. In anesthetized cats, administration of moxonidine into the vertebral artery induces a greater hypotensive effect than i.v. injection of same doses, indicating the central nervous system as the site of hypotensive action. Similar to clonidine, the hypotensive action of moxonidine is abolished by pretreatment of the animals with a selective alpha 2-antagonist. Direct application of moxonidine into the cisterna magna of anesthetized rabbits revealed a 10-fold greater hypotensive potency than clonidine, in contrast to i.v. application where moxonidine was 10-fold less potent than clonidine. At least 10-fold higher doses of moxonidine were needed to cause side effects (sedation, inhibition of gastric secretion), when compared with clonidine. Interruption of presynaptic noradrenergic pathways completely abolished the hypotensive action of moxonidine. Thus moxonidine is endowed with a specific central site of action, presumably by stimulating central presynaptic alpha 2-adrenoceptors. This specific central hypotensive action enables a greater dissociation between the antihypertensive effect on the one hand, and the side effects on the other.

Antimicrobial properties of methdilazine and its synergism with antibiotics and some chemotherapeutic agents.

Abstract: The antihistamine methdilazine (Md) was found to possess a significantly high antibacterial action when tested against 367 strains of bacteria belonging to both Gram-positive and Gram-negative genera. Different groups of bacteria could be arranged in order of their decreasing sensitivity towards Md as follows: S. aureus, V. cholerae, E. coli and Shigella. The range of minimum inhibitory concentration (micrograms/ml) varied between 25 and 200 in most cases, although few strains were sensitive even at 10 micrograms/ml level of Md. 10 different bacteria sensitive to Md and a number of antibiotics when tested for their interaction with Md on one hand and any of the antibiotics of chemotherapeutic agents on the other, it was found that Md in combination with aminoglycosides and several chemotherapeutics showed enhancement of antibacterial effects resulting in synergism. The chemotherapeutic agents bromodiphenhydramine (Bn), diphenhydramine and methyldopa showed distinct synergism when tested in combination with Md. Determination of the area of inhibition zones for the degree of synergism with Md and streptomycin (Sm) produced statistically significant result (p less than 0.01) in comparison with their individual effect. This could also be corroborated by the fractional inhibitory concentration (FIC) index which was 0.49 for Sm-Md and 0.5 for Bn-Md combinations. The synergism of Sm-Md combination was confirmed by in vivo studies.

Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration

Abstract: The pharmacokinetics (half-life time of absorption and elimination, total clearance, distribution volume etc.), effects on hemostasis (clotting times, blood cell counts) and renal excretion of hirudin were investigated on healthy volunteers after single subcutaneous (600, 800 or 1000 antithrombin units (AT-U)/kg; n = 3 per each dose) or intravenous (1000 AT-U/kg; n = 3) injections. Hirudin concentrations in citrated plasma and urine were determined by means of a radioimmunobioassay, whereby the inhibitor is detected by its thrombin binding capacity. Plasma profiles were adequately described by the Bateman equation (subcutaneous injection) and by an open two-compartment model (intravenous injection), respectively. Within 24 h about half of the applied hirudin dose was renally excreted in active form. The prolongation of clotting times (thrombin time, partial thromboplastin time (PTT), Quick) was dependent on the hirudin plasma level. The PTT proved to be the most reliable test for representation of the actual inhibitor plasma concentrations. Generally, the blood cell counts were unchanged by the hirudin administration. All test subjects tolerated the hirudin injection without visible or measurable side effects.

In vitro and in vivo studies of the non-sedating antihistamine epinastine.

Abstract: Epinastine (3-amino-9,13b-dihydro-1H-dibenz [c,f]imidazo[1,5-a]azepine hydrochloride, WAL 801 CL) was tested in vitro and in vivo in comparison with other H1-receptor antagonists. In the guinea pig ileum and in receptor binding studies the test substance showed a high affinity to H1-receptors. The following rank order was determined: WAL 801 CL greater than astemizole greater than terfenadine. These results were confirmed in vivo. The studies were carried out with oral and intravenous administration of WAL 801 CL to assess the inhibition of histamine-induced reactions in the skin or the lung of rats, dogs and guinea pigs. 10- to 100fold antihistaminic doses of WAL 801 CL showed no effect on the sleeping-waking behaviour of cats. From this and other results it is suggested that the compound does not penetrate in the central nervous system. The action pattern of WAL 801 CL as a non-sedating antihistamine corresponds more to that of terfenadine than that of ketotifen.

Clinical evaluation of a monophasic ethinylestradiol/desogestrel-containing oral contraceptive.

Abstract: A multicenter trial was conducted in 267 centers in Italy to evaluate the efficacy acceptability and safety of a monophasic oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg desogestrel (Marvelon). 13290 women were followed up for a total of 74.967 cycles. No pregnancies due to method failure were reported and only 3 were the result of patient failure. Cycle control was good. There was a decrease in the occurrence of irregular cycles and in the duration and amount of menstrual bleeding; the incidence of breakthrough bleeding and spotting was low. No severe side effects occurred and the incidence of minor complaints was generally lower during treatment than in the pretreatment cycle. Body weight and blood pressure were not significantly altered. (authors) (summaries in ENG GER)

Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers.

Abstract: The pharmacodynamic effects and the pharmacokinetic parameters of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) 20 mg and furosemide 40 mg were compared after oral and intravenous administration in 6 healthy volunteers. The plasma elimination half-life for i.v. and oral torasemide was 2.2 h and 2.8 h, its bioavailability after oral administration was 91%, about 25% of the total body clearance was due to renal excretion both after iv. or oral application. For furosemide, a plasma elimination half-life of 0.6 h for i.v. and 0.8 h for oral application was found. The bioavailability was 40%, and about 62% of the drug was excreted via the kidney. Both drugs produced a similar diuretic and natriuretic effect. However, torasemide showed an increased duration of action compared to furosemide and a higher relation between urinary Na and K excretion, both after i.v. and oral administration, suggesting less loss of potassium after To. Both agents were well tolerated.

Reversible prevention of platelet activation by (E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide (ajoene) in dogs under extracorporeal circulation.

Abstract: Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), an organosulfur compound derived from garlic inhibits platelet activation induced ex vivo by all known agonists. The effect of ajoene on the thrombocytopenia associated with the circulation of blood through extracorporeal devices such as dialyzers or oxygenators was studied under the following conditions: Ex vivo using fresh, heparinized human blood, circulating through a dialyzer or oxygenator, and in vivo, in dogs subjected to extracorporeal circulation. In both experimental conditions ajoene proved very efficacious in preventing platelet loss (60-65% loss in controls vs. 15-20% loss in the presence of ajoene, p less than 0.01). Moreover, recuperation of platelet function was achieved after 3-4 h in the in vivo experiments.

A multicentric study of loratadine, terfenadine and placebo in patients with seasonal allergic rhinitis.

Abstract: This multicentric study compared 14-day treatment with loratadine (Clarityne) 10 mg once daily, terfenadine 60 mg twice daily and placebo in outpatients with seasonal allergic rhinitis. Of 275 patients enrolled, 256 (87 in the loratadine group, 89 in the terfenadine group and 80 in the placebo group) were evaluable for efficacy and 266 (90, 91 and 85 in respective groups) were evaluable for safety. Investigators graded the severity of 4 nasal and 4 nonnasal signs/symptoms and investigators and patients rated overall disease condition and therapeutic response on treatment days 3, 7 and 14; patients recorded when signs/symptoms of rhinitis were relieved, as well. Hematology and blood chemistry tests were conducted before and after therapy, and patients were questioned throughout the study about possible adverse experiences. At all visits, loratadine and terfenadine were significantly superior to placebo (p less than or equal to 0.004), and the two active medications were statistically comparable, based on mean totals of sign/symptom severity scores and ratings of overall disease condition and therapeutic response. By patients' last valid visit, mean totals of sign/symptoms severity scores improved by 56% and 53% for loratadine and terfenadine groups, respectively, but exacerbated by 5% for the placebo group. Moreover, an excellent or a good therapeutic response was observed in 58/87 (67%) loratadine-treated patients and 58/89 (65%) terfenadine-treated patients, as compared to 13/80 (16%) placebo-treated patients (p less than 0.01). A total of 61/76 (30%) patients in the loratadine group and 57/78 (73%) in the terfenadine group versus 22/71 (31%) in the placebo group experienced relief within the first 3 days of therapy (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma and urine pharmacokinetics of free and of short-chain carnitine after administration of carnitine in man.

Abstract: To 6 healthy volunteers 30 mg/kg of L-carnitine (1,3-hydroxy-4-N-trimethylamino-butyrate) were injected intravenously and plasma levels (mumol/l) of free and short-chain carnitine were determined at different times between 0.033 and 24 h. The urinary excretion of L-carnitine and short-chain carnitine in 24 h was also measured. After a period of wash-out the subjects received 100 mg/kg of L-carnitine orally and plasma levels were determined between 0.5 and 24 h. The urinary excretion of L-carnitine was measured for a period of 18.5-33 h after treatment. 3 of the volunteers also received 30 mg/kg of L-carnitine orally. Carnitine plasma levels were determined at different times between 0.5 and 18 h, while the urinary excretion of L-carnitine was measured for 48 h following the treatment. The results could indicate the presence of saturation phenomena in the absorption process for the oral doses used; specific research is required to ascertain this phenomena. The transfer of carnitine from central to extravascular volume is relatively rapid, as is its urinary excretion. The short half-life of carnitine and acetyl-carnitine can suggest the use of new forms of administration (slow-release).

Pharmacokinetics of loxiglumide after single intravenous or oral doses in man.

Abstract: Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278.

Antihypertensive effects of the new calcium antagonist benidipine hydrochloride in rats.

Abstract: Using spontaneously hypertensive rats (SHR), DOCA-NaCl hypertensive rats (DHR) and normotensive rats (NTR), the antihypertensive action of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dic arb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was comparatively evaluated with those of nicardipine and hydralazine. Administration of KW-3049 at 0.5, 1 and 3 mg/kg (p.o.) showed dose-dependent antihypertensive action. This action appeared gradually and it lasted longer than those of nicardipine and hydralazine. The administration of KW-3049 at 0.5 mg/kg (p.o.) did not show any effect on the blood pressure of NTR, but a long-lasting blood pressure lowering action was observed by the administration at 1 and 3 mg/kg (p.o.). This antihypertensive action specific to the hypertensive animals was similar to that of nicardipine, however, it was different from that of hydralazine, with which the blood pressure in SHR, DHR and NTR was lowered in similar degrees. Also, administration of KW-3049 caused tachycardia concomitant with the fall of blood pressure, however, it was mild as compared with those of nicardipine and hydralazine. When KW-3049 at doses of 3 and 10 mg/kg (p.o.) once a day was continuously administered to SHR for 31 days and changes of the antihypertensive action were observed, no tolerance developed and rebound hypertension following the discontinuation of medication did not occur. When the effect on the urinary volume and electrolyte excretion was evaluated in rats loaded with physiological saline solution, a natriuretic effect was observed by the administration of KW-3049 at 0.5, 1 and 3 mg/kg (p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of nisoldipine. III. Biotransformation of nisoldipine in rat, dog, monkey, and man.

Abstract: After intraduodenal administration of 14C-labelled (+/-) 3-isobutyl-5-methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate (nisoldipine, Bay k 5552) to rats approx. 68% of the dose was excreted in the bile in the first 6 h. In an isolated perfused rat liver model the excretion with the bile was 56% of the total dose within 3 h. The recovery of radioactivity from orally administered [14C] nisoldipine was approx. 32% (rat), 23% (dog), 73% (monkey) and 74% (man), resp., in the urine. The unchanged drug was neither detected in the urine nor in the bile, but nisoldipine was present in plasma of the rat 30 min after dosing and up to 24 h in man. The drug was extensively metabolized: 18 biotransformation products were identified by comparison with synthetic reference compounds using combined GC-MS, 1 NMR-spectroscopy, mass spectrometry, gas chromatography/radio-gas chromatography and two-dimensional thin layer chromatography, 6 of them being quantitatively important (about 80% of the radioactivity excreted in urine). The metabolites identified accounted for approx. 82% (rat: bile and urine), 19% (dog, due to the low renal excretion), 58% (monkey: urine) and 64% (man: urine) of the excreted dose, resp. The following biotransformation steps occurred: hydroxylation of the isobutyl moiety, dehydrogenation of the 1,4-dihydropyridine system, oxidative ester cleavage, hydroxylation of one of the methyl groups in 2- or 6-position and subsequent oxidation to the carboxylic acid, oxidation of one of the methyl groups of the isobutyl moiety to the carboxyl group reduction of the aromatic nitro group (minor biotransformation reaction) and glucuronidation as phase II reaction.

In vitro skin penetration of griseofulvin in rat and human skin from an ointment dosage form.

Abstract: Penetration and permeation of griseofulvin into and across the rat skin after application of three ointment formulations containing either dimethylacetamide (DMAC) or diethylene glycol monoethylether (DGME) or the ointment base alone (control--without DMAC or DGME) were studied, in vitro. Penetration and permeation of griseofulvin into and across the human skin after application of DGME ointment was also studied. Permeation of griseofulvin across the rat skin was highest for the DMAC ointment, followed by the DGME ointment and lowest for the control. Concentration of griseofulvin in the upper layers of the skin (i.e., surface to 100 micron depth) was also highest for DMAC and lowest for the control. However, the skin levels from the DGME ointment could not be distinguished (statistically) from the other two formulations. In comparison to rat skin, human skin is much less permeable. Amount of griseofulvin (from DGME ointment) that permeated through the rat skin was 14 times the amount that permeated through the human skin. Concentration of griseofulvin in the upper layers of the rat skin were 4 times the concentration of the drug in the upper layers of the human skin. The concentration of griseofulvin in the various layers of the human skin after one topical application were far greater than those reported after prolonged peroral administration.

Electrophysiological characterization of the class III activity of sotalol and its enantiomers. New interpretation of use-dependent effects.

Abstract: 1. Sotalol (Sotalex) and both its optical isomers were studied in electrophysiological experiments with respect to their class III activity of antiarrhythmic drugs. The three substances prolonged action potentials (AP) of guinea-pig papillary muscle and left atrium in concentrations greater than or equal to 3 mumol/l, whereas other AP parameters (resting potential, amplitude and upstroke velocity) remained unchanged. Similar results were observed if papillary muscles were partially depolarized by elevating the extracellular potassium concentration from 4.7 mmol/l to 10-12 mmol/l. 2. The effects of sotalol showed marked frequency dependence (0.017-2 Hz): At slow driving rates sotalol brought about an enhanced AP prolongation as measured by APD30 and APD90. 3. The results were compatible with numerical AP simulation studies on the basis of the assumption that sotalol inhibits time-dependent K-outward current. This leads to the consequence that longer control APs (at low driving rates) are prolonged more effectively by sotalol than shorter ones (at high driving rates). 4. Sotalol effects dynamically followed APD changes due to alterations of driving rate: If APD was decreased under increasing driving frequencies, AP prolongation was diminished. 5. Paired pulse experiments showed that class III activity of sotalol was preserved in premature or delayed single action potentials.

Calcium antagonistic and spasmolytic activities of a new 1,5-benzothiazepine derivative in isolated canine and monkey arteries

Abstract: Effects of TA-3090 ((+) (2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate)and diltiazem on contractions induced by different spasmogens were investigated in isolated canine and monkey arteries. Ca2+-antagonistic action in canine arteries, assessed by suppression of Ca2+-induced contraction in Ca2+-free, K+-depolarizing solution, was as follows; basilar (pA2 = 8.34) greater than coronary (pA2 = 7.95) greater than renal (pA2 = 7.46) = mesenteric artery (pA2 = 7.36). The potency of TA-3090 was 10 times greater in basilar artery and 2 to 3 times greater in the other arteries than that of diltiazem. The effect of TA-3090 on the arterial segment was more persistent than that of diltiazem. Relative vasorelaxing potency of TA-3090 to diltiazem in K+-induced contractions was greatest in the basilar artery among the tested arteries of both monkeys and dogs. Spasmolytic activities of TA-3090 on 5-HT-, PGF2 alpha-, U-46619 (thromboxane A2/prostaglandin H2 agonist) and oxyhemoglobin-induced contractions in canine basilar arteries were more potent than those of diltiazem, especially on 5-HT-induced contraction. In addition, TA-3090 suppressed 3,4-diaminopyridine-induced rhythmic contraction in the canine coronary artery. These results indicate that TA-3090 has potent Ca2+-antagonistic and spasmolytic activities, and these actions are most selective for basilar artery.

Unique presynaptic alpha 2-receptor selectivity and specificity of the antihypertensive agent moxonidine.

Abstract: The characteristics of the alpha-receptor activating property of the new antihypertensive agent moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methyl-2-methyl-5-pyrimidinamine, BDF 5895) was studied using peripheral vasculature and brain membranes of various animals. Moxonidine exerted a full agonist effect in elevating diastolic blood pressure in the pithed rat. Activation of postsynaptic alpha 1- and alpha 2-receptors contribute to the vasoconstrictory effect in rats. In the vasculature of the rabbit, moxonidine was a full agonist at presynaptic alpha 2-receptors in inhibiting transmitter release induced by electrical stimulation of pulmonary artery strips. At postsynaptic sites, exogenously applied moxonidine was a full agonist at alpha 1-receptors in the isolated aorta, pulmonary artery and vena cava of the rabbit. Selectivity for alpha 2-receptors in the pulmonary artery was 106-fold. In rat brain membranes, moxonidine showed 288-fold greater selectivity for alpha 2-receptors, when the displacement of [3H]-rauwolscine was compared with the displacement of [3H]-prazosin. On the whole, clonidine exhibited greater potency than moxonidine on both alpha-receptor subtypes, but moxonidine consistently showed greater alpha 2-receptor selectivity than clonidine. In the guinea pig myocardium, moxonidine caused neither bradycardia nor tachycardia in the isolated right atrium and produced a negligible positive inotropic effect at 100 mumol/l in the isolated papillary muscle.

Clinical trials with the new antitussive levodropropizine in adult bronchitic patients.

Abstract: The results of 6 clinical trials involving a total of 174 patients are reported Levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526) was compared in double-blind manner with placebo, morclofone and cloperastine The antitussive activity and therapeutic efficacy of the drug were shown to be greater than those of placebo and morclofone and similar to those of cloperastine Levodropropizine was effective in about 80% of patients; in responders, cough frequency was reduced by an average of 33-51% Levodropropizine was generally well tolerated and mild side-effects were reported for only 3% of patients

Antianginal effects of the new calcium antagonist benidipine hydrochloride in anesthetized rats and spontaneously hypertensive rats. Electrocardiographic study.

Abstract: Antianginal effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in various experimental angina-pectoris models (anesthetized rats, spontaneously hypertensive rats (SHR] were compared with those of nifedipine, propranolol and hydralazine. Furthermore, the effects of these drugs on the pressure-rate product were evaluated. 1. Vasopressin test (SHR): The administration of KW-3049 at 10 micrograms/kg (i.v.) developed an inhibitory effect comparable to that of nifedipine at 200 micrograms/kg (i.v.) against the ischemic ECG changes caused by the intravenous administration of vasopressin at 1 U/kg. The effects of KW-3049 at 3 and 10 mg/kg (p.o.) lasted for 8 h or more. 2. Coronary occlusion test (rat): The rise of T-wave of epicardial ECG following ligation of coronary artery was inhibited by the administration of KW-3049 at doses of 30 and 100 micrograms/kg i.v. Nifedipine at dose of 200 micrograms/kg i.v. was slightly effective. 3. Isoproterenol (isoprenaline) test (rat): The fall of ST in ECG by the continuous infusion of isoprenaline (10 micrograms/kg/min) was almost completely prevented by propranolol (500 micrograms/kg i.v.). Also, KW-3049 (200 micrograms/kg i.v.) and nifedipine (200 micrograms/kg i.v.) significantly inhibited the decline of ST, in which the former was more effective than the latter. 4. Anoxia test (SHR): The fall of ST and rise of T-wave of ECG, induced by stopping artificial respiration of gallamine-immobilized SHR, were suppressed by the administration of KW-3049 at doses of 10 and 30 micrograms/kg i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Wedelolactone and coumestan derivatives as new antihepatotoxic and antiphlogistic principles.

Abstract: For the study of structure-activity relationships, the antihepatotoxic wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan) and 6 coumestan derivatives were synthesized by the application of a modified method of Wanzlich. An evaluation of the biological characteristics of the synthetic compounds and acuminatin from Musa acuminata showed that most of the wedelolactone derivatives significantly protected primary cultured liver cells from the toxicity of CCl4, galactosamine (Galc), and phalloidin, and strongly inhibited the activity of 5-lipoxygenase in porcine leukocytes. The hepatocyte protective activity was dependent on the C-7 substitution with pharmacological efficacy decreasing in the following order: EtO greater than MeO greater than OH greater than CH3(CH2)9. In addition, a free OH at C-5 of the wedelolactone molecule was shown to be important in protecting hepatocytes from CCl4 and Galc damage. Similar observation regarding the effect of C-7 substitution in wedelolactone was obtained in the 5-lipoxygenase test. In general, an increase in the lipophilicity in ring A increased the inhibition of 5-lipoxygenase activity. The synthetic wedelolactone was also found to have stimulatory effect on the RNA synthesis in isolated nuclei from hepatocytes.

Cardiovascular effects of a new 1,5-benzothiazepine calcium antagonist in anesthetized dogs.

Abstract: Cardiovascular effects of TA-3090 ((+)(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), a new 1,5-benzothiazepine derivative, were studied in pentobarbital anesthetized dogs. TA-3090 administered intraarterially (i.a.) was 3 times more potent than diltiazem in increasing vertebral and coronary blood flows. In the autoperfused preparation, TA-3090 i.a. exhibited weak negative inotropic effect as compared with its coronary vasodilating effect; negative inotropy was less than 10% at a dose which increased coronary blood flow by 50%. The selectivity of TA-3090 for coronary artery was greater than that of verapamil. Intravenous administration of TA-3090 (0.025-0.2 mg/kg) produced increases in cardiac output and arterial, especially vertebral and coronary blood flow as well as in left ventricular dp/dtmax. The increasing effect in blood flow was most prominent in the vertebral artery. Upon intraduodenal administration of 2 and 5 mg/kg TA-3090, the increases in vertebral and coronary blood flow lasted for more than 2-5 h; the effect of TA-3090 on vertebral blood flow was approximately twice as potent as that of diltiazem. Thus, TA-3090 could be demonstrated to possess potent and long-lasting vasodilating activity with selectivity for vertebral and coronary arteries, exerting however, weak negative inotropic effect.

Induction of colony-stimulating factor and stimulation of stem cell proliferation by injection of muroctasin.

Abstract: Modulation of myelopoiesis by anomeric mixture of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutamyl]-N6-stearoyl-L-lysin e (MDP-Lys(L18), muroctasin), a muramyl dipeptide analog, was investigated in mice. When BDF1 mice were subcutaneously treated with a single dose of 100 micrograms of MDP-Lys(L18), an increase in the number of peripheral blood leukocytes, a rise in the serum levels of colony-stimulating factor (CSF), proliferation of multipotential stem cells in the bone marrow and the spleen, and an expansion of granulocyte-macrophage progenitors in the bone marrow were observed. These findings suggest that the increase in the number of peripheral blood leukocytes in BDF1 mice by MDP-Lys(L18) is due to CSF production and stimulation of stem cell proliferation.

Comparative study on the antihypertensive efficacy of torasemide and indapamide in patients with essential hypertension.

Abstract: In a double-blind randomized multicenter study the antihypertensive efficacy of 2.5 mg torasemide (1- isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3-sulfony)urea) and 2.5 mg indapamide was compared in patients with essential hypertension, known as responders to diuretic therapy. After a wash-out period of 4 weeks patients with a sitting diastolic blood pressure of 100-115 mmHg were included in the 12-weeks active treatment period. After 4 weeks of treatment with a once daily 2.5 mg dose of each drug, doses could once be doubled if blood-pressure decrease was considered to be insufficient. 66 patients qualified for the statistical evaluation, 32 in the torasemide group and 34 in the indapamide group. In these patients both drugs caused a similar fall in blood pressure leading to a normalization of blood pressure in most of the patients. Serum parameters remained within normal limits. Only serum potassium was significantly lower with 2.5 mg indapamide compared to 2.5 mg torasemide at the end of the study. No side effects were reported for both drugs. As the lowest effective dose of a diuretic should be used for the treatment of hypertensive patients, 2.5 mg torasemide, which is below the threshold dose for significantly enhanced diuresis, seems to be the recommended dose for antihypertensive treatment.