piperidines and vadocaine

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methyl-piperidyl)-propionanilide hydrochloride; INN vadocaine) is a novel compound with antitussive and local anesthetic actions. In this study, the single dose and steady-state pharmacokinetics of vadocaine hydrochloride tablet were evaluated in 28 healthy volunteers. In part 1, the pharmacokinetics of a single dose of vadocaine hydrochloride tablet were compared with the pharmacokinetics of a vadocaine hydrochloride solution. The peak concentrations of vadocaine were achieved at 1 h both after the tablet and the solution and there were no statistically significant differences in serum concentrations or in pharmacokinetic parameters. In part 2, the steady-state pharmacokinetics of vadocaine tablet were studied using the dosage of 30 mg vadocaine hydrochloride t.i.d. for four days. The peak concentrations of vadocaine were achieved on the 1st day at 1 h (61.5 +/- 6.1 ng/ml) and on the 4th day at 1.5 h (64.5 +/- 7.9 ng/ml). According to the serum concentrations and pharmacokinetic parameters, no cumulation of vadocaine was observed. Also no side-effects were reported during the study. In conclusion, vadocaine used in the tablet form is suitable for multiple dosing and the pharmacokinetic profile is almost similar to vadocaine administered in aqueous solution.

Topics: Adult; Antitussive Agents; Humans; Male; Piperidines; Random Allocation; Solutions; Tablets

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is a new anilide derivative which resembles lidocaine in chemical structure. The safety and antitussive effects of this new compound were studied in 6 healthy male volunteers in the first Phase I clinical trial. Vadocaine was administered in single doses of 5, 10, 15, 20, 30 and 50 mg. At these dose levels vadocaine had no effects on the cardiovascular system, the haematological variables, blood biochemistry or urinary sediment examined as safety evaluation. The antitussive properties of the compound were studied using inhaled citric acid for induction of the cough response. The antitussive properties of vadocaine were most effective at a dose of 15 mg, although no statistical significance was found. Neither was any dose-response relationship noted. However, at this dose level vadocaine is apparently safe and its antitussive properties seem promising enough for further evaluation.

Topics: Adult; Antitussive Agents; Blood Chemical Analysis; Blood Pressure; Cough; Drug Evaluation; Electrocardiography; Heart Rate; Humans; Male; Piperidines

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel compound with potent antitussive and local anaesthetic action. The antitussive profile of this compound was evaluated in 40 healthy volunteers in double-blind, placebo-controlled cross-over study design using inhaled citric acid a cough inducer. In Part I, vadocaine was compared in 20 healthy volunteers at two dose levels (10 and 30 mg) with codeine phosphate (50 mg) and a placebo. In part II, vadocaine (30 mg) and a placebo were compared in 20 healthy volunteers. In Part I, no statistically significant differences were found between the 3 compounds tested. However, statistically significant rises from the pre-dose value in the cough threshold stimulus level were observed following 10 and 30 mg doses of vadocaine. Neither codeine phosphate nor the placebo produced any statistically significant change in the cough threshold stimulus level. In Part II, vadocaine at a dose of 30 mg dose was found to be a potent antitussive with a statistically significant difference (p less than 0.0001) as compared with the placebo. The maximum cough threshold stimulus level was achieved 2 h after administration and was 72.6% higher than at pre-dose. With the placebo the cough threshold stimulus level also rose to some extent after 4 h, although the change was not statistically significant. The use of inhaled citric acid in graded concentrations for induction of the cough response was found to be a reliable method when the baseline cough threshold stimulus level is maintained within narrow limits throughout the entire study population.

Topics: Adult; Antitussive Agents; Citrates; Citric Acid; Cough; Double-Blind Method; Humans; Male; Piperidines

Mucociliary function is a major cleansing mechanism of the respiratory tract. Many drugs used in the treatment of respiratory diseases impair the ciliary beat frequency (CBF) of mucous membrane. Our aim was to study by means of a photoelectric technique, the effects of two antitussives--dextromethorphan and vadocaine--and two antihistamines--hydroxyzine and diphenhydramine--on the rat tracheal CBF in vitro. The CBF was measured from tracheal explants immersed in drug solutions. Dextromethorphan (1.0 mg/ml and 10.0 mg/ml) caused 16.9-20.8% decrease in the CBF during the 40 min. measurement period. Vadocaine (0.1 mg/ml and 0.5 mg/ml) decreased the CBF by 6.9%. Higher vadocaine concentrations caused a dose-dependent inhibitory effect so that mucociliary function stopped totally within 20 min. with 5.0 mg/ml vadocaine solution. Both diphenhydramine and hydroxyzine totally stopped the ciliary activity during 20 min. with concentrations of 2.5 mg/ml and 1.0 mg/ml. respectively. Locke-Ringer solution used as a control did not cause any change in the CBF. These results suggest that the antihistamines diphenhydramine and hydroxyzine are more ciliostatic than the antitussives dextromethorphan and vadocaine on the rat tracheal cilia in vitro. The results suggest further in vivo studies. The used photoelectric detection method proved to be suitable for evaluating drug effects on the CBF of respiratory mucosa.

Topics: Animals; Cilia; Dextromethorphan; Diphenhydramine; Hydroxyzine; Male; Mucociliary Clearance; Piperidines; Rats; Rats, Inbred Strains; Time Factors; Trachea

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methyl-piperidyl) propionanilide hydrochloride, OR K-242-HCl) is a novel compound, which chemically resembles amide-type local anaesthetics. Vadocaine has been proved to be an antitussive drug both in animal and in human studies. The steady state pharmacokinetic profile of vadocaine and its main metabolite in healthy volunteers after a dosage of 30 mg t.i.d. for seven days were studied. The safety of vadocaine was evaluated by ECG monitoring and by hematological and biochemical laboratory tests. Blood and urine samples were taken on the 1st, 3rd and 7th days of the study. The peak concentrations of vadocaine were on the 1st day 72.9 +/- 6.5 ng/ml at 1 h, on the 3rd day 86.4 +/- 10.3 ng/ml at 1.5 h, and on the 7th day 86.4 +/- 7.0 ng/ml at 1.5 h. AUC0-infinity values were 327.0 +/- 43.1, 449.6 +/- 81.0 and 430.5 +/- 77.1 (ng/ml)h, respectively. No side-effects or any clinically significant changes in ECG or laboratory tests were detected during the study. According to the serum concentrations and pharmacokinetic parameters the steady state level was achieved already after the third 30 mg dose of vadocaine. No cumulation of intact compound or its metabolite was seen during the study.

Topics: Adult; Antitussive Agents; Biotransformation; Electrocardiography; Humans; Male; Piperidines

Lidocaine and vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine), which is structurally related to lidocaine, inhibited the second phases of human platelet aggregation induced by adenosine diphosphate (ADP, 10 mumol/l) or epinephrine (10 mumol/l) and partly aggregation induced by collagen (2.5 micrograms) at concentration relevant to local anesthetic action (0.1-1.0 mmol/l). Codeine was effective at slightly higher concentrations. The concomitant formation of thromboxane B2 (TXB2) was inhibited at similar concentrations. The aggregation induced by arachidonic acid (200 mumol/l) and the first phases of ADP (10 mumol/l)- or epinephrine (10 mumol/l)-induced aggregations were inhibited by all the compounds at the concentrations 1-10 mmol/l, codeine being the most potent inhibitor. The only exception was vadocaine, which inhibited the first phase of epinephrine-induced aggregation at concentrations greater than or equal to 0.25 mmol/l. Vadocaine may possess a2-adrenergic blocking activity. At low concentrations (less than or equal to 0.1 mmol/l), all the compounds stimulated/tended to stimulate the second phase of ADP-induced aggregation and concomitant formation of TXB2. They strongly stimulated TXB2 formation induced by exogenous arachidonic acid even at concentrations causing inhibition of aggregation. Codeine was the most and vadocaine the least potent in this respect. Lidocaine as well as vadocaine (0.1 mmol/l) and codeine (1.0 mmol/l) potentiated the antiaggregatory effect of dibutyryl-cyclic AMP (dB-cAMP) on the ADP-induced aggregation. Lidocaine (0.1 mmol/l) and codeine (1.0 mmol/l) similarly potentiated the effect of the adenylate cyclase stimulator prostaglandin E1 (PGE1).

Topics: Adenosine Diphosphate; Alprostadil; Antitussive Agents; Bucladesine; Codeine; Female; Humans; In Vitro Techniques; Lidocaine; Male; Piperidines; Platelet Aggregation; Thromboxane B2

Topics: Animals; Antitussive Agents; Humans; Piperidines

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound structurally resembling local anaesthetics. Its antitussive profile was studied in several animal models. In guinea-pigs, vadocaine reduced by about 70% the cough episodes induced by sulphur dioxide or ammonia. The effective dose was 2.5 mg/kg p.o., and codeine phosphate was less effective. In cats, vadocaine (3 mg/kg i.v.) inhibited by about 80% for 10 min the cough reflex initiated by mechanical irritation of the trachea. When vadocaine was given via the vertebral artery, it was about 10 times more active than by the intravenous route. Codeine was 3 times as active as vadocaine by both routes. This result indicates an important central component in the antitussive action of vadocaine. In another cat model, 5 mg/kg of vadocaine was somewhat weaker than 1 mg/kg of codeine in inhibiting the cough caused by electrical stimulation of the laryngeal nerve (Domenjoz' method). In dogs, both oral and intravenous doses of 6 mg/kg of vadocaine and 2 mg/kg of codeine were approximately equiactive, inhibiting by 60-80% the cough induced by electrical stimulation of the trachea. Concentrations of vadocaine in serum were around 1 microgram/ml during oral administration. By both routes, the antitussive activity (inhibition of cough by 50% or more) lasted at least 2 h. Vadocaine caused local anaesthesia in the guinea-pig wheal preparation at concentrations of 0.25% and 0.5%, and on the guinea-pig cornea at 0.5%. Duration of anaesthesia was longer than that of lidocaine. Vadocaine did not affect the guinea-pig tracheal strip preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anesthetics, Local; Animals; Antitussive Agents; Cats; Codeine; Cornea; Dogs; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Irritants; Male; Piperidines; Reflex

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound which is effective in several animal models at doses of 2.5-6 mg/kg. It has both central and peripheral local anaesthetizing properties. The present studies were aimed at exploring the specificity of the central antitussive activity of vadocaine. Vadocaine administered in doses of 25 and 50 mg/kg was not found to be effective in any of a series of experiments, although some antinociceptive activity was shown in the hotplate test and in the writhing test at a dose of 75 mg/kg. Some deteriorative activity was noted at a dose of 75 mg/kg in tests measuring motor coordination (rotarod) and spontaneous motility. This high dose of vadocaine did not affect pentobarbital sodium-induced sleeping time nor protect the animal from pentetrazole-induced convulsions. As expected, codeine phosphate was found to be a more potent antinociceptive drug than vadocaine, also enhancing spontaneous motility. Both the control anaesthetics benzonatate and lidocaine proved rather ineffective. Benzonatate (50 mg/kg) did not alter any of the results, whereas lidocaine (50 mg/kg) caused a decrease in the number of writhings. In conclusion, vadocaine can be said to initiate minor deterioration of the central nervous system only at doses about 10 times higher than those which show antitussive activity. Acute lethal doses are still 2 to 5 times higher. The central antitussive action of vadocaine can therefore be considered fairly specific.

Topics: Analgesics; Animals; Anticonvulsants; Antitussive Agents; Barbiturates; Brain; Female; Male; Mice; Motor Activity; Piperidines; Psychomotor Performance; Rats; Rats, Inbred Strains; Reaction Time; Sleep; Time Factors

Intravenous administration of opioids, e.g. morphine and codeine, causes bronchoconstriction in animals and susceptible patients such as asthmatics. Therefore, the effects of two opioid antitussives (codeine and dextromethorphan), two non-opioid antitussives (vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) and clobutinol), and lidocaine on basal lung mechanics and methacholine (MeCh, 6 micrograms/kg i.v.)-induced airway obstruction were investigated in anaesthetized guinea-pigs. Intravenous administration of codeine (10-20 mg/kg) produced a dual response in the airways; initial bronchoconstriction was followed by attenuation of the MeCh-response. Dextromethorphan (10 and 15 mg/kg) caused bronchoconstriction only. Both the opioids affected dynamic lung compliance (CDyn) more than lung resistance (RL). At doses between 1 and 20 mg/kg i.v., vadocaine, clobutinol, and lidocaine had no obvious effect on the airways. Dextromethorphan and vadocaine, both at doses of 10 and 15 mg/kg, and clobutinol (15 and 20 mg/kg) caused irreversible bradycardia and hypotension, whereas codeine (5-20 mg/kg) increased blood pressure, and to a lesser extent heart rate. These results suggest that intravenous administration of an opioid antitussive influences the small peripheral airways more than the large airways, whether the opioid has euphoric analgesic properties or not. In contrast to this, non-opioid antitussives such as vadocaine and clobutinol are without effect. At large doses, all antitussives influence the cardiovascular system considerably.

Topics: Amino Alcohols; Animals; Antitussive Agents; Blood Pressure; Female; Guinea Pigs; Heart Rate; Hemodynamics; Lidocaine; Lung; Methacholine Compounds; Piperidines; Respiratory Function Tests

Urethane-anaesthetized rats and guinea-pigs were used to compare the cardiovascular, electrocardiac and ventilator effects of Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine), lidocaine hydrochloride and codeine phosphate. In rats, vadocaine and lidocaine, only at the largest dose tested (64 mumol/kg i.v.), reduced mean arterial pressure (MAP), heart rate (HR) and ventilation rate (VR). Codeine reduced VR dose-dependently, MAP decreased only at the largest dose of 64 mumol/kg, and HR was not affected at the doses tested. In guinea-pigs, neither vadocaine nor lidocaine had any clear effects on MAP. HR was significantly reduced at the doses of 4 and 16 mumol/kg of vadocaine and 16 and 64 mumol/kg of lidocaine. Vadocaine and lidocaine 16 mumol/kg i.v. caused a significant reduction in VR. Lidocaine 64 mumol/kg did not further reduce VR. The electrocardiac effects included prolongation of P-Q interval both in the vadocaine and lidocaine group. Prolongation of Q-Tc, deepening of Q and S, decrease in R amplitude, and inversion of T waves were seen only in the vadocaine group. To induce changes in the P-Q interval, four times less vadocaine than lidocaine was needed. The acute toxic dose of vadocaine in rats ranged from 64 to 100 mumol/kg i.v.; lidocaine and codeine caused no lethalities in rats at the dose range 1-64 mumol/kg i.v. In guinea-pigs, the lethal dose of 64 mumol/kg i.v. produced AV blocks followed by asystole or ventricular fibrillation. At the dose of 64 mumol/kg i.v. of lidocaine 3 guinea-pigs out of 11 died.

Topics: Anesthesia; Animals; Antitussive Agents; Blood Pressure; Electrocardiography; Guinea Pigs; Heart Rate; Hemodynamics; Injections, Intravenous; Male; Piperidines; Rats; Rats, Inbred Strains; Respiration; Urethane

The effects of two novel antitussive compounds, vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) and N-(2,4-dimethyl-6-methoxyphenyl)-4-(diethylamine)butanamide hydrochloride (OR K-269-HCl) on the suppression of withdrawal signs (hypothermia and weight loss) induced by repeated morphine administration were compared to those of acute morphine and codeine administrations. Moreover, spontaneous and precipitated withdrawal-induced hypothermia, weight loss and behavioural changes from repeated codeine, vadocaine and OR K-269-HCl administrations were studied. Acute administration of morphine clearly reversed the hypothermia and weight loss induced by spontaneous withdrawal from morphine. Codeine was not able to suppress the hypothermia and weight loss induced by morphine withdrawal. Acute injections of vadocaine and OR K-269-HCl did not alter these withdrawal signs either. Moreover, acute administration of codeine tended to prevent the weight loss induced by codeine withdrawal and caused behavioural changes. Spontaneous or precipitated withdrawal from repeated vadocaine or OR K-269-HCl administration caused neither hypothermia, weight loss nor behavioural changes. These results support the view that compounds vadocaine and OR K-269-HCl are free from morphine-like addictive properties.

Topics: Animals; Antitussive Agents; Behavior, Animal; Body Temperature; Body Weight; Codeine; Female; Mice; Morphine; Piperidines; Substance Withdrawal Syndrome; Substance-Related Disorders

The absorption and fate of vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) was studied using both unlabelled compound (rabbits, rats and dogs) and tritium-labelled compound (rats). Although vadocaine was orally absorbed in dogs, no oral absorption was found in the rabbits. The elimination of the intravenously given compound was very fast (t1/2 only about 0.6 h in the rabbits). Most of the drug was metabolized both in rats and dogs. In rats, less than 0.2% of the compound was found intact in 24-h urine. In dogs, the 24-h recovery was 1-5% of the dose. After intravenous injection to rats, 43% of the radioactivity given as tritium-labelled vadocaine was recovered in urine and 19% in faeces. After oral dosing, 37% was recovered in urine and 31% in faeces. Hence, the total 7-day recovery of the radioactivity given as tritium-labelled vadocaine was 62-68% of the dose.

Topics: Administration, Oral; Animals; Antitussive Agents; Biological Availability; Dogs; Female; Half-Life; Male; Piperidines; Rabbits; Rats

The tissue distribution of tritium-labelled vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) was studied in female mice by whole-body autoradiography at different times (15 min - 24 h) after intravenous injection. Radioactivity disappeared rapidly from blood and was fairly selectively localized in the liver, the gall bladder and the intestinal contents. Vadocaine is evidently metabolized in the liver and a remarkable part of the drug and its metabolites are excreted into the bile. Accumulation of radioactivity in the kidneys shows that also renal elimination is important. A considerable accumulation into the lungs supports the peripheral anaesthetizing mechanism in the antitussive action of vadocaine. No detectable penetration into the brain was seen. At 24 h, only traces of the radioactivity could be detected in the liver and lungs.

Topics: Animals; Antitussive Agents; Autoradiography; Chromatography, Thin Layer; Female; Mice; Piperidines; Tissue Distribution

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is an anilide derivative with antitussive and local anaesthetic properties. The pharmacokinetics of this new compound were studied in two Phase I clinical trials during safety evaluation. 6 (Part I) and 8 (Part II) healthy male volunteers participated in these studies. The pharmacokinetics were studied after single oral doses of 5, 10, 15, 20, 30 and 50 mg (Part I) and 100, 200, 300, 400 and 500 mg (Part II) of vadocaine in aqueous solution. Vadocaine was rapidly absorbed at each dose level. The AUCo----infinity value and 24-h urinary recovery of intact compound increased linearly as functions of the dose. The elimination half-life varied from 2.2 +/- 0.2 h to 3.7 +/- 1.6 h in a dose range from 5 to 50 mg, and from 2.7 +/- 0.3 h to 4.0 +/- 1.0 h in a dose range from 100 to 500 mg. The peak concentration of vadocaine after the highest dose was 2317.3 +/- 31.5 ng/ml at 1 h. When higher doses were used renal clearance did not change, although total body clearance seemed to diminish. Over 90% of vadocaine is metabolized, and the metabolic pathways may become saturated at a dose of 400 mg.

Topics: Adult; Antitussive Agents; Half-Life; Humans; Male; Piperidines; Reference Values

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is an anilide derivative with antitussive and local anaesthetic action. The safety of this new compound was studied in 8 healthy male volunteers in a Phase I clinical trial. Vadocaine was administered orally as a single dose of 50, 100, 200, 300, 400 and 500 mg. At the two highest dose levels used, 400 and 500 mg, vadocaine induced side-effects originating in the central nervous system; ECG analysis revealed small prolongations in the P-Q interval and QRS complex after 400 and 500 mg. At a dose of 500 mg the P-Q interval was prolonged by a maximum of 38% (184 ms at 0.5 h; 134 ms pre-dose). The compound had no effect on blood and urinary parameters measured for safety evaluation. On the basis of these results, a 300 mg dose of vadocaine appears to be safe in man in all respects. This dose level is 10 times the therapeutic dose (30 mg). Vadocaine is sufficiently safe for future clinical trials in patients with cough.

Topics: Adult; Antitussive Agents; Blood Pressure; Electrocardiography; Heart Rate; Humans; Male; Piperidines

OR-K-242-HCl is an antitussive compound. Because it resembles lidocaine structurally, one of its target organs may be the heart. In anaesthetized guinea pigs OR-K-242-HCl depressed function of the heart. The aim of the present study was to test effects of OR-K-242-HCl on the conduction velocity of the heart in the conscious beagle dog. OR-K-242-HCl was administered 6 mg/kg and 12 mg/kg i.v. and 6 mg/kg, 12 mg/kg, 24 mg/kg, and 36 mg/kg orally. The doses for lidocaine (reference substance) were 6 mg/kg, and 12 mg/kg i.v. and 6 mg/kg, 12 mg/kg, and 24 mg/kg orally. Five consecutive noisefree cycles of ECG were used before and every 15 min up to three hours after the drug administrations. For each cycle PQ-, QTC-, RR-interval, as well as, QRS-complex and heart rate were calculated. Both OR-K-242-HCl and lidocaine prolonged the conduction velocity in the atria and ventricles. After i.v. and oral administration OR-K-242-HCl induced stronger and more uniform responses than lidocaine. The oral drug administrations produced more sustained responses than the intravenous injections for both compounds.

Topics: Administration, Oral; Animals; Dogs; Electrocardiography; Female; Heart Conduction System; Heart Rate; Injections, Intravenous; Lidocaine; Male; Piperidines