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1.
Arzneimittelforschung ; 38(8): 1139-41, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3196406

ABSTRACT

Enantiomers of phenylpiperazinepropane-1,2-diol derivatives were synthesized with the purpose to obtain a better antitussive activity/sedative effect ratio. (S)-isomers showed better pharmacological profiles than (R)-isomers and corresponding racemates. Among the (S)-isomers, the unsubstituted compound, levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), has the most favourable antitussive activity/sedative effect ratio and was selected for pharmaco-toxicological evaluation.


Subject(s)
Antitussive Agents/chemical synthesis , Propylene Glycols/chemical synthesis , Animals , Antitussive Agents/adverse effects , Chemical Phenomena , Chemistry , Guinea Pigs , Isomerism , Male , Mice , Propylene Glycols/adverse effects , Sleep/drug effects
2.
Arzneimittelforschung ; 38(8): 1144-50, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3196408

ABSTRACT

The general pharmacological profile of levodropropizine (S(-)3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), a new antitussive drug, was compared with that of dropropizine racemate. Levodropropizine had weaker central sedative effects than the racemate and it did not induce physical dependence in rats. When given intravenously or intraperitoneally, levodropropizine did not exert any significant effects on the cardiovascular and respiratory systems. Receptor binding data excluded interaction with beta-adrenergic, muscarinic and opiate receptors. On the contrary, levodropropizine has affinity for H1-histaminic and alpha-adrenergic receptors. The affinity was also confirmed with isolated organ preparations. On the basis of this study, levodropropizine appears to have a better tolerability index than the racemate.


Subject(s)
Antitussive Agents/pharmacology , Propylene Glycols/pharmacology , Airway Resistance/drug effects , Animals , Antitussive Agents/administration & dosage , Behavior, Animal/drug effects , Blood Pressure/drug effects , Brain/drug effects , Cats , Digestive System/drug effects , Dogs , Electrocardiography , Electroencephalography , Female , Guinea Pigs , Heart/drug effects , Heart Rate/drug effects , Male , Mice , Nervous System/drug effects , Propylene Glycols/administration & dosage , Rabbits , Random Allocation , Rats , Respiration/drug effects , Sleep/drug effects
3.
Arzneimittelforschung ; 38(8): 1141-3, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3196407

ABSTRACT

The antitussive activity of levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), was evaluated in anaesthetized guinea-pigs and rabbits and in unanaesthetized guinea-pigs. Levodropropizine was shown to have good antitussive activity. Intravenously, it was 1/10 to 1/20 as active as codeine and comparable to dropropizine, from which it is derived, on mechanically and electrically induced coughing in rabbits and guinea-pigs. After oral administration to the guinea-pig the antitussive activity of levodropropizine was comparable with those of both dropropizine and codeine against coughing induced by irritant aerosols.


Subject(s)
Antitussive Agents/therapeutic use , Cough/drug therapy , Propylene Glycols/therapeutic use , Administration, Oral , Animals , Antitussive Agents/administration & dosage , Codeine/administration & dosage , Codeine/therapeutic use , Dose-Response Relationship, Drug , Electric Stimulation , Guinea Pigs , Injections, Intravenous , Male , Piperazines/administration & dosage , Piperazines/therapeutic use , Propylene Glycols/administration & dosage , Rabbits
4.
Arzneimittelforschung ; 38(8): 1150-5, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3196409

ABSTRACT

Levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526), a new antitussive drug, was submitted to toxicological studies. Acute toxicity, both oral and intraperitoneal, in rats and mice and oral toxicity in guinea-pigs was low. Subchronic and chronic toxicity studies were performed in rats and dogs. For both species the maximum tolerated oral dosage was 24 mg/kg/d. Dose-related clinical signs were observed, consisting mainly in salivation in rats and sedation, peripheral vasodilatation and increased heart rate in dogs. Liver toxicity was found in both species at higher dosages. In rats, food intake and body weight gain were reduced. There were no effects on fertility, nor any teratogenic effects. Foetal and peri- and post-natal toxic effects were observed in rats only at 150 mg/kg/d. A set of mutagenicity tests yielded negative results. Therefore, levodropropizine is safe up to dosages 10 times greater than the one intended for clinical use and only slight adverse reactions were recorded at a dosage 30 times greater.


Subject(s)
Antitussive Agents/toxicity , Propylene Glycols/toxicity , Abnormalities, Drug-Induced , Animals , Body Weight/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Tolerance , Eating/drug effects , Female , Fertility/drug effects , Fetal Death/chemically induced , Guinea Pigs , Liver/drug effects , Male , Mice , Mutagenicity Tests , Pregnancy , Rabbits , Rats , Rats, Inbred Strains
5.
Drugs Exp Clin Res ; 13(5): 293-6, 1987.
Article in English | MEDLINE | ID: mdl-3119304

ABSTRACT

Ketoprofen lysine (KL) at a dose of 160 mg b.i.d. has been shown to have favourable anti-inflammatory and analgesic properties in a large number of patients. In the present paper investigators describe their experience with a new therapeutic schedule of KL, 320 mg given once a day to patients with various rheumatic disorders. With this new schedule there was satisfactory clinical improvement of most of the clinical parameters and good tolerability, with a low incidence of gastric troubles. The favourable clinical effects and the patients' good compliance with once-a-day KL make it a useful drug for successful treatment of rheumatic disorders.


Subject(s)
Ketoprofen/therapeutic use , Lysine/analogs & derivatives , Phenylpropionates/therapeutic use , Rheumatic Diseases/drug therapy , Drug Administration Schedule , Drug Tolerance , Female , Humans , Ketoprofen/administration & dosage , Ketoprofen/analogs & derivatives , Ketoprofen/pharmacology , Lysine/administration & dosage , Lysine/pharmacology , Lysine/therapeutic use , Male , Middle Aged
6.
Int J Clin Pharmacol Res ; 7(4): 259-63, 1987.
Article in English | MEDLINE | ID: mdl-3474214

ABSTRACT

Suprofen is a new potent analgesic with antiinflammatory properties that appears to inhibit prostaglandin synthetase in a tissue-selective manner, having relatively little effect on the kidneys of experimental animals. The effects were studied of one week of treatment of rheumatoid arthritis patients with suprofen or ibuprofen on Na+ and K+ excretion, creatinine clearance, urinary enzymes that are markers for tubular damage, and urinary prostaglandins such as PGE2 and 6-keto PGF1 alpha (a stable metabolite of prostacyclin). Neither compound caused changes in renal function related to the week of treatment, but significant decreases in prostaglandins were observed: this change was fully reversible after discontinuation of the drug.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Kidney/drug effects , Phenylpropionates/adverse effects , Suprofen/adverse effects , 6-Ketoprostaglandin F1 alpha/urine , Aged , Aged, 80 and over , Arthritis, Rheumatoid/urine , Dinoprost , Double-Blind Method , Female , Humans , Ibuprofen/adverse effects , Male , Middle Aged , Prostaglandins F/urine , Random Allocation , Suprofen/therapeutic use
7.
Pharmacol Res Commun ; 17(11): 1017-26, 1985 Nov.
Article in English | MEDLINE | ID: mdl-3937162

ABSTRACT

The effects of tripotassium dicitrato bismuthate (TDB) on gastric acid, pepsin and mucoprotein secretion in rats and on hydrochloric-peptic secretion and plasma gastrin levels in dogs were investigated. In Shay rats, TDB did not affect acid secretion but significantly lowered pepsin concentration and increased the amount of bound mucoproteins. In addition, gastric mucosal lesions were significantly prevented by the drug. In dogs, chronically fitted with both gastric fistulae and Heidenhain pouches, acid secretion and plasma gastrin levels stimulated by a meat meal were unaffected by TDB, while pepsin concentration and pepsin output were significantly decreased. On the basis of these results, the antiulcer activity of TDB appears to be ascribed to the protection of the gastric mucosa through an increase in mucoprotein synthesis and a decrease of pepsin activity.


Subject(s)
Anti-Ulcer Agents/pharmacology , Bismuth/pharmacology , Gastric Mucosa/metabolism , Organometallic Compounds , Animals , Dogs , Female , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastrins/blood , Mucoproteins/metabolism , Pepsin A/metabolism , Rats , Rats, Inbred Strains , Species Specificity , Stomach Ulcer/physiopathology , Time Factors
8.
Arzneimittelforschung ; 34(1): 30-1, 1984.
Article in English | MEDLINE | ID: mdl-6367754

ABSTRACT

Tri-potassium di-citrato bismuthate given intragastrically to rats 60 min before administration of necrotizing agents such as 85% ethanol, 0.2 N sodium hydroxide or acidified indomethacin, reduced the formation of mucosal lesions dose-dependently. Prostaglandin I2 (PGI2)-like material, determined by bioassay, was higher in the gastric mucosa of animals treated with bismuth subcitrate complex than in control animals.


Subject(s)
Anti-Ulcer Agents , Bismuth/pharmacology , Gastric Mucosa/drug effects , Organometallic Compounds , Animals , Epoprostenol/metabolism , Ethanol/pharmacology , Gastric Mucosa/metabolism , Indomethacin/pharmacology , Male , Rats , Rats, Inbred Strains , Sodium Hydroxide/pharmacology , Stomach Ulcer/chemically induced
10.
Arzneimittelforschung ; 33(10): 1497-500, 1983.
Article in English | MEDLINE | ID: mdl-6418181

ABSTRACT

The lysine salt of 2-(3-benzoylphenyl)propionic acid (ketoprofen lysine) was administered at the dose of 160 mg either in two conventional capsules (Artrosilene) or in one slow-release capsule in a randomized sequence to 8 volunteers. Serum and urine concentrations of ketoprofen were determined by HPLC. The slow-release preparation had a bioavailability greater than 90% as compared with the conventional capsule and produced lower and longer lasting ketoprofen serum levels. These results suggest that two daily administrations of the new formulation should be suitable for therapeutic use.


Subject(s)
Ketoprofen/metabolism , Lysine/analogs & derivatives , Phenylpropionates/metabolism , Adult , Biological Availability , Delayed-Action Preparations , Humans , Ketoprofen/administration & dosage , Ketoprofen/analogs & derivatives , Ketoprofen/blood , Ketoprofen/urine , Kinetics , Lysine/administration & dosage , Lysine/metabolism , Male , Middle Aged
11.
Neurosci Lett ; 14(1): 31-6, 1979 Sep.
Article in English | MEDLINE | ID: mdl-231228

ABSTRACT

The effects of bromocriptine and lisuride on cyclic AMP concentrations in homogenates and in intact slices of rat neostriatum were investigated. Significant increases in cyclic AMP concentration were found after a 10-min exposure to bromocriptine and lisuride in striatal intact slices. On the contrary, as previously found, the two dopaminergic ergot derivatives did not stimulate dopamine-senstiive adenylate cyclase present in striatal homogenates. The stimulatory effects observed only in intact tissues were blocked by the specific dopamine receptor blocking agent fluphenazine. It is tempting to conclude that dopaminergic ergot derivatives have a site of action different from that stimulated by classic dopamine agonists in tissue homogenates.


Subject(s)
Bromocriptine/pharmacology , Corpus Striatum/drug effects , Cyclic AMP/metabolism , Ergolines/pharmacology , Lisuride/pharmacology , Animals , Bromocriptine/antagonists & inhibitors , Corpus Striatum/metabolism , Dopamine Antagonists , Fluphenazine/pharmacology , In Vitro Techniques , Lisuride/antagonists & inhibitors , Male , Rats
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