piperidines and pitofenone

To study the efficacy and safety of a parenteral formulation of 'Manyana' (a combination of diclofenac + pitofenone + fenpiverinium) in ureteric, biliary and intestinal colic, an open labelled study was conducted at two centres. A total of 206 patients were enrolled and evaluated for decrease in pain with time on a visual analogue scale. A statistically significant difference was observed in pain within 30 minutes of drug administration and the pain relief lasted for as long as 24 hours post dosing. The study shows definite synergism between the antispasmodics pitofenone and fenpiverinium with the NSAID-diclofenac, reducing the prostaglandin levels and also the spasm related to colic.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Benzophenones; Biliary Tract Diseases; Colic; Diclofenac; Drug Combinations; Female; Humans; Injections, Intramuscular; Intestinal Diseases; Male; Middle Aged; Parasympatholytics; Piperidines; Ureteral Diseases

A single-blind, randomized clinical trial was carried out to compare the analgesic effectiveness in patients with renal colic of single intramuscular doses of diclofenac sodium (75 mg) versus a dipyrone (1 g)/spasmolytics combination, and diclofenac sodium (75 mg) versus pethidine (75 mg). The first study involved three centres, the second study one centre. In total, 107 patients were treated with diclofenac sodium, 85 with dipyrone/spasmolytics, and 25 with pethidine. Assessments were made during the first hour after drug administration of the degree of pain relief, the severity of pain using a visual analogue scale, and the duration of analgesia. A global assessment of treatment efficacy was made by the participating physicians at the end of the study period. Patients treated with diclofenac sodium showed an earlier onset of analgesia and a higher incidence of total pain relief compared to those treated with dipyrone/spasmolytics or pethidine. Although the mean duration of analgesia was only slightly greater in the diclofenac sodium group than in the dipyrone/spasmolytics group, a significantly longer effect was seen when diclofenac sodium was compared with pethidine (p less than 0.01). Pain severity assessments revealed that diclofenac sodium caused a significantly greater improvement in pain after 60 minutes compared to dipyrone/spasmolytics (p less than 0.05) and after 30 minutes compared to pethidine (p less than 0.05). Global efficacy assessments by the physician rated diclofenac sodium as significantly superior to dipyrone/spasmolytics (p less than 0.01) and pethidine (p less than 0.001). Moreover, diclofenac sodium was better tolerated than either of the comparative treatments. The results indicate that intramuscular diclofenac sodium is a useful alternative to the drugs commonly used in India in the treatment of renal colic.

Topics: Adolescent; Adult; Aged; Benzophenones; Colic; Diclofenac; Dipyrone; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Kidney Calculi; Male; Meperidine; Middle Aged; Pain Measurement; Parasympatholytics; Piperidines; Single-Blind Method

A new HPLC method for separation and determination of impurities in paracetamol, codeine phosphate hemihydrate and pitophenone hydrochloride in the presence of fenpiverinium bromide in combined suppository dosage form was developed and validated. The separation of paracetamol and its impurities 4-aminophenol, 4-nitrophenol, 4-chloracetanilid; codeine and its impurities methylcodeine, morphine, codeine dimer and 10-hydroxycodeine; pitophenone and its impurities 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl] benzoic acid, 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl]benzoic acid 2-(1-piperidinyl)-ethyl ester, methyl ester of 2-(4-hydroxybenzoyl) benzoic acid and fenpiverinium was achieved by using ion-pair reversed phase liquid chromatography with UV detection. Validation parameters such as the precision, accuracy, linearity, limit of detection (LOD), limit of quantification (LOQ) and robustness were verified for all the mentioned impurities of codeine phosphate hemihydrate and 4-aminophenol and 2-[4-[2-(1-piperidinyl)ethoxy]benzoyl] benzoic acid as the main degradation products of paracetamol and pitophenone hydrochloride, respectively. The described method was found to be useful for analysis of the stability samples and therefore suitable for routine purity testing of the drug product.

Topics: Acetaminophen; Benzophenones; Chromatography, Reverse-Phase; Codeine; Drug Contamination; Molecular Structure; Piperidines; Suppositories

Palladium-catalyzed chemoselective decarboxylative cross coupling of benzoic acids with α-oxocarboxylic acids was realized via an arene sp(2) C-H functionalization process. This work represents the first example of transition-metal-catalyzed cross-coupling reactions with two acids acting in different roles. The synthetic utility of this method was confirmed by the synthesis of pitofenone, an antispasmodic used in the combined drug Spasmalgon.

Topics: Acylation; Benzilates; Benzoates; Benzophenones; Carboxylic Acids; Catalysis; Decarboxylation; Molecular Structure; Palladium; Piperidines

Biliary, ureteric and intestinal colic are extremely common clinical conditions associated with smooth muscle spasm. In the present study, antispasmodic activity was carried out against acetylcholine (10-640 ng/ml)-induced contractions on guinea pig ileum. Acetylcholine (10-640 ng/ml) induced concentration-dependent contraction of smooth muscle. Diclofenac, in varying concentration (9.4 x 10(-5) mol/l and 14.1 x 10(-5) mol/l) shifted the concentration response curve of acetylcholine to the right without suppressing the maximal response. However, in higher concentration diclofenac (18.9 x 10(-5) mol/l) blocked the response in an unsurmountable fashion. Further, analgin (11.09 x 10(-5), 16.63 x 10(-5) and 22.18 x 10(-5) mol/l) in equimolar concentrations did not alter the concentration response curve of acetylcholine, but in higher concentration analgin (44.36 x 10(-5) mol/l) also blocked the response in an unsurmountable fashion. Pitofenone (2.5 x 10(-6) mol/l) also, shifted the concentration response curve of acetylcholine to right in a parallel fashion with no change in maximal response. The present study confirms the potent antispasmodic activity of diclofenac-pitofenone combination in comparison to analgin-pitofenone in molar equivalent concentration (in comparison to diclofenac) against acetylcholine-induced contractions of guinea pig ileum.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzophenones; Cholinergic Agents; Diclofenac; Dipyrone; Dose-Response Relationship, Drug; Female; Guinea Pigs; Ileum; Male; Muscle Contraction; Muscle, Smooth; Parasympatholytics; Piperidines; Spasm

Ester analogues of methyl-2-(4-(2-piperidinoethoxy)benzoyl)-benzoate hydrochloride (pitofenone) (2) were prepared with an aim to find a more potent and metabolically stable antispasmodic compound. The compounds were evaluated for their in vitro and in vivo antispasmodic activity, and stability to in vitro enzymatic hydrolysis. Of the compounds synthesised, HL 752 (21) showed the most potent and long-lasting antispasmodic activity and was selected as the candidate for clinical development.

Topics: Animals; Benzoates; Benzophenones; Dogs; Drug Stability; Esters; Female; Guinea Pigs; Hydrolysis; Ileum; In Vitro Techniques; Male; Parasympatholytics; Piperidines

Pitofenone, a spasmolytic compound, inhibited the acetylcholinesterase activity from bovine erythrocytes and from electric eel. It is a potent inhibitor of this enzyme from the two sources, with Ki values of 36 and 45 microM, respectively. Of the five compounds structurally related to pitofenone, only those containing a piperidine moiety show acetylcholinesterase inhibition. All these inhibitions are reversible, linear, and noncompetitive in nature. A qualitative correlation between the anticholinesterase and the corresponding antimuscarinic activity for some of these compounds was apparent. Good separation of these two effects would be a desirable feature for newer muscarinic antagonists.

Topics: Acetylcholinesterase; Animals; Benzophenones; Cattle; Cholinesterase Inhibitors; Electrophorus; Erythrocytes; Molecular Structure; Parasympatholytics; Piperidines; Structure-Activity Relationship

The electrical activity of the sphincter of Oddi and gastro-intestinal tract had been recorded on 21 negative atropineesterase conscious rabbits by means of chronically implanted electrodes located in the digestive wall. An analysis of the action of different spasmolytic and analgesic drugs was realized. Electromyograms of the sphincter of Oddi presented (a) isolated or in series spike potentials occurring independently of electrical activities of the duodenum (b) recurring spike potentials correlated with intestine spikes. The independent activity of the sphincter of Oddi was not controlled by the cholinergic system, contrary to the intestine-dependent activity (effect of the fempiverinium, atropine like drug). The pitofenone had inhibited the spike potentials of both the sphincter and intestine because its papaverinic effect. The noramidopyrine, analgesic drug without morphine-like effects, had induced activation and inhibition at low and high posology respectively.

Topics: Ampulla of Vater; Animals; Atropine Derivatives; Benzophenones; Dipyrone; Drug Combinations; Drug Interactions; Duodenum; Electromyography; Female; Gastrointestinal Motility; Male; Muscle, Smooth; Parasympatholytics; Piperidines; Pyrazolones; Rabbits; Sphincter of Oddi

The effects of the constituents of Baralgin ( metamizole , fenpiverinium , and pitofenone ) on mechanical activity were studied in isolated human preparations of the upper urinary tract. Metamizole in concentrations up to 10(-3) mol/l did influence neither spontaneous phasic activity nor activation by high external potassium, norepinephrine, or acetylcholine. Fenpiverinium blocked the increase in frequency of phasic-rhythmic contractions and the tonic tension development induced by acetylcholine. Fenpiverinium did influence neither spontaneous phasic activity nor activation by high potassium or norepinephrine. Pitofenone (10(-3)mol/l) antagonized completely spontaneous phasic-rhythmic as well as norepinephrine- or acetylcholine-induced phasic activity. The tonic activation induced by norepinephrine and acetylcholine was nearly completely inhibited. Pitofenone (10(-6) to 10(-3) mol/l) antagonized the high potassium-induced activation in a concentration-dependent way. The EC50 of pitofenone amounted to 2 X 10(-4) mol/l. Uptake measurements of 14C- pitofenone (2 X 10(-4) mol/l) in isolated ureteral segments showed the drug to be accumulated in the ureteral tissue; a tissue/medium ratio of about 3 was found at an exposure time of 60 min. The accumulation of the drug was reversible after washing in drug-free solution, indicated by the loss of radioactivity increasing with longer washing times. The results show that pitofenone has a direct relaxant effect on smooth muscle of the upper urinary tract, whereas fenpiverinium has exclusively anticholinergic properties. Metamizole had no direct effect on smooth muscle activity, and its clinical effects may be rather due to its analgesic action.

Topics: Adult; Aged; Aminopyrine; Analgesics; Benzophenones; Carbon Radioisotopes; Dipyrone; Drug Combinations; Humans; Middle Aged; Muscle Contraction; Parasympatholytics; Piperidines; Urinary Tract