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PubMed1985

5-HT-uptake inhibition potentiates antinociception induced by morphine, pethidine, methadone and ketobemidone in rats.

The effect of the specific 5-HT-uptake inhibitor citalopram on the antinociception induced by morphine, pethidine, methadone and ketobemidone was examined in rats by means of the hot plate test. Further the 5-HT-uptake-inhibiting potency of these opioid-receptor stimulants was examined in vitro in rat brain synaptosomes. In doses devoid of antinociceptive activity, citalopram in a dose-dependent manner potentiated the antinociception induced by the four opioid analgesics. The potentiation of the ketobemidone-induced antinociception was not influenced by the spasmolytic agent A 29 (N,N-dimethyl-3,3-diphenyl-1-methylallylamine) which together with ketobemidone constitutes the active substances in Ketogan. The 5-HT-uptake-inhibiting potencies of the opioid receptor stimulants were from 21 to more than 56000 times lower than that of citalopram, the order of potency being methadone greater than pethidine greater than ketobemidone greater than morphine. The results support the suggested role of 5-HT in morphine-induced antinociception and indicate a similar role in the antinociceptive effect induced by other opioid-receptor stimulants.

Analgesics↗

PubMed1998

Establishment and characterization of two cell lines from N-methyl-N-nitrosourea-induced mouse glandular stomach carcinomas.

We previously reported the induction with N-methyl-N-nitrosourea (MNU) of mouse glandular stomach carcinomas showing a gastric phenotype but variation in histologic appearance, as with human gastric carcinomas. In the present study, we established two cell lines, designated MGT-40 and MGT-93, from MNU-induced mouse glandular stomach carcinomas. These cell lines are keratin-positive and grow as epithelial monolayers in culture, requiring transforming growth factor alpha, epidermal growth factor or insulin/transferrin for optimal growth in addition to 10% fetal bovine serum. Retention of the differentiated phenotype for gastric surface mucous cells has been confirmed by cathepsin E immunohistochemistry and reverse transcriptase-polymerase chain reaction for mouse spasmolytic polypeptide. Neither transplantability in nude mice nor colony formation on soft agar was observed, except in one subline. Chromosome analysis revealed aneuploidy with modal chromosome numbers ranging from 58 to 78 and no specific structural abnormalities. This is the first report of cell lines derived from mouse glandular stomach carcinomas. They should prove useful for studies of the mechanisms of regulation of growth and differentiation.

Adenocarcinoma↗

PubMed2004

Otilonium bromide inhibits muscle contractions via L-type calcium channels in the rat colon.

The aim of this study is to evaluate in vitro the effect of otilonium bromide (OB) on the mechanical and electrical activities of the rat colonic smooth muscle using muscle bath, microelectrodes and patch-clamp techniques. Otilonium bromide dose dependently inhibited the spontaneous activity (logIC(50) +/- SE: -5.31 +/- 0.05). This effect was not modified by TTX (10(-6) mol L(-1)). Cyclic depolarizations were abolished by OB (10(-4) mol L(-1)). Electrical field stimulation induced inhibitory junction potentials (IJPs) followed by a depolarization with superimposed spikes causing a contraction. In the presence of OB (10(-4) mol L(-1)) IJPs were recorded, but spikes and contractions were abolished. Otilonium bromide (3 x 10(-6) mol L(-1)) inhibited inward current obtained in isolated cells (amphotericin perforated patch technique). The otilonium-sensitive current amplitude was maximal (75pA) around 0 mV. The effect of different doses of OB was tested by depolarizing cells from -70 mV to 0 mV. OB dose dependently inhibited the inward current with an EC(50) of 885 nmol L(-1). Abolishment of the otilonium-sensitive current by 3 x 10(-6) mol L(-1) nifedipine confirmed that it was an L-type Ca(2+) current. Our results show that OB inhibits the spontaneous and triggered muscular contractions. This effect is produced by the inhibition of muscular action potentials carried by L-type calcium current, confirming the spasmolytic properties of OB.

Action Potentials↗

PubMed1976

Comparison of the effect of anileridine and pethidine on the intracholedochal pressure during constant fluid perfusion.

Anileridine and pethidine have a spasmolytic action on animal intestine. Pethidine is known to have a spasmogenic effect at the choledocho-duodenal junction of man, but there is no study of the effect of anileridine on the biliary tract. In the present study the effects of anileridine and pethidine on the intracholedochal pressure during constant fluid perfusion in man were compared. The maximal elevation of the choledochal passage pressure was significantly greater after anileridine than after pethidine. However, the difference between anileridine and pethidine seemed to be less than that reported previously between morphine and pethidine. The effect of anileridine was of shorter duration than of pethidine. Anileridine and pethidine are not ideal analgesics when the normal activity of the biliary ductal system has to be maintained in pain or during cholangiography.

Adult↗

PubMed1982

Single-dose kinetics and bioavailability of ketobemidone.

The single-dose kinetics and the oral and rectal bioavailability of ketobemidone have been studied in patients after surgery. Plasma concentrations were determined following intravenous administration of Ketogin 2 ml, containing ketobemidone chloride 10 mg and the spasmolytic substance N, N-dimethyl-3, 3-diphenyl-l-methylallylamine chloride 50 mg and following oral or rectal administration of Ketogin. Ketobemidone was analyzed by gas chromatography-mass spectrometry using a deuterated internal standard. Ketobemidone disappeared rapidly from plasma after i.v. or oral administration, yielding a mean plasma half-life between 2.25 and 2.45 h. After rectal administration the plasma half-life was somewhat prolonged (3.27 h), probably due to late absorption., The bioavailability of oral ketobemidone was 34% +/- 16% s.d. (n = 6), and when given rectally 44% +/- 9% s.d. (n = 5). In contrast to earlier investigations performed without plasma analysis, ketobemidone was found to have a rapid elimination when given intravenously, orally or rectally.

Administration, Oral↗

PubMed1982

Multiple dose kinetics of ketobemidone in surgical patients.

Twelve patients scheduled for major abdominal surgery were selected for a study of the kinetics of ketobemidone during the day of surgery and in a follow-up study 3-5 days after surgery. In six patients ketobemidone was administered as ketobemidone plain and in the other six, it was given as Ketogin, a combination formula containing a spasmolytic substance in addition to ketobemidone. Plasma samples were collected for approximately 24 h following induction of anesthesia, during which time multiple doses of ketobemidone were administered. A single-dose study was performed 3-5 days after surgery using the same drug. No significant differences were found between the two formulations of ketobemidone. Plasma clearance did not change significantly between the two periods of study, being 18.0 +/- 4.4 ml . kg-1 . min-1 peroperatively and 21.7 +/- 7.6 ml . kg-1 . min-1 postoperatively. Peroperative Vd area was significantly larger than post-operative Vd area, 5.84 +/- 2.62 l . kg-1 and 3.63 +/- 0.38 l . kg-1, respectively. T1/2 terminal decreased from 3.84 +/- 1.6 h peroperatively to 2.06 +/- 0.44 h postoperatively.

Analgesics, Opioid↗

PubMed1986

Premedication for day-case surgery: double-blind comparison of ketobemidone + dimethylaminodiphenylbuten (A-29) and morphine + scopolamine.

A double-blind comparison of the effect of Ketogan (ketobemidone and A-29, an anticholinergic and spasmolytic agent) and morphine + scopolamine as premedication was performed in 113 women admitted for abortion and in 114 women admitted for gynaecological dilatation and curettage. Anaesthesia was thiopentone and nitrous oxide and oxygen, occasionally supplemented with enflurane. It was found that 1 ml morphine + scopolamine (10 mg + 0.4 mg) was more sedative than 1 ml ketogan (ketobemidone 5 mg + A-29 25 mg). After ketogan there was less nausea and dryness of the mouth before induction of anaesthesia than after morphine + scopolamine. Ketogan had the same tranquillizing effect but less hypnotic effect preoperatively than morphine + scopolamine. During the 3-h postoperative observation period the patients premedicated with ketogan woke up significantly sooner and had more pain than those given morphine + scopolamine. More patients required postoperative antiemetics in the ketogan-premedicated group than in the morphine + scopolamine-premedicated group.

Abortion, Legal↗

PubMed1995

Effects of halothane and isoflurane on antigen- and leukotriene-D4-induced constriction of guinea pig trachea.

We investigated the mechanism of the action of volatile anesthetics on the airway smooth muscle constricted by an antigen and leukotriene-D4 (LTD4). Excised tracheal rings from ovalbumin-sensitized guinea pigs were suspended in eight tissue baths. Halothane or isoflurane was aerated into four tissue baths, while the remaining four served as time controls. To assess the antispasmogenic activity of halothane and isoflurane, concentration-response curves for antigen and LTD, were constructed exposed to anesthetics and compared to controls. The spasmolytic activity of halothane and isoflurane was measured in the tracheal rings constricted by a single antigen challenge or by EC50 of LTD. Both halothane and isoflurane produced significant rightward shifts of ovalbumin and LTD, concentration-response curve with corresponding increases in the EC50 values. Halothane increased the EC50 value for LTD, from 5.38 +/- 0.43 x 10-9 M to 1.2 +/- 0.18 x 10-8 M, and for ovalbumin from 1.2 +/- 0.06 x 10-4 mg/ml to 3.03 +/- 0.28 x 10-4 mg/ml. Isoflurane increased the EC50 value for LTD, from 5.17 +/- 0.64 x 10-9 M to 8.98 +/- 1.01 x 10-9 M, and for ovalbumin from 1.21 +/- 0.09 x 10-4 mg/ml to 2.61 +/- 0.19 x 10-4 mg/ml. Furthermore, halothane and isoflurane significantly reduced the magnitude of the antigen-and LTD4-induced constriction. In 30 min intervals, 1% and 2% halothane reduced the magnitude of the ovalbumin-induced constriction by 32% and 50%, respectively, while isoflurane (2% and 4%) caused relaxation of 16% and 35%, respectively. The magnitude of LTD4-induced constriction was reduced by 17% and 24%, with 1% and 2% halothane, respectively. Isoflurane (2% and 4%) reduced this constriction by 25% and 25% respectively. In conclusion, halothane and isoflurane attenuate and prevent the constrictive response of airway smooth muscle to allergen and LTD. A direct, nonspecific dilating effect is suggested as the mechanism responsible for the observed effects.

Anesthetics, Inhalation↗

PubMedDate not supplied

Recent progress in pharmacological therapy of male subfertility--a review.

A review of pharmacological therapy in male infertility shows that apart from specific therapy with gonadotropins in hypogonadotropic hypogonadism, treatment in normogonadotropic idiopathic oligozoospermia and asthenozoospermia is still empirical and often unsuccessful. Modern therapy is based on three pharmacological groups of compounds: gonadotropins, androgens and kininogenases, the latter releasing pharmacologic active kinin peptides from kininogen. In addition, antiestrogens and gonadotropin-releasing hormones seem to be promising agents for the near future. The use of antibiotics is of great importance in the therapy of male genital tract infections which often to a reduced fertility. Several other drugs (amino acids, psychopharmaceuticals, spasmolytic agents, trijodothyronine, glucocorticoids, vitamins) seem to be suitable in individuals cases, but in greater group of patients these agents do not improve fertility. Using the mentioned hormonal and nonhormonal pharmacological agents considerable progress can be demonstrated in the therapy of male infertility. However, before initiating any therapy it is important to exclude patients whose cause of infertility is untreatable or those who require surgery. Finally, it is hoped that additional progress in treatment of male infertility will soon be made possible by further improvement of fundamental research in andrology. Especially important is the development of better criteria for selection of patients for any form of therapy in order to make more specific and less empirical approaches for treatment of male infertility available.

Anti-Infective Agents↗

PubMed1986

Prostaglandin synthetase inhibition with indomethacin rectal suppositories in the treatment of acute and chronic urinary calculus obstruction.

The effect of indomethacin suppositories on both acute urinary colic and urinary calculus, resistant or refractory to conventional therapy with analgesics and spasmolytics was investigated. Fifty-five patients with acute urinary colic refractory to treatment with repeated injections of antispasmodics and analgesics had dramatic or complete pain relief after receiving indomethacin suppositories (100 mg) (P less than 0.01). Fifteen of the 55 patients passed urinary stones within 30 days of treatment with indomethacin. Three out of 30 other patients with renal or ureteric stones were treated with indomethacin suppositories (100 mg) twice daily. Twenty-one of the 30 patients passed their stones within 30 days of treatment. It is concluded that indomethacin suppositories can relieve acute urinary colic resistant to treatment with analgesic/antispasmodic drugs, and facilitate expulsion of urinary calculi. The mechanism of action of indomethacin is discussed in terms of its analgesic and anti-inflammatory effects and its prostaglandin synthesis inhibition.

Adolescent↗

PubMed2004

Comparison of the effect of diclofenac with hyoscine-N-butylbromide in the symptomatic treatment of acute biliary colic.

BACKGROUND: Although non-steroidal anti-inflammatory drugs (NSAID) and spasmolytics have been used to relieve biliary colic, the role of these drugs in the natural history of biliary colic has not been clarified. The objective of the present study is to compare the efficacy of intramuscular diclofenac with intramuscular hyoscine in the treatment of pain of acute biliary colic, and to study their role in the natural history of biliary colic and in the prevention of cholelithiasis-related complications. METHODS: Seventy-two consecutive patients with biliary colic were enrolled in this prospective, randomized, double-blind study. They received either a single 75 mg intramuscular dose of diclofenac (n = 36) or similarly administered 20 mg of hyoscine (n = 36). Pain severity was recorded on a visual analogue scale 30 min, 1 h, 2 h and 4 h after injection of the drug. Patients were then followed closely for the next 72 h for persistence or relapse of pain, or development of acute cholecystitis, or drug related complications. RESULTS: Diclofenac provided much more rapid relief of pain than hyoscine, as shown by significantly lesser pain scores after injection of the drug. 91.7% of patients on diclofenac were completely relieved of pain at 4 h as compared to 69.4% with hyoscine (P = 0.037). Progression to acute cholecystitis was seen in only 16.66% of patients on diclofenac as compared to 52.77% on hyoscine (P = 0.003). CONCLUSIONS: In patients with biliary colic, diclofenac gives much faster and more effective pain relief in a significantly larger number of patients as compared with hyoscine. Most remarkably, diclofenac can prevent progression of biliary colic to acute cholecystitis in a significant number of patients.

Acute Disease↗

PubMed1993

Pharmacological options for the treatment of acute ureteric colic. An in vitro experimental study.

The effects of opiate and non-steroidal anti-inflammatory agents on the in vitro canine ureter were compared using a new model for the assessment of ureteric pharmacology. A pressure measuring catheter attached to a pressure transducer and pre-calibrated pen recorder was ligated into the lumen of 2.5 cm segments of normal canine ureter. The segments were immersed in an organ bath at physiological pH and temperature and spontaneous contractility was observed in 90% of them. Morphine had a spasmogenic effect on ureteric activity which was unaffected by naloxone. This effect was similar to that of histamine and prostaglandin F2 alpha and was abolished by chlorpheniramine but not by cimetidine. Pethidine produced a transient stimulation followed by inhibition of ureteric activity which was unaffected by naloxone. Both indomethacin and diclofenac produced an abrupt inhibition which was reversible with prostaglandin F2 alpha. These data suggest that pethidine or a non-steroidal anti-inflammatory agent may by virtue of their spasmolytic effects be a superior choice of therapy for the acutely obstructed ureter.

Acute Disease↗

PubMed1982

Obstetric implications of burns in pregnancy.

Analysis of 50 patients with burns in pregnancy has allowed the objective consideration of obstetric implications. Patients in the second and third trimester of pregnancy with burns of greater than or equal to 50% should be delivered immediately as maternal death is otherwise certain and fetal survival rate is not improved by waiting. Vaginal delivery has always proved possible, even in the presence of perineal burns but caesarean section should be considered and may be preferred. Patients in the first trimester may survive with more extensive burns and possible reasons for this are discussed. Pregnancy testing on admission should be mandatory in burns of women of reproductive age. In patients with burns of less than 40% in the second and third trimesters, spasmolytics should be used to suppress spontaneous labour and to cover operations. Greater fetal maturity without worsening maternal prognosis can thus be achieved. Insufficient data exist to recommend this for burns of between 40 and 50%.

Acute Disease↗

PubMed1968

The effect of drugs on the constriction of isolated depolarized blood vessels in response to calcium or barium.

1. The rat isolated anterior mesenteric artery was perfused at a constant rate with a calcium-free depolarizing solution. Injection close to the cannula of 0.05-0.1 ml. of solutions of CaCl(2) (117 mM) or BaCl(2) (100 mM) caused a rise in perfusion pressure.2. The responses to injected CaCl(2) solution could be obtained repeatedly but those to successive injections of BaCl(2) solution slowly declined. When the responsiveness to barium had almost disappeared, it could be restored by the addition to the perfusing fluid of a small amount of calcium (0.05 mM).3. The contractile effects of calcium or barium were antagonized by the addition to the perfusing fluid of several anti-inflammatory substances, certain local anaesthetics and certain spasmolytic drugs.4. Perfusion of the mesenteric artery with a depolarizing solution containing 0.2 mM-CaCl(2) caused a persistent rise of the perfusion pressure. This was rapidly and completely reversed by the addition of indomethacin (4 mg/100 ml.) or cinchocaine hydrochloride (2 mg/100 ml.) to the perfusing fluid.5. The uptake of (45)Ca by rat aorta depleted of calcium was reduced by amethocaine hydrochloride (10 mg/100 ml.) or cinchocaine hydrochloride (2 mg/100 ml.) but not by indomethacin (10 mg/100 ml.) or desipramine hydrochloride (1 mg/100 ml.).

Anesthetics, Local↗

PubMed1973

Effects of oxyfedrine on isolated portal vein and other smooth muscles.

1. Oxyfedrine (0.01-1.0 mug/ml), inhibited spontaneous myogenic activity in rat isolated portal vein and carbachol-induced contractions of rat isolated uterus, and relaxed the rabbit duodenum and the guinea-pig tracheal chain preparation. These actions were prevented by the beta-adrenoceptor blocking drug alprenolol. Oxyfedrine was a relatively weak beta-adrenoceptor stimulant (10-100 times less active than isoprenaline) but its actions were more prolonged.2. In the same concentrations, oxyfedrine reduced or prevented the inhibition of myogenic activity of the rat portal vein induced by isoprenaline and by repeated doses of oxyfedrine itself, acting as a partial agonist at beta-adrenoceptor sites.3. Oxyfedrine, 1-12 mug/ml increased myogenic activity in the rat portal vein. This effect was not due to direct or indirect stimulation of alpha-adrenoceptors (because it was unaffected by phentolamine) or to potentiation of acetylcholine or 5-hydroxytryptamine.4. Oxyfedrine (>20 mug/ml) inhibited spontaneous myogenic activity in the portal vein and relaxed the saphenous vein contracted with noradrenaline. This spasmolytic effect of the drug was not due to beta-adrenoceptor stimulation or to inhibition of phosphodiesterase since it was unaffected by alprenolol and by concentrations of imidazole which antagonized the effects of the active phosphodiesterase inhibitor, papaverine. In the portal vein this effect of oxyfedrine was similar to that of the calcium inhibitor iproveratril; some of the effects of oxyfedrine on venous smooth muscle may be mediated through effects on calcium transport.

Adrenergic beta-Agonists↗

PubMed1973

Myogenic peristalsis in isolated preparations of chicken oesophagus.

1. Nicotine, 20 mug/ml, briefly and partially blocked the longitudinal contractions of a chick vagus nerve-oesophagus preparation to nerve stimulation, but potentiated them in the presence of hyoscine, 10 mug/ml.2. Strychnine, 20 mug/ml, antagonized the longitudinal contractions of the chick oesophagus to nerve stimulation, though not to acetylcholine or 5-hydroxytryptamine. Hyoscine, 10 mug/ml, enhanced the nerve-blocking action of strychnine.3. These observations suggest that in the vagus nerve of the chicken, hyoscine either blocks certain types of fibre selectively or interacts with pharmacological receptors for strychnine and nicotine.4. Tetrodotoxin, 1 mug/ml, propranolol, 40 mug/ml, cocaine, 200 mug/ml, or strychnine, 100 mug/ml, which render autonomic nerves inexcitable, potentiated the spontaneous movements of isolated preparations of chicken oesophagus at normal intra-luminal pressure; they also potentiated peristaltic response to increased intra-luminal pressure.5. These observations suggest that the preparations contain intramural nerves that inhibit the musculature.6. Peristalsis in the chicken oesophagus was unaffected by nicotine, 20 mug/ml, tubocurarine, 20 mug/ml, hyoscine, 10 mug/ml, phentolamine, 1 mug/ml, propranolol, 0.5 mug/ml, mepyramine, 1 mug/ml, methysergide, 0.1 mug/ml, and morphine, 20 mug/ml. It was produced in preparations of chicken oesophagus after removal of the mucous membrane. Papaverine, 20 mug/ml, inhibited the peristalsis and had a spasmolytic action in the musculature.7. These observations suggest that the peristalsis in isolated preparations of chicken oesophagus is dependent solely upon myogenic contractility.

Acetylcholine↗

PubMed1980

Effects of endorphins on different parts of the gastrointestinal tract of rat and guinea-pig in vitro.

1 The spasmogenic and spasmolytic effects of beta-lipotropin (LPH) fragments and one analogue were investigated on different parts of the gastro-intestinal tract of guinea-pig and rat in vitro.2 Changes in muscle tone were observed in colon and rectum and to a lesser extent in jejunum and ileum of both species. Rat colon and rectum contracted to the peptides. Guinea-pig colon and rectum relaxed after an initial short-lasting contraction.3 On the rat rectum (D-ala(2))met-enkephalin, leu-enkephalin, gamma-endorphin, alpha-endorphin and beta-LPH 80-91 caused dose-dependent contractions, their ED(50) values being 0.96 x 10(-12) mol, 1.05 x 10(-11) mol, 1.22 x 10(-11) mol, 1.08 x 10(-10) mol, 2.65 x 10(-10) mol and 6.5 x 10(-9) mol, respectively.4 Naloxone dose-dependently shifted the dose-response curve of met-enkephalin to the right. Atropine, hexamethonium, burimamide, mepyramine, propranolol and indomethacin did not influence the response to met-enkephalin.5 In the presence of tetrodotoxin, the ED(50) for met-enkephalin and the maximal contractor response induced by met-enkephalin, appeared to be increased.6 The 5-hydroxytryptamine (5-HT) antagonists, methysergide and cyproheptadine, reduced the contractor response in a non-competitive manner. The alpha-adrenoceptor antagonist phentolamine, in contrast, caused an increase of the maximal response to met-enkephalin of up to 200%. Noradrenergic and tryptaminergic systems, therefore, might be involved in the changes in muscle tone induced by met-enkephalin.7 These results demonstrate that rectum and colon of guinea-pig and rat are very sensitive to opioid-like peptides.

Animals↗

PubMed1984

Effects of five different organic calcium antagonists on guinea-pig isolated trachea.

The relaxant effects of five organic calcium antagonists (nicardipine, diltiazem, PY 108068, verapamil and bepridil) on guinea-pig isolated trachea were tested against contractions induced by acetylcholine, histamine, 5-hydroxytryptamine, potassium chloride (KCl) and tetraethylammonium (TEA) in a medium containing the normal amount of calcium and against calcium dose-response curves in a calcium-free, potassium-enriched medium. These effects were compared with those of spasmolytic or specific acetylcholine or histamine antagonists. In contrast to the other drugs tested, organic calcium antagonists exerted a specific inhibitory effect on KCl- and TEA-induced contractions. Their degree of activity was in the order: nicardipine greater than diltiazem greater than PY 108068 greater than verapamil greater than bepridil. All calcium antagonists inhibited calcium dose-response curves at similar concentrations. Organic calcium antagonists therefore seem to exert a specific inhibitory effect on depolarizing agents in the guinea-pig isolated trachea, unlike other tissues, notably some vascular smooth muscles.

Animals↗