General pharmacology of a Pseudomonas vaccine prepared from outer-membrane fractions of Pseudomonas aeruginosa.

CFC-101 is a novel Pseudomonas vaccine with high effectiveness against Pseudomonas infection and is currently under clinical evaluation. The general pharmacological properties of this vaccine were evaluated in mice, rats, guinea pig ileum, and dogs. In vivo doses of 0.2, 2.0 and 20 mg/kg given by intramuscular route, or in vitro concentrations up to 50 micrograms/ml were used. Intramuscular administration of CFC-101 vaccine had no effect on the central nervous system except that the body temperature of rats was slightly decreased at the highest dose, 20 mg/kg. CFC-101 vaccine did not affect the function of smooth muscles, gastrointestinal system, and cardiovascular and respiratory systems. In water and electrolytes excretion test, a decrease in urine output and an elevation of the excretion of Na+, Cl- and total protein at the highest dose (20 mg/kg) were observed. In summary, CFC-101 vaccine had no pharmacological effect in these studies even up to the 100-fold clinical dose, 2 mg/kg.

[General pharmacological study of iodixanol, a new non-ionic isotonic contrast medium].

The general pharmacological study of iodixanol, a non-ionic isotonic contrast medium, was conducted. 1) Iodixanol administered intravenously over a dose range of 320 to 3,200 mgI/kg had little or no effect on the general behavior, spontaneous locomotor activity, hexobarbital sleeping time, pain response, electroshock- or pentylenetetrazol-induced convulsion (mouse), EEG or body temperature (rabbit), gastrointestinal propulsion (mouse) or skeletal muscle contraction (rabbit). Iodixanol had no specific interaction with acetylcholine, histamine, serotonin, nicotin, BaCl2 (ileum), methacholine (trachea), isoprenaline (atrium) or oxytocin (pregnant uterus), nor had any effect on spontaneous contractility (atrium and uterus), or transmural electrostimulation-induced contractility (vas deferens) at concentrations of < or = 3.2 x 10(-3) gI/ml in vitro. Iodixanol had no effect on the cardiovascular system of dog, except that it increased femoral blood flow and respiratory rate at doses of > or = 1,000 mgI/kg. Iodixanol at 3,200 mgI/kg i.v. reduced urine output with a decrease in Na+ and Cl- excretion, whereas at 320 mgI/kg i.v., it slightly increased urine output (rat). 2) Injections of iodixanol into the cerebroventricular (0.96, 9.6 mgI/mouse and 3.2, 32 mgI/rat), left ventricular (1,920, 6,400 mgI/dog) or coronary artery (640, 1,920 mgI/dog) had no conspicuous effect on the central nervous system or the cardiovascular system, respectively. There was no marked difference among iodixanol, iohexol and iopamidol in this respect. Vascular pain during injection into the femoral artery (300-320 mgI/guinea pig) appeared to be less intense with iodixanol, compared with the other contrast media iohexol and iopamidol. These results suggest that intravenous injection of iodixanol is relatively free from pharmacological activity, and effects of iodixanol on the central nervous system (intracerebroventricular injection) and cardiovascular system (intra-left ventricular and -coronary injections) are comparable to those of iohexol and iopamidol. Furthermore, intra-femoral injection of iodixanol has less of a tendency to produce vascular pain than those of iohexol and iopamidol.

Analgesic activity of the lysozyme peptide N-(N-L-threonyl-L-alpha-aspartyl)-L-tyrosine in the monkey and the dog.

N-(N-L-Threonyl-L-alpha-aspartyl)-L-tyrosine (CAS 115053-54-8, SPA-S-646) was originally derived from lysozyme. It has previously been found to have analgesic properties following oral and intravenous administration to laboratory rodents. In the rhesus monkey, intramuscular administration of SPA-S-646 caused a dose-related analgesia. This effect was not seen following oral administration, but when given via the rectum, analgesia was again observed. In the dog, a single dose of 50 mg/kg was active by the intramuscular route but not the oral route. It is thought that unlike the rat, the digestive systems of the rhesus monkey and the dog degrade the tripeptide into inactive constituents.

General pharmacology of [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3- dihydro-1H-pyrrolizine-5-yl]-acetic acid in experimental animals.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (ML 3000) is a newly synthesized compound with analgesic, antipyretic and anti-inflammatory activity. The general pharmacological effects of ML 3000 following oral administration were investigated in experimental animals. The results showed that with regard to the CNS, ML 3000 did not affect behaviour in the Irwin test, locomotor activity or hexobarbital-induced sleep at doses of 30, 100 and 300 mg/kg. ML 3000, at a single dose of 100 mg/kg administered intraduodenally, had no notable effect on the cardiovascular system or respiration in anaesthestised rats and dogs nor on neuromuscular function in anaesthetised cats. No evidence of gastric damage or disturbance of peristalsis was observed following oral administration of ML 3000. In vitro, ML 3000 evoked a weak spasmogenic response in the guinea-pig ileum with a dose-related inhibition of acetylcholine, histamine and barium chloride-induced responses. A small transient reduction in urine volume was observed after the highest dose accompanied by decreases in electrolyte excretion at doses of 100 and 300 mg/kg in rats. The results demonstrate that ML 3000 has no notable general pharmacological effects under the experimental conditions reported.

Acute and chronic anti-inflammatory properties of [2,2-dimethyl-6-(4- chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

The carrageenan-induced paw oedema in the rat was chosen as the experimental model for acute antiphlogistic activity. ED50 values of 3 mg/kg p.o. for indometacin and of 17 mg/kg p.o. for [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2, 3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000) at calculated plasma levels (micrograms/ml) of approximately 5.0 and 20.0 were recorded for indometacin and ML 3000, respectively. The activity ratio of indometacin: ML 3000 is therefore about 1:6 with regard to the oral dose and about 1:4 with regard to the calculated plasma level. Indometacin is more potent than ML 3000 on the one hand, but on the other hand ML 3000 is better tolerated by the stomach in this experimental study: the ulcerogenic dose UD50 (indometacin) is 7 mg/kg p.o., whereas ML 3000 is tolerated well up to the highest tested dose of 100 mg/kg p.o. The adjuvant arthritis in the rat served as the model for chronic antiphlogistic activity. ML 3000 at doses of 20 mg/kg/d p.o. and higher, and indometacin at a dosage of 2 mg/kg/d p.o. produced a similar rate of reduction of the adjuvant-induced secondary lesions and paw swelling of the injected and uninjected paws, following prophylactic as well as therapeutic treatment with the compounds.

Gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl-7-phenyl- 2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid in the rat.

The gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000, CAS 156897-06-2) has been tested in comparison with indometacin, after both single and multiple administrations for 5 and 11 days in an in vivo rat assay. A single oral administration of ML 3000 at doses of 10, 30 and 100 mg/kg produced no gastrointestinal damage. Repeated oral administration of ML 3000 at daily doses of 10, 30 and 100 mg/kg produced slight gastrointestinal damage, but the effect was minimal and was not found to be statistically significant. Indometacin produced highly statistically significant gastric and duodenal damage following one single administration of 10 mg/kg. Repeated oral administration, at 3 mg/kg each day, produced moderate and statistically significant gastric and slight duodenal damage on Day 5 of dosing. However, by Day 11 pronounced duodenal damage was observed which was shown to be statistically highly significant. These results indicate that ML 3000 is clearly better tolerated by the gastrointestinal tract than indometacin after single and multiple administration up to 11 days in rats.

Antitussive effects of levodropropizine in the dog.

The antitussive activity of levodropropizine (S(-)3-(4-phenyl-piperazine-1-yl)-propane-1,2-diol, DF 526, CAS 99291-25-5) was evaluated after oral administration to the conscious dog. Levodropropizine had a good antitussive activity, comparable with, but having a longer duration of action than dropropizine, the racemate from which it is derived. The antitussive activity of levodropropizine in the dog was approximately 1/20 of that of codeine phosphate.

Pharmacological effects of cefclidin on the central nervous system.

The effects of cefclidin (CFCL), a novel antibacterial agent, on the central nervous system (CNS) were examined in a variety of animal models. The effects of cefazolin (CEZ) were also examined for comparative purposes. In the animal models used CFCL whilst having some effects at the doses examined, failed to show an overall consistent effect on the CNS. In contrast CEZ produced changes in the parameters measured which were generally consistent with a proconvulsant action.

Antiemetic activity of the new 5-HT3 antagonist DAU 6215 in animal models of cancer chemotherapy and radiation.

The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1-1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.

Antitussive action of the new anilide derivative vadocaine hydrochloride compared with codeine phosphate in four animal models.

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)

The physical dependence liabilities of oxybutynin and morphine in rats.

The anticholinergic/antispasmodic agent oxybutynin does not induce physical dependence in rats when administered by oral gavage twice daily for 40 days; nor did challenge with naloxone precipitate withdrawal signs in these (oxybutynin-treated) animals. In contrast, morphine treatment resulted in a high degree of physical dependence as evidenced by the withdrawal signs noted after treatment was halted. Challenge with naloxone also induced severe withdrawal signs in morphine-treated rats. Withdrawal signs characterised by squealing, teeth chattering and "wet-dog" shakes were seen in one from five morphine-treated rats challenged with oxybutynin.

Study of the effects of oral administration of CDP-choline on EEG changes and lethality induced by epidural compression in the anaesthetised cat.

The effects of repeated oral administration of cytidine diphosphate choline (CDP-choline, citicoline, Somazina) and vehicle on the EEG changes induced by epidural brain compression have been studied in the anaesthetised cat. The effects on arterial pressure and heart rate were also monitored. CDP-Choline-treated cats exhibited a statistically significant increase in resistance to the effects of mechanical compression of the brain when compared with the vehicle-treated group. In addition the onset of abnormal EEG waveforms occurred at greater levels of brain compression in drug-treated cats. CDP-Choline also imparted protection against the cardiovascular and respiratory effects of brain compression; animals were apparently less susceptible to cardiac and respiratory failure under the influence of the test compound. A statistically significant protection against the lethal effects of epidural compression was also noted in CDP-choline treated cats. It may be concluded that repeated oral treatment with CDP-Choline provides an apparent protection against the effects of acute mechanical compression of the brain.

Cardioregulatory properties of indoramin in the rat.

The antihypertensive action of the competitive alpha-adrenoceptor antagonist indoramin is not accompanied by reflex tachycardia in animals or man. The possibility that the established local anaesthetic property of indoramin is involved in its cardioinhibitory action has been investigated. Indoramin evoked a dose-dependent bradycardia in anaesthetized/pithed rats. The decrease in heart rate was slightly greater than that evoked in anaesthetized intact animals suggesting that indoramin had a direct action on the heart. Reflex tachycardia was simulated in pithed rats be increasing the frequency of cardiac nerve stimulation from 0.3 to 1 Hz. Indoramin and the local anaesthetic agents, lignocaine and procaine, reduced the positive chronotropic response without markedly altering the basal rate. The response curves were parallel. In contrast, phentolamine decreased the positive chronotropic response, but only at high doses which were associated with a marked decrease in the basal rate. Thymoxamine and prazosin had so significant effects on the chronotropic response. These experiments suggest that the cardioregulatory action of indoramin is attributable to its local anaesthetic property had this action further distinguishes it from the other alpha-adrenoceptor antagonists tested.

Hypertension: its effect on the stimulated release of dopamine-beta-hydroxylase in the rat.

Plasma dopamine-beta-hydroxylase (DBH) concentrations have been postulated as providing an index of sympathetic nerve activity. Using a microspectrophotometric assay system, plasma DBH concentrations have been measured in emergent blood from autoperfused heart, spleen and mesentery of normotensive, deoxycorticosterone (doca)/NaCl-treated, Goldblatt (1 kidney) renal and spontaneously hypertensive rats following sympathetic nerve outflow stimulation. Changes in plasma DBH concentrations as a result of sympathetic nerve outflow stimulation rates of 1--25 Hz for the mesentery and spleen and 1--4 Hz for the heart, were found to be frequency-dependent in all groups. Significantly greater amounts of DBH were found in the perfusate from the spleen (1--25 Hz) and mesentery (3--25 Hz) but not the heart (0.5--4Hz) of renal hypertensive rats compared with normotensive controls. Significantly greater concentrations of DBH were released from the spleen but not the mesentery in all hypertensive groups following high stimulation frequencies of 12 and 25 Hz. It is concluded that there is a relation between plasma DBH concentrations and sympathetic nerve activity. Furthermore, greater amounts of the enzyme are released from the spleen and mesentery of chronic renal hypertensive rats following sympathetic nerve stimulation.

Dopamine-beta-hydroxylase release following acute selective sympathetic nerve stimulation of the heart, spleen and mesentery.

In increase in the concentration of dopamine-beta-hydroxylase (DBH) in the blood perfusates of the heart, spleen and mesentery of pithed rats was detected following selective sympathetic nerve stimulation. Furthermore, the concentration of enzyme released by each organ correlated with the stimulation frequency. The results provide further corroborative evidence that the concentration of DBH in the plasma is related to the degree of sympathetic tone. If the sampling methods described were applied to non-spinalized animals, the concentrations of DBH in organ perfusates could be used as an index of sympathetic nervous tone and thus provide a useful preparation for the study of drugs on the sympathetic nervous system.