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Biomedical subjects

A Eschalier

Publications and source records attributed to A Eschalier.

At least 91 records · Page 5Linked to original sources
PubMed1994

Seven-day antinociceptive effect of a sustained release vapreotide formulation.

This work studies the antinociceptive effect of a sustained (7 day) release dosage form of vapreotide, a peptidic analogue of somatostatin, in rats submitted to a nociceptive mechanical stimulus (paw pressure). One intramuscular injection (0.6 mg/animal) induced a significant antinociceptive effect for 7 complete days with a maximal increase in vocalization thresholds of 68 +/- 5% and a plateau of activity during the first 4 days. This action was totally inhibited by naloxone (1 mg kg-1, s.c.) injected 24 h or 6 days after vapreotide, suggesting an opioidergic involvement throughout the antinociceptive effect. These findings suggest potential interest in human therapy.

Analgesics↗
PubMed1994

Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics.

The streptozocin-induced diabetic rat has been put forward as a model of chronic pain with signs of hyperalgesia and allodynia that may reflect signs observed in diabetic humans. The aim of this work was to assess, in streptozocin-induced diabetic rats, the pharmacological activity to several analgesic drugs known to be effective (clomipramine, amitriptyline, desipramine, clonidine, lidocaine), ineffective (aspirin), or with a doubtful effectiveness (morphine) in human painful diabetic neuropathy. The animals were submitted to a mechanical pain test (paw pressure) and the ability of the drugs to reverse diabetes-induced hyperalgesia was tested. The tested antidepressants (0.125-8 mg/kg, i.v.) were slightly effective in diabetic rats; amitriptyline and clomipramine induced a weak effect, whereas desipramine was more active, suggesting noradrenergic specificity. This was confirmed by the effectiveness of clonidine (50, 100, 150 micrograms/kg, s.c.). Lidocaine (1-9 mg/kg, i.v.) had prolonged efficacy on mechanical hyperalgesia. Aspirin (100 mg/kg, i.v.) was without effect and morphine (0.5-4 mg/kg, i.v.) induced a dose-dependent antinociceptive effect but at doses twice as high as those used in normal rats. These results demonstrate the high pharmacological predictivity of this model of painful diabetes and suggest that in this pathological condition, among the drugs acting on monoaminergic transmission, noradrenergic drugs seem the most active.

Analgesics↗
PubMed1994

A method to perform direct transcutaneous intrathecal injection in rats.

This work describes a method for performing direct intrathecal (i.t.) injections in rats without introducing a spinal catheter. Its ease of use in awake animals yields rapid and reproducible results with no sign of motor impairment. The quality of each injection was ensured by the observation of an injection-induced tail-flick. A 10-microL injection of methylene blue was well localized yielding a very limited diffusion along the spinal cord. The method was validated by demonstrating that morphine (i.t.) had a marked antinociceptive effect and that naloxone (i.t.) blocked the effect of systemic (s.c.) morphine in mononeuropathic rat.

Administration, Cutaneous↗
PubMed1994

Comparison between percutaneous and subcutaneous routes of administration of apomorphine in rabbit.

Apomorphine (0.5 mg/kg) was administered subcutaneously and percutaneously to rabbit in order to compare the pharmacokinetic data obtained according these two different routes. For the percutaneous administration, an apomorphine gel was prepared by dissolution of apomorphine in an hydroxypropylmethylcellulose gel of medium viscosity. The evaluation of plasma levels after percutaneous route showed an absorption in all the animals. The time to peak plasma concentration (29.4 +/- 7.8 min) was close than after the subcutaneous route (25.8 +/- 4.9 min). The absorption of apomorphine was of 90% at minute 68 and minute 321 min after the subcutaneous and the percutaneous route, respectively. The peak plasma concentration and the area under the curve were significantly greater with the subcutaneous route. The bioequivalence of the percutaneous route was 35% of the subcutaneous administration. Those data suggested that the percutaneous route of apomorphine could be evaluated in humans to test its efficacy in the treatment of motor fluctuations in parkinsonian patients.

Absorption↗
PubMed1994

Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half-life repeated administration. Comparison with acute administration.

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z-10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

Amitriptyline↗
PubMed1994

Evidence for a central long-lasting antinociceptive effect of vapreotide, an analog of somatostatin, involving an opioidergic mechanism.

The antinociceptive effect of the octapeptide vapreotide, an analog of somatostatin, was studied after systemic injection in normal mice using the hot plate and abdominal stretching assays, and in normal rats using the paw pressure analgesiometric assay. Vapreotide was ineffective at 1 microgram/kg s.c. in the hot plate test in mice, but 30 min after injection it induced an antinociceptive effect at s.c. injected doses of 8, 64, 512 and 4096 micrograms/kg, with an ED50 of 213 +/- 5 micrograms/kg. For the three highest doses this effect persisted 24 hr after the injection (maximal increase: +80 +/- 23% for 512 micrograms/kg) and disappeared at 48 hr. In the phenylbenzoquinone stretching test, in mice, the ED50 was 186 +/- 6 micrograms/kg (maximal decrease: -63 +/- 5%); the effect persisted 24 hr only for the same two highest doses. Using the paw pressure test, in rats, a dose-dependent increase in paw withdrawal and vocalization thresholds was observed for 21 and 24 hr, respectively, after s.c. injections of 16, 64 and 512 micrograms/kg. Global scores obtained for vocalization thresholds were significantly increased (vs. paw withdrawal thresholds) for 64 and 512 micrograms/kg. Carrageenan-induced nociception in rats was reduced for 21 hr by 64 and 512 micrograms/kg s.c.; scores of the contralateral noninflamed paw were also increased. Vapreotide administered locally in the inflamed paw was inactive. No change in edema volume was obtained after systemic injection of vapreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Vocalization elicited by activation of A delta- and C-fibres in the rat.

Complex vocal responses in both the audible and ultrasonic frequency ranges were elicited by a single 2 ms electrical pulse applied to the tail. The first two cries exhibited consistent latencies and durations, were intensity-dependent and were triggered by peripheral fibres with conduction velocities of 7.3 +/- 0.8 and 0.7 +/- 0.1 ms-1, respectively. These behavioural responses are reminiscent of first and second pain triggered by A delta- and C-peripheral fibres in humans. They were followed by irregular audible cries with a fundamental frequency of 1.5 kHz and '22 kHz ultrasonic calls'.

Animals↗
PubMed1993

RP-67580, a specific tachykinin NK1 receptor antagonist, relieves chronic hyperalgesia in diabetic rats.

The effect of a non-peptide NK1 receptor antagonist, RP-67580, and of its enantiomer, RP-68651, on nociceptive thresholds in normal and streptozocin-induced diabetic rats submitted to paw pressure is reported. RP-67580 (1, 3, 9 mg/kg s.c.) dose dependently reduced the diabetes-induced mechanical hyperalgesia observed 4 weeks after induction of diabetes. In normal rats, RP-67580 failed to increase nociceptive thresholds. RP-68651 was inactive in both diabetic and normal rats. These results suggest that (i) substance P is involved in the diabetes-induced chronic hyperalgesia, and (ii) NK1 receptor antagonists merit to be studied more extensively in relation with this pathological condition.

Analgesics↗
PubMed1993

Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain.

Painful diabetic neuropathy is one of the most common complications of insulin-dependent diabetes in man. Conflicting results have been obtained in experimentally diabetic animals subjected to pain stimuli. This work aimed to systematically study the response of rats made diabetic (hyperglycemia > or = 14 mM) by injection of streptozocin (STZ) (75 mg/kg, i.p.), to various pain stimuli: mechanical, thermal (warm and cold) and chemical. The time course of the scores was followed for 4 weeks simultaneously with the clinical symptoms (weight, body and skin temperature, motility) and hyperglycemia. A decrease in reaction thresholds to noxious heat stimuli (44 degrees C and 46 degrees C) and to non-painful thermal (cold: 10 degrees C, and warm: 38-42 degrees C) and mechanical stimulation (paw pressure) was observed. This can be considered as evidence for hyperalgesia and allodynia, respectively. These troubles appeared gradually and required at least 2 weeks of diabetes to reach statistical significance. Four weeks after the induction of diabetes, the scores obtained in diabetic rats injected with formalin were greater than those in normal rats, indicating hyperalgesia. Variation in sensitivity to pain occurred at the same time as arrested weight increase, fall in skin temperature, some amyotrophy measured in terms of hind-paw volume, and the usual polyuria-polydipsia syndrome. Spontaneous motor activity of the rats was lowered. This model is thus of interest as the observed reactions to noxious and non-noxious stimuli correspond to hyperalgesia and allodynia, symptoms encountered in painful diabetic neuropathy in man. Operating conditions for this model are discussed.

Animals↗
PubMed1993

Relation between clinical efficacy and pharmacokinetic parameters after sublingual apomorphine in Parkinson's disease.

Apomorphine was administered sublingually in two single doses (0.3 and 0.6 mg/kg) to seven patients with idiopathic Parkinson's disease (PD) to assess the relation between clinical efficacy, dosage, and pharmacokinetic parameters of apomorphine. On day 1 and day 3, patients were given 0.3 mg/kg and 0.6 mg/kg of apomorphine, respectively (3 mg tablets). Before apomorphine administration and during the following 4 h, motor score was assessed by measuring tremor, akinesia scores, rising from a chair, and walking speed. The delay to turn on was not different between the two doses but after the 0.3 mg/kg dose, only three patients turned on, whereas all the patients treated with 0.6 mg/kg turned on. Apomorphine (0.3 mg/kg) induced a shorter duration of the "on" period than 0.6 mg/kg (0.3 mg/kg: 24.2 +/- 14.6 min; 0.6 mg/kg: 86.7 +/- 14.9 min). The time to obtain the peak plasma concentration (tmax) obtained with the two doses were not different (0.3 mg/kg: 31.5 +/- 3.4 min; 0.6 mg/kg: 38.3 +/- 2.8 min). Peak plasma concentrations (Cmax) and areas under the curve (AUC) were significantly higher after 0.6 mg/kg than 0.3 mg/kg (Cmax: 0.3 mg/kg: 7.5 +/- 3.2 ng/ml; 0.6 mg/kg: 22.7 +/- 3.6 ng/ml; p < 0.01; AUC: 0.3 mg/kg: 929 +/- 109 ng/ml/min; 0.6 mg/kg; 2,277 +/- 209 ng/ml/min; p < 0.01). There was a significant linear correlation between the duration of therapeutic effect, AUC, and Cmax (r = 0.86, p < 0.01 for AUC; r = 0.63, p < 0.05 for Cmax). These results show that sublingual apomorphine could be of interest in the treatment of "off" phases in parkinsonian patients with motor fluctuations.

Administration, Sublingual↗
PubMed1992

High-performance liquid chromatographic determination of amitriptyline and its main metabolites using a silica column with reversed-phase eluent. Application in mice.

A method was developed for the assay of amitriptyline, amitriptyline N-oxide, nortriptyline, desmethylnortriptyline and E (trans) and Z (cis) isomers of 10-hydroxyamitriptyline and of 10-hydroxynortriptyline in plasma and brain of animals, using high-performance liquid chromatography with ultraviolet detection (254 nm). Single extraction was performed at pH 10.5 from 0.25 ml of plasma or 1 ml of brain mixture. Chromatographic separations were achieved with a silica column and an aqueous methanol mobile phase containing ammonia. This procedure offers high sensitivity (8-10 ng/ml), high linearity (r > 0.99) and acceptable precision (coefficient of variation < or = 13.3%). The method was used to determine levels of amitriptyline and its major metabolites in mice 30 min after a single intraperitoneal administration of amitriptyline (20 mg/kg).

Amitriptyline↗
PubMed1992

Antinociceptive activity of metapramine in mice. Relationship with its pharmacokinetic properties.

The antinociceptive effect of acutely and chronically (every brain elimination half-life time) administered metapramine, a tricyclic antidepressant without anticholinergic or cardiotoxic effects, was studied in three different pain tests. In the hot plate test, its action was more potent when jumping was used as a pain parameter (acute ED50 = 19 +/- 3 mg/kg, i.p.) than when pain was assessed by licking of forepaws (only 20 mg/kg, i.p. was weakly active). Five chronic doses of 15 mg/kg were as active in the tail-flick test as an acute dose of 20 mg/kg (only active dose). Metapramine was more effective in the PBQ-induced writhing test after acute (ED50 = 9.9 +/- 0.1 mg/kg, i.p.) and chronic administration. A significant linear correlation was found between the effect in this test and plasma and overall brain levels of metapramine. No correlation was observed with levels of its three desmethylated metabolites. The usefullness of using a well-defined pattern of administration based on pharmacokinetic parameters and the involvement of monoaminergic mechanisms and of some metabolites of metapramine are discussed.

Animals↗
PubMed1992

Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

Animals↗
PubMed1992

Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice.

The purpose of this study was to compare the analgesic effect of acute injections (1.25 and 20 mg/kg, ip) of several antidepressants with different effects on monoamine reuptake, on two pain tests in mice (hot-plate and phenylbenzoquinone-induced abdominal writhes). Serotonergic inhibitors (citalopram, fluvoxamine and clomipramine) were more effective in the hot-plate test whereas noradrenaline reuptake inhibitors (desipramine and maprotilline) were more effective in the writhing test. The mixed antidepressants (amitriptyline and to a lesser degree trimipramine) were more effective in the two tests than the other antidepressant drugs. Changes in motor activity of clomipramine and amitriptyline could not account for the modifications of pain threshold. Amineptine (a dopamine reuptake inhibitor) failed to induce any antinociceptive effect in the hot-plate test and was hyperalgesic in the writhing test, which could be explained by an increased motor activity. These findings indicate that the antinociceptive potency of reuptake inhibitors varies according to their monoamine specificity and the nature of stimuli. They would suggest that the preferential choice of serotonergic antidepressants in the management of chronic pain is arguable.

Animals↗
PubMed1992

[Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease].

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.

Administration, Sublingual↗
PubMed1991

Long-lasting antinociceptive effect of RC-160, a somatostatin analog, in mice and rats.

The effect of RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) was studied in mice by means of the hot plate test and in rats with the tail flick test. In mice, 512 micrograms/kg (s.c.) induced an antinociceptive effect maximal (+88 +/- 17%) at the 6th hour after injection but still significant at the 24th hour; 16 micrograms/kg (s.c.) was active for 3 h; 64, 256 and 1024 micrograms/kg were active 30 min, 3 and 24 h after injection. The effects of these last three doses were not different. The antinociceptive action was as high at 24 h as at 3 h (e.g. for 512 micrograms/kg, 44 +/- 9% and 51 +/- 12%, respectively); 48 h after injection the scores of the treated groups were not different from the score for saline treatment in the tail flick test, 512 micrograms/kg induced a significant antinociceptive effect for 12 h (maximal at the 3rd hour: +60%). No behavioral changes, and particularly no motor activity modifications were observed.

Amino Acid Sequence↗
PubMed1991

Relation between plasma concentration and clinical efficacy after sublingual single dose apomorphine in Parkinson's disease.

Five patients with Parkinson's disease were given a single sublingual dose of apomorphine in 3 mg tablets (2 patients received 18 mg and 3 patients took 39 mg). The therapeutic effect appeared within 33.0 min and lasted 137 min. There was a significant correlation between peak concentration, area under the curve, dose (mg/kg) and the duration of the therapeutic effect.

Administration, Sublingual↗