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PubMed2001

Comparison of PDE 4 inhibitors, rolipram and SB 207499 (ariflo), in a rat model of pulmonary neutrophilia.

Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.

Adrenalectomy↗
PubMed1988

A comparison of the stimulus effects of codeine in rhesus monkeys under the contingencies of a two lever discrimination task and a cross self-administration paradigm: tests of generalization to pentazocine, buprenorphine, tilidine, and different doses of codeine.

The stimulus effects of codeine were assessed in three monkeys trained to perform first under the contingencies of a cross self-administration paradigm and then under a two lever discrimination task. Codeine-trained monkeys generalized to pentazocine, buprenorphine, and codeine under both procedures in doses different from the training dose. Codeine-trained monkeys did not generalize to tilidine. These results indicate that monkeys do not behave in a qualitatively different way when presented with the study drugs under both contingencies. However, there were marked quantitative differences between the generalization effects of doses of pentazocine, buprenorphine, and codeine to doses other than that used in training between the two paradigms. Much higher doses of codeine and pentazocine, but not of buprenorphine, were necessary for inducing generalization effects in the two lever task than in the cross self-administration procedure. The possible reasons for these quantitative differences are discussed. It is concluded that the cross self-administration procedure is more sensitive for the assessment of opioid-like stimulus properties of drugs than the two lever discrimination task.

Animals↗
PubMed1988

Facilitatory and inhibitory muscarine receptors on the rat phrenic nerve: effects of pirenzepine and dicyclomine.

Neuronal transmitter stores of the rat phrenic nerve were labelled by an incubation with [3H]choline. Release of [3H]acetylcholine was elicited either by a short (100 pulses, 5 Hz) or by a long (1500 pulses, 5 or 25 Hz) period of electrical nerve stimulation. Pirenzepine and dicyclomine enhanced transmitter release evoked by the short stimulation period. Both antagonists reduced transmitter release evoked by the long stimulation period. Pirenzepine reduced transmitter release at low concentrations (1 nmol/l) whereas a higher concentration was necessary for the enhancing effect; the opposite pattern was found for dicyclomine. A low concentration of oxotremorine (10 nmol/l) enhanced and a high concentration (1 mumol/l) reduced transmitter release evoked by the short stimulation period. Both effects could be prevented by a low concentration of pirenzepine (10 nmol/l). It is concluded that facilitatory and inhibitory muscarine receptors are present on the motor nerve. A short stimulation period activates predominantly the negative muscarinic feedback, whereas during a long period of continuous nerve stimulation the positive muscarinic feedback mechanism is additionally activated. Both the facilitatory and inhibitory receptors might be regarded as M1-receptors but differences in the pharmacological properties between both receptor populations appear possible.

Acetylcholine↗
PubMed1991

Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065.

Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p. - or s.c.- implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.

Animals↗
PubMed1995

Humoral and haemodynamic effects of idrapril calcium, the prototype of a new class of ACE-inhibitors, in essential hypertensive patients.

Idrapril is the prototype of a new class of ACE inhibitors, characterised by the presence of a hydroxdmic group. Six untreated in-patients with essential hypertension were given single oral doses of the calcium salt of idrapril, idrapril calcium (200 mg) and placebo according to a double blind, randomised experimental design. Supine and upright blood pressure, heart rate, plasma idrapril serum UCE, active renin and angiotensin II were measured at timed intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours (3.01 microgm x ml(-1)), and by 12 hours the compound had almost disappeared (67 ng x ml(-1)). Derived t1/2 was 1.4-2.2 h. ACE activity was suppressed [from 77.9 to 3.3 after 2 hours and 11.8 after 12 hours nmol(-1) x min(-1) x ml] and angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5 (after 24 hours) pg x ml(-1)]. Compared to placebo, idrapril calcium significantly lowered both supine blood pressure starting at 4 hours (idrapril calcium 140/93 mmHg; placebo 157/101 mmHg; placebo 147/100 mmHg), and upright blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100 mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg). Idrapril calcium appears to be an effective ACE inhibitor in essential hypertension, with a hypotensive action for up to 24 h.

Absorption↗
PubMed1995

Biosynthesis of cytochrome f in Chlamydomonas reinhardtii: analysis of the pathway in gabaculine-treated cells and in the heme attachment mutant B6.

Chlamydomonas reinhardtii uses two c-type cytochromes for photosynthetic electron transfer: the thylakoid membrane-bound cytochrome f of the cytochrome b6f complex and the soluble cytochrome c6. Previously, a class of photosynthesis-minus, acetate-requiring mutants was identified which were deficient in both c-type cytochromes, and biochemical analyses of cytochrome c6 biosynthesis in these strains indicated that they were each blocked at the step of heme attachment to apocytochrome c6. In order to demonstrate that the deficiency in cytochrome f results from the same biochemical and genetic defect, cytochrome f biosynthesis was examined in the B6 mutant (a representative of this phenotypic class) and in spontaneous suppressor strains derived from B6. Pulse-radiolabeling experiments show that B6 synthesizes a form of cytochrome f that is rapidly degraded in vivo. This polypeptide is membrane associated and migrates with an electrophoretic mobility identical to that of standard apocytochrome f produced in vitro but slightly greater than that of standard holocytochrome f produced in vivo by wild-type cells. These findings suggest that the B6 strain is unable to convert apocytochrome f to holocytochrome f and that apocytochrome f is unstable in vivo. In the suppressed strains, accumulation of both holocytochrome f and holocytochrome c6 is restored. One suppressor mutation (strain B6R) displays uniparental inheritance whereas another (B6T3) displays Mendelian inheritance. In both cases, the three phenotypes, photosynthesis-plus, b6f+ and cyt c6+ co-segregate in genetic crosses. This study therefore confirms that the dual cyt b6f-/cytc6- deficiency in B6 results from a single mutation that affects a step in holocytochrome formation that is common to the biosynthetic pathways of both plastidic c-type cytochromes. The study also confirms that pre-apocytochrome f synthesis, processing and association with the membrane is not dependent on heme attachment. Synthesis of cytochrome f does, however, appear to be dependent on heme availability. In cells depleted of tetrapyrrole pathway intermediates by gabaculine treatment, cytochrome f synthesis was significantly reduced. Since gabaculine treatment did not affect the stability of cytochrome f nor the accumulation of cytochrome f-encoding transcripts, the reduction is attributed to post-transcriptional regulation of preapocytochrome f synthesis via a pathway that is sensitive to the availability of heme or a tetrapyrrole pathway intermediate.

Animals↗
PubMed1979

Mutagenicity studies of 4-(2-carboxyethyl) phenyl trans-4-aminomethylcyclohexane carboxylate hydrochloride (DV-1006). A new antiulcer drug.

An antiulcer drug, 4-(2-carboxyethyl) phenyl trans 4-aminomethylcyclohexane carboxylate hydrochloride (DV-1006), was studied for mutagenicity using bacterial systems, in vitro and in vivo cytogenetics, and dominant lethal tests. No mutagenicity of DV-1006 was observed either in the rec-assay on Bacillus subtilis or in the Salmonella/microsome test (Ames test). In in vitro cytogenetics, DV-1006 had no effects on the chromosomes of chinese hamster cells at cytotoxic doses. Rats were treated singly or on 5 consecutive days orally with dose levels of 16, 160, or 1600 mg DV-1006/kg for detecting cytogenetic effects in vivo. As a result, no increase of the incidence of chromosomal aberrations in bone marrow cells was observed in any group of DV-1006. A single or 5 daily oral administration of DV-1006 (16 or 1600 mg/kg) to male mice and subsequent mating for 8 weeks produced no dominant lethal mutational effects. These results show that DV-1006 has no mutagenic potential.

Animals↗
PubMed1976

A death case involving tilidine.

A fatal poisoning case due to the combination of a relative overdose of barbiturates (600 mg daily) and 750 mg of tilidine is reported. The concentrations of barbiturates and tilidine with its metabolites were determined in blood, liver, and urine.

Adult↗
PubMed1978

[Critical comments on a case history "a death case involving tilidine" (author's transl)].

The author looks critically at the description of a suicide case involving a barbiturate dose that could not be determined exactly and doses of hydroxyzine and tilidine. Drugs with a short and a medium short duration of action obviously had the greatest effect. There was no description of an investigation of the gastric contents. The concentration of barbiturates in the blood alone was sufficient to cause death. The deceased also took hydroxyzine, and then finally 750 mg tilidine in capsule form. Tilidine's action is relatively slow in onset. The author discusses tilidine's possible contribution to the cause of death and comes to a different conclusion from the authors of the case report, especially as regards the key words "Tilidine--Intoxication". The authors of the case report ought to have called it "A Death Case Involving Barbiturates, Hydroxyzine and Tilidine" rather than giving is such a suggestive title as "A Death Case Involving Tildine". This would have been a more accurate representation of the facts and would have assisted the reader to grasp the complex toxicological situation more clearly.

Barbiturates↗
PubMed1978

The opiate-like action of tilidine is mediated by metabolites.

The analgesic effect of tilidine in rats is completely antagonized by the narcotic antagonist naloxone. Radioreceptor assays revealed, however, that the main metabolites of tilidine, nortilidine and bisnortilidine, rather than tilidine exhibit affinity to opiate receptors. These findings were confirmed in studies using the electrically stimulated guinea pig ileum and the mouse vas deferens. Chronic tilidine administration to rats caused a considerable degree of physical dependence, which was expected from the ability of the intact animal to metabolize tilidine. In the isolated ileum from chronically morphinized guinea pigs, both nortilidine and bisnortilidine fully substituted for morphine in preventing induction of withdrawal, indicating dependence liability of these metabolites.

Analgesia↗
PubMed1978

Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines.

Intranigral injection of muscimol induced hyperactivity in rats and antagonized haloperidol-induced catalepsy. Intranigral injection of gabaculine, an inhibitor of GABA transaminase, induced similar effects 5h after injection, when the nigral GABA content was increased 7-fold. On the other hand, injections of muscimol (30 ng) into the globus pallidus potentiated the cataleptic effect of haloperidol, and muscimol alone in high doses (100 and 200 ng) induced catalepsy. Gabaculine also induced catalepsy of medium intensity and potentiated the effect of haloperidol 24h after injection, when GABA was increased in the globus pallidus as well as in the substantia nigra. Injections of muscimol into either the globus pallidus or substantia nigra increased striatal HVA and enhanced haloperidol-induced elevation of HVA. Three benzodiazepines, nitrazepam, diazepam and chlordiazepoxide administered orally, potentiated the effect of muscimol (30 ng) injected into the globus pallidus and induced catalepsy. A similar effect was not obtained with phenobarbital. It is suggested that stimulation of GABA receptor or increase of GABA content in the sustantia nigra antagonize haloperidol-induced catalepsy by activation of nigral dopaminergic system, and that enhancement of pallidal GABA function induces catalepsy by non-dopaminergic mechanisms. Potentiation of haloperidol-induced catalepsy by benzodiazepines may be due to enhancement of GABA-ergic transmission within the globus pallidus.

4-Aminobutyrate Transaminase↗