Craving patterns in methadone maintenance treatment with dextromoramide as adjuvant.

A study was performed to establish the effect on opiate craving among six long-term opiate-dependent subjects in methadone maintenance treatment. Subjects currently stabilised on methadone, received 5 or 10 mg dextromoramide besides methadone. During the study the usual methadone dose was diminished according to the individual subject's expectation of the effect of dextromoramide addition.

L-Methadone and D,L-methadone in methadone maintenance treatment: a comparison of therapeutic effectiveness and plasma concentrations.

The clinical effectiveness of l-methadone maintenance treatment (LMMT) carried out using d,l-methadone or l-methadone have been compared with ambulatory heroin-dependent subjects. A total of 40 heroin-dependent subjects, previously maintained on l-methadone in Frankfurt am Main, were divided into two groups under randomised double-blind conditions and received either an equivalent dose of l-methadone as d,l-methadone or remained on the previous l-methadone treatment. Requests for a change in the dose of d,l-methadone and l-methadone were recorded, urine samples for determination of illicit drug use were collected and the individual level of opiate craving was determined over a 22-day observation period.

Determination and pharmacokinetics of dextromoramide in methadone maintenance therapy.

To study the pharmacokinetics of dextromoramide in long-term opiate addicts on methadone maintenance therapy (MMT) a reverse-phase HPLC technique was developed to monitor dextromoramide and methadone concentrations in plasma simultaneously. After liquid-liquid extraction from plasma, dextromoramide and methadone were determined using a Supelcosil LC-ABZ column and a mobile phase of KH2 phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) and UV detection at 206 nm.

Craving despite extremely high methadone dosage.

A clinical case study is presented of an opiate addict, currently under methadone maintenance treatment (MMT), who claims the need of a higher daily methadone dose. He is admitted to a closed metabolic ward, where he receives 250 mg methadone per day. During 24 h both pharmacokinetic parameters and craving levels are measured simultaneously.

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts.

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10-225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65-630 ng x ml(-1) and from 5 to 55 ng x ml(-1), whereas the peak concentrations were 124-1255 ng x ml(-1) and 10-301 ng x ml(-1) for methadone and the AUC(0-24 h) for EDDP varied from 5.

Rat alpha 2 macroglobulin is a selective inhibitor of antigen-induced leucotrienes in rat isolated lungs.

Exogenously administered, purified rat alpha 2 macroglobulin (alpha 2M, recognized as an acute phase reactant with anti-inflammatory properties) greatly inhibits the increase of the pulmonary resistance during the antigen-induced bronchoconstriction in rats in vivo, whereas a BaSO4 pretreatment (a method to induce a broad spectrum of serum acute phase reactants, including alpha 2M) covers a broader bronchoprotection: suppression of the decrease of the dynamic lung compliance as well. To explain these differences we studied the influence of both alpha 2M and BaSO4 on the antigen-induced bronchoconstriction in rat isolated lungs in relation to the mediator release in lung-effluents. We report here that in this model alpha 2M only inhibits the antigen-induced SRS-A release, whereas the concomitant release of histamine and 5-HT was unaffected.

The effects of alpha M-foetoprotein, an acute phase protein, and BaSO4-induced injury on IgE-mediated, systemic anaphylaxis in the rat.

A recently developed method for inducing fatal, IgE-mediated, bronchial and cardiovascular anaphylaxis in the rat was used to compare the effects of exogenously administered, purified alpha M-foetoprotein (alpha M FP) and BaSO4 pretreatment (as mean to induce an acute phase reaction with increased alpha M FP serum levels) with regard to mortality, bronchoconstriction and cardiovascular events. The BaSO4 pretreatment protected the rats almost completely against mortality, whereas exogenously administered alpha M FP offered no protection at all. With respect to the antigen-induced bronchoconstriction alpha M FP greatly inhibited the increase of the pulmonary resistance (RI), whereas the BaSO4 pretreatment suppressed either the dynamic lung compliance (Cdyn) or RI considerably.

Effect of naloxone on blood pressure and survival in different shock models in rats.

The effect of naloxone on a number of experimental shock models, using the anaesthetized rat, was studied with special emphasis on mean arterial blood pressure (MABP) and chance of survival. Only a slight increase in MABP was noted in haemorrhagic shock models whereas survival was not affected. Naloxone was without effect in endotoxin shock (i.

The effect of prednisolone and ketotifen on the antigen-induced bronchoconstriction and mediator release in rat isolated lungs.

Using a new method for inducing IgE-mediated, systemic anaphylaxis in the rat both prednisolone and ketotifen had been shown previously to be effective in suppressing the bronchial anaphylaxis in vivo. In order to study the mode of action underlying their bronchoprotective effect, both agents were also tested on the antigen-induced bronchoconstriction in rat isolated lungs in relation to the mediator release in the lung-effluent. The presence of histamine, 5-hydroxytryptamine (5-HT) and SRS-A could be detected biologically in the lung-effluent during bronchoconstriction.

Characterization of various antiallergic agents using a new method for inducing systemic anaphylaxis in the rat.

Five different types of antiallergic agents were studied using a newly developed method for inducing IgE-mediated bronchial and cardiovascular anaphylaxis in the rat. With the exception of the histamine H1 antagonist mepyramine (no activity at all), each antiallergic tested showed a different and characteristic profile of antiallergic activity. Prednisolone and the SRS-A antagonist FPL 55712 protected the rats completely against mortality, whereas cromoglycate and ketotifen offered only partial protection.

A new method for inducing fatal, IgE-mediated, bronchial and cardiovascular anaphylaxis in the rat.

Brown-Norway rats, sensitized with trinitrophenyl (TNP) haptenized ovalbumin and AIPO4 as adjuvant 12 days before, were challenged with trinitrophenyl haptenized bovine serum albumin intravenously, while lung function (Vt, V, Ppl, Fres, Cdyn, and Rl) and cardiovascular function (BP and Fheart) were measured continuously. This resulted in a highly reproducible, plasma IgE-antiTNP related, immediate anaphylactic response characterized by a short-lasting (8-10 min) bronchoconstriction, together with a long-lasting fall in blood pressure. All rats died in shock within 21-150 min.

Inhibitory effects of BaSO4 on experimentally induced inflammation in the rat mediated by alpha M-foetoprotein.

The influence was studied of BaSO4 (i.p.) pretreatment on the mediator induced inflammatory responses: oedema formation, measured plethysmographically, increased vascular permeability to protein, measured by the extravascular accumulation of 125I-labeled albumin (125I-HSA) and vasodilatation, measured by the accumulation of 51Cr-labeled erythrocytes.

Smooth muscle contracting compounds in the venom of Megascolia flavifrons (Hym: Scoliidae) with notes on the stinging behaviour.

1. The wasp Megascolia flavifrons stings larvae of the stag beetle Oryctes nasicornis on the ventral side of all segments, except the last three, which do not contain nerve ganglia. 2.

Hypotensive effects of plasma protein fraction. The relation between prekallikrein activator, bradykinin generation, and blood pressure in an animal model.

In a rat model, the relationship between the activity of PKA in human PPFs, the changes in arterial BK concentration, and the changes in blood pressure on infusion of PPF was investigated. The rat was chosen as a model because it is reported to be one of the few animals sensitive to human PKA. However, hypotensive reactions after infusion of human PKA-containing PPF were observed only in the presence of a bradykinin-potentiating peptide (BPP9a).

Further studies on the structure-activity relationships of bradykinin-potentiating peptides.

Several pentapeptides were synthesized and tested for bradykinin-potentiating activity. From these and previous data it appeared that an (L)-aromatic amino acid residue (preferably Trp) in position 3 is essential for high activity. Position 3 represents a stereospecific pillar function, whereas the other positions and the lipophilicity/hydrophilicity balance are important for additional activity.

Efficacy of theophylline and its N-7-substituted derivatives in experimentally induced bronchial asthma in the guinea-pig.

A study has been made of the bronchospasmolytic actions of theophylline and some ot its N-7-substituted derivatives administered by i.v infusion in anaesthetized guinea pigs, in which experimental bronchial asthma was induced by i.v.

Structure-activity relationships of bradykinin potentiating peptides.

A number of A-VI-5 (Val-Glu-Ser-Ser-Lys) analogues and fragments were synthetized and tested on bradykinin potentiating activity so as to establish the nature of the active group(s) or structural characteristics of some bradykinin potentiating pentapeptides. It could be concluded that (1) the polar groups of the side-chains, such as the two hydroxyl groups of the serine residues, the omega-carboxyl group of the glutamic acid residue and the omega-amino group of the C-terminal lysine, are not essential for the bradykinin potentiating activity; (2) the chain length (at least 5 amino acids) and the lipophilicity of the N-terminal amino acid as well as the whole peptide are of much more importance; (3) the free N-terminal NH2-group is not essential; (4) aromatic amino acids in position 3 of the peptide chain result in highly active bradykinin potentiating peptides.

The mechanism of action of two bradykinin-potentiating peptides on isolated smooth muscle.

Bradykinin-induced contractions in the guinea-pig ileum were potentiated by the peptides A-VI-5 (Val-Glu-Ser-Ser-Lys) and BPP5a (Pyr-Lys-Trp-Ala-Pro), while the contractions induced by other agonists were not affected. Neither peptide added alone caused any response. Previous addition of the peptides shortened the latent period following the addition of bradykinin to a value corresponding to the contraction height with an equivalent dose of bradykinin added alone.

The bradykinin potentiating activity of two pentapeptides on various isolated smooth muscle preparations.

Two bradykinin potentiating peptides A-VI5 (Val-Glu-Ser-Ser-Lys) and BPP5a (Pyr-Lys-Trp-Ala-Pro), were compared with respect to their potentiation of a number of different bradykinin effects on six isolated smooth muscle preparations. Apart from the considerable difference in effective concentrations, no essential qualitative difference was observed between these two peptides. Therefore the assumption of a different mechanism of action for the two peptides, which have a completely different structure, could not be substantiated.

The effect of catecholamine depletion on the bradykinin-induced relaxation of isolated smooth muscle.

The effect of depletion of catecholamines by tyramine or reserpine on the bradykinin-induced relaxation of the rat duodenum aan rabbit ileum was the object of this study. The relaxation was not affected by catecholamine depletion due to repeated addition of tyramine to the isolated organs from either normal or reserpine-treated animals. From these findings and on the basis of other data in the literature it can be concluded that the bradykinin relaxation is not due to a release of catecholamines, but rather to a direct effect on the smooth muscle cells.