Chronic morphine treatment causes down-regulation of spinal adenosine A1 receptors in rats.

Recent studies suggest that the release of adenosine in the spinal cord may be a significant component of the morphine antinociceptive action. We wanted to know whether the spinal adenosine system is involved in morphine tolerance. Animals were rendered tolerant to morphine, and A1 adenosine receptor binding activity was measured.

Intravenous recombinant tissue-type plasminogen activator in acute myocardial infarction.

The efficacy and safety of intravenously administered recombinant tissue-type plasminogen activator (rt-PA, Boehringer Ingelheim Corp.) was investigated in 10 patients with acute myocardial infarction (AMI). rt-PA was given as a 10 mg bolus dose followed by infusions of 50 mg, 20 mg and 20 mg in three successive hours.

Chronic effect of [D-Pen2,D-Pen5]enkephalin on rat brain opioid receptors.

In previous studies, we have demonstrated that chronic etorphine or [D-Ala2,D-Leu5]enkephalin (DADLE) treatment of rats results in the reduction of mu- and delta-opioid receptor binding activities as tolerance develops. As both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu- and delta-receptors, these studies could not determine whether down-regulation of a specific receptor type occurs. Therefore, in the present studies, animals were rendered tolerant to the delta-opioid receptor-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and receptor binding activities were measured.

Decrease in mu-opioid receptor binding capacity in rat brain after chronic PL017 treatment.

In previous studies, we have demonstrated that chronic treatment of rats with either etorphine or D-Ala2, D-Leu5-enkephalin (DADLE) resulted in the reduction of opioid receptor binding activities during the course of tolerance development. In both cases, mu-opioid receptor binding capacity was attenuated together with the delta-opioid receptor binding capacity. Because both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu and delta receptors, these studies could not determine whether down-regulation of a specific receptor type is possible.

The characterization of EIAV reverse transcriptase and its inhibition by 5'-triphosphates of 2'-deoxyuridine analogs, PFA and PAA.

A characterization of equine infectious anemia virus reverse transcriptase (EIAV RT) and its inhibition by 5'-triphosphate analogs was undertaken to explore the possibility of using EIAV RT as an in vitro model for studying human immunodeficiency virus (HIV). EIAV RT activity was found to be dependent on the bivalent cations Mg++ and Mn++. The optimal pH for enzyme reaction was pH 8.

Inhibition of HIV-1 reverse transcriptase by 5'-triphosphates of 5-substituted uridine analogs.

The 5'-triphosphates of some 5-substituted 2'-deoxyuridine analogs were investigated for their effects on purified recombinant reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) as well as cellular DNA polymerase alpha. The triphosphates were competitive inhibitors of the viral enzyme with dTTP as the variable substrate and poly(rA)oligo(dT) as template, and preferentially inhibited the viral polymerase. Ordering the compounds according to their decreasing binding affinities, as reflected by their increasing inhibition constants for the reverse transcriptase, gave nPrearaUTP greater than nPrdUTP greater than EtdUTP greater than nPredUTP greater than HMdUTP greater than CEdUTP.

Pacemaker activity is modulated by tissue levels of cyclic adenosine 3',5'-monophosphate in human atrial fibers.

We studied the role of tissue cyclic AMP levels in the chronotropic effects of theophylline on automatic human atrial fibers obtained from the hearts of 17 patients undergoing corrective open-heart surgery. Atrial fibers were perfused with Tyrode solution and transmembrane action potentials were recorded with a conventional microelectrode technique. In normal Tyrode solution, theophylline (0.

[Synthesis of antiviral agents acyclic nucleo-sides of 4-substituted pyrrolo [2,3-d] pyrimidine].

Naturally occurring nucleosides of pyrrolo [2,3-d] pyrimidine, tubercidin, sangivamycin and toyocamycin were known as antibodies not only for their potent antitumor activity but also for their significant antiviral effects. However, none of them was developed to be a useful drug due to their high toxicity. In order to reduce the toxicity of this kind of compounds and reveal the relationship between structure and biological activity, a series of acyclic analogues of tubercidin with varied 4-substituted amino groups were synthesized.

Inhibition of human hepatitis B virus DNA polymerase and duck hepatitis B virus DNA polymerase by triphosphates of thymidine analogs and pharmacokinetic properties of the corresponding nucleosides.

Replication of hepadnaviruses involves a viral DNA polymerase containing both a DNA-dependent and an RNA dependent activity. This polymerase is a potential target for chemotherapy against hepatitis B. We have used human hepatitis B virus DNA-dependent DNA polymerase from human serum and duck hepatitis B virus DNA-dependent DNA polymerase from duck serum as well as RNA-dependent DNA polymerase activity from duck hepatitis B-infected duck liver.

Decrease in delta-opioid receptor density in rat brain after chronic [D-Ala2,D-Leu5]enkephalin treatment.

Chronic treatment of Sprague-Dawley rats with [D-Ala2,D-Leu5]enkephalin (DADLE) resulted in the development of tolerance to the antinociceptive effect of this opioid peptide. When opioid receptor binding was measured, time-dependent decreases in [3H]diprenorphine binding to the P2 membranes prepared from the cortex, midbrain and striatum were observed. Scatchard analysis of the saturation binding data revealed a decrease in Bmax values and no change in the Kd values of [3H]diprenorphine binding to these brain regions, indicative of down-regulation of the receptor.

Role of receptor regulation in opioid tolerance mechanisms.

The molecular basis of opioid tolerance/dependence has long eluded researchers, but recent advances in receptor regulation have suggested a useful conceptual approach to the problem. In NG108-15 neuroblastoma x glioma hybrid (NG) cells, opioid agonists inhibit adenylate cyclase in a dose-dependent, naloxone-antagonizable fashion. Chronic treatment with opioid agonists results in a series of molecular processes that, in a tolerance-like fashion, counteract this inhibition.

Decrease in delta and mu opioid receptor binding capacity in rat brain after chronic etorphine treatment.

The modulatory effect of continued activation of opiate receptors with agonist on the receptor level was examined in current studies. Rats were rendered tolerant to etorphine by s.c.

Diagnosis of tertian malaria by enzyme-linked immunosorbent assay.

A method of ELISA diagnosis of tertian malaria based on detecting Plasmodium vivax antigen in red blood cells (RBC) was developed, using 0.16 ml of packed, washed, and sonicated RBC. 68 blood samples from tertian malaria cases were examined; 67 (98.

Determination of the sizes of the opioid receptors in their membrane environment by radiation inactivation.

Opioids, like other drugs, are thought to initiate their effects by association with their specific receptors. However, very little is known about the opioid receptor as a molecular entity. The binding components have been solubilized in detergent and purified by different approaches, but the molecular size of soluble opioid receptor complexes reported by different groups varied from 23,000 to 750,000.

Heterogeneity of [3H]ethyl beta-carboline-3-carboxylate binding sites and [3H]gamma-aminobutyric acid binding sites.

Binding properties of [3H]flunitrazepam ([3H]FNZ), [3H]ethyl beta-carboline-3-carboxylate ([3H]beta CCE), [3H]muscimol ([3H]MUSC) and [3H]gamma-aminobutyric acid ([3H]GABA) to bovine cortical membranes and to their Triton extracts were studied. GABA, 1 X 10(-5) M, stimulated [3H]FNZ binding of frozen, thawed and washed membranes by an increase in affinity without alteration of the maximal number of binding sites, and this GABA stimulated [3H]FNZ binding can be inhibited by bicuculline methobromide. Freeze, thaw and wash with Triton X-100 removed the low affinity [3H]MUSC binding sites.

Purification of Epstein-Barr virus DNA polymerase from P3HR-1 cells.

The Epstein-Barr virus DNA polymerase was purified from extracts of P3HR-1 cells treated with n-butyrate for induction of the viral cycle. Sequential chromatography on DNA cellulose, phosphocellulose, and blue Sepharose yielded an enzyme preparation purified more than 1,300-fold. The purified enzyme was distinct from cellular enzymes but resembled the viral DNA polymerase in cells infected with herpes simplex virus type 1 or 2.

Effects of prostaglandin E2, 16,16-dimethyl prostaglandin E2 and a prostaglandin endoperoxide analogue (U-46619) on gastric secretory volume, [H+] and mucus synthesis and secretion in the rat.

The effects of orally administered prostaglandin E2, 16,16-dimethyl prostaglandin E2 and U-46619, an analogue of the prostaglandin endoperoxide PGH2, on gastric secretory volume, acid and mucus were studied in the rat. All of the compounds significantly increased the volume of gastric secretion, mucus secretion, measured as N-acetylneuraminic acid and mucus synthesis measured as the incorporation of [3H]-glucosamine into mucosal glycoprotein; however, only PGE2 and 16,16-dimethyl PGE2 inhibited acid secretion. U-46619, 1.

Phosphorylation of four acyclic guanosine analogs by herpes simplex virus type 2 thymidine kinase.

Four acyclic guanosine analogs, the (R) and (S) enantiomers of 9-(3,4-dihydroxybutyl)guanine, 9-(4-hydroxybutyl)guanine, and acyclovir were compared in enzyme kinetic experiments, using purified herpes simplex virus type 2 thymidine kinase. All four analogs showed competitive patterns of inhibition in the phosphorylation of thymidine by the viral thymidine kinase, but different affinities and relative rates of phosphorylation were observed.