Natural variation within the principal arginine-specific protease gene, prpR1, of Porphyromonas gingivalis

Patients who were treated for fractures of the limbs were assigned to 1 of 2 groups for the management of postoperative pain. In Group 1 (postoperative patient-controlled analgesia group), 46 patients were given postoperative continuous epidural anaesthesia in combination with narcotic analgesics and this was regulated by the patient using a device. The 46 patients in Group 2 (control group) received suppositories or intramuscular injections of narcotic analgesics on their request. Patients in Group 1 needed suppositories and intramuscular injection of narcotic analgesics less often than those in Group 2, and had more satisfactory pain relief according to the visual analogue scale for pain assessment made on the first, second and third postoperative day. The time spent by nurses for pain management in Group 1 was less than that in Group 2. It appears that this patient-controlled method, combined with postoperative continuous epidural anaesthesia, is a safe, effective and efficient method for the management of postoperative pain.     

Deletions of the short arm of chromosome 9, including the interferon-alpha/-beta genes, in acute lymphocytic leukemia. Studies on loss of heterozygosity, parental origin of deleted genes and prognosis

A restriction fragment length polymorphism (RFLP) analysis of the alpha- and beta-interferon (IFN) genes was performed in malignant cells from 52 patients with acute lymphocytic leukemia (ALL). Normal cell DNA was available for comparison in 23 of the patients. Ten patients were found to have gross alterations of their alpha- and beta-IFN genes. Leukemic cells from 2 ALL patients showed a complete loss of alpha- and beta-IFN genes. Seven patients had a hemizygous loss of one of the alpha- and beta-IFN alleles, as shown by RFLP analysis and/or loss of signal intensity. In one other patient the malignant clone was reduced to homozygosity with regard to the alpha- and beta-IFN genes, without loss of signal intensity. In patients without hemizygous deletions, the overall incidence of complete homozygosity for the alpha- and beta polymorphisms was higher than expected. Analysis of the data indicates that the total frequency of ALL clones with gross alterations of the IFN-loci is around 30%. A 9p24 probe detected hemizygous deletions in 2 cases of IFN gene deletions. In the other tested cases the deletions were interstitial. No deletions of 9p24 were detected in patients without allelic losses of IFN genes. In 5 cases of allelic IFN gene deletions, DNA from parents was available for comparison. In 4 cases the deleted allele was derived from the mother, whereas in the fifth it originated from the father. Pediatric ALL patients with IFN-gene deletions or homozygosity for all polymorphisms in the IFN-loci had a significantly worse prognosis than heterozygotes. We conclude that deletion of alpha- and beta-IFN genes is a relatively common event in ALL and that RFLP analysis of the IFN genes may provide additional prognostic information in childhood ALL. Whether or not the IFNs act as tumor-suppressor genes in this disease is not yet known.     

The ecotoxicity and the biodegradability of lactic acid, alkyl lactate esters and lactate salts

The ecotoxicity of lactic acid, its alkyl esters and selected metal salts was studied experimentally with the micro alga Selenastrum capricornutum, the crustacean Daphnia magna and the fish species Brachydanio rerio and Pimephales promelas. In addition, the biodegradation of lactate esters was also studied. The aim of the study was to provide predicted environmental data for additional alkyl homologues and metal salts. The ecotoxicity data are evaluated by means of Structure Activity Relations (SAR), using literature data on a non-polar narcotic mechanism of toxicity as a baseline for comparison. Lactate salts were evaluated by comparison to the toxicity of the metal ion. For the fish and D. magna, it was evident that methyl, ethyl, propyl and to a lesser extent butyl lactate were slightly more toxic in comparison to baseline non-polar narcotic toxicity data. The toxicity tests carried out with lactate-salts demonstrated clearly that the toxicity in standard tests is only determined by the associated cation and not by the lactate part. Lactic acid and its alkyl esters were degraded for more than 60% in the ready biodegradability tests and from the data presented, it is evident that the majority of alkyl lactates are readily biodegradable. The results presented in this study indicate that alkyl lactate esters show some differences in their ecotoxicity when compared to non polar narcotic compounds in but that these differences are generally small. When aquatic toxicity is considered together with their rapid tendency to biodegrade, it is concluded that lactate esters show generally favourable environmental characteristics.     

Interaction of estradiol, progesterone and corticosterone on uterine connective tissue degrading enzymes

The impact of ovarian hormones and corticosterone acetate on uterine connective tissue degrading enzymes were studied in mature albino rats. Ovariectomy resulted in a significant increase in the activities of alpha- and beta-galactosidases and glucosidases in the uterus. Administration of estradiol to ovariectomized rats brought back the activities of alpha-galactosidase and alpha-glucosidase to normalcy. While beta-galactosidase and beta-glucosidase were significantly decreased. Administration of progesterone to ovariectomized rats resulted in the increase of alpha- and beta-galactosidases and glucosidases. Administration of corticosterone to ovariectomized rats produced a further increase in alpha- and beta-galactosidases and glucosidases in the uterus. Adrenalectomy in ovary intact rats produced a decrease in alpha-galactosidase however, beta-glucosidase was significantly increased. Administration of corticosterone to ovary intact rats significantly increased the activities of alpha- and beta-galactosidases, while alpha- and beta-glucosidases were found to be decreased. Ovariectomy resulted in a significant increase in the activities of cathepsin-D and cathepsin-E. Administration of estradiol to ovariectomized rats brought back the activity of cathepsin-D to normalcy, whereas cathepsin-E was significantly increased. Administration of progesterone as well as estradiol to ovariectomized rats significantly increased the levels of cathepsin-E, however, cathepsin-D was brought back to normalcy. Administration of corticosterone to ovariectomized rats as well as ovariectomy + adrenalectomy significantly increased the activity of cathepsin-D and cathepsin-E. Adrenalectomy significantly decreased the activity of cathepsin-D, while administration of corticosterone increased the cathepsin-D and cathepsin-E in the uterus. Therefore, these results suggest that estradiol is a potent ovarian steroid protecting the extra cellular matrix components. The effect of progesterone appears to modulate and act hand in hand with estradiol. Corticosterone appears to have an opposite effect to that of estradiol.     

Glial cell line-derived neurotrophic factor/neurturin-induced differentiation and its enhancement by retinoic acid in primary human neuroblastomas expressing c-Ret, GFR alpha-1, and GFR alpha-2

Neuroblastomas often undergo spontaneous differentiation and/or regression in vivo, which is at least partly regulated by the signals through neurotrophins and their receptors. Recently, glial cell line-derived neurotrophic factor (GDNF) and a second family member, neurturin (NTN), have been found to mediate their signals by binding to a heterotetrameric complex of c-Ret tyrosine kinase receptors and glycosylphosphatidylinositol-linked proteins, GFR alpha-1 (GDNFR-alpha) or GFR alpha-2 (TrnR2/GDNFR-beta/NTNR-alpha/RETL2). Here, we studied the effect of GDNF and NTN on human neuroblastomas in the short-term primary culture system, as well as the expression of c-Ret, GFR alpha-1, GFR alpha-2, GDNF, and NTN. GDNF (1-100 ng/ml) induced morphological differentiation in 34 of 38 primary neuroblastomas and an accompanying increase in c-Fos induction. These effects were markedly enhanced by treatment with 5 microM all-trans-retinoic acid. Although GDNF alone induced a rather weak differentiation independent of the disease stages, the enhancement of neurite outgrowth induced by treatment with both GDNF and all-trans-retinoic acid was significantly correlated with younger age (less than 1 year; P = 0.0039), non-stage 4 diseases (P = 0.0023), a single copy of N-myc (P = 0.027), and high levels of TRK-A expression (P = 0.0062). To examine the expression levels of GFR alpha-1, we cloned a short form of the human GFR alpha-1 gene with a 15-bp deletion by screening a human adult substantia nigra cDNA library. Many primary neuroblastomas expressed c-Ret, GFR alpha-1, and GFR alpha-2 as well as their ligands, GDNF and NTN, suggesting the presence of a paracrine or autocrine signaling system within the tumor tissue. The effect of NTN on primary culture cells of neuroblastoma was similar to that of GDNF. These imply that the GDNF(NTN)/c-Ret/GFR alpha-1(GFR alpha-2) signaling may have an important role in regulating the growth, differentiation, and cell death of neuroblastomas.     

Naloxone antagonizes narcotic self blockade of emesis in the cat

Morphine, levorphanol, fentanyl and methadone given by intracerebroventricular (i.c.v.) injection blocked the vomiting response to a standard emetic test dose of apomorphine subsequently injected i.c.v. Of these narcotics, only morphine initially evoked vomiting. Systemic pretreatment with naloxone (5 mg/kg i.p. or i.v.) uniformly abolished the antiemetic activity of all the represented narcotic agents, moreover, naloxone thus administered was followed consistently by emetic responses to those narcotics which separately failed to evoke vomiting. When naloxone was injected i.c.v. in addition to being given systemically, both antiemetic and emetic activities of the narcotic agents were essentially abolished, whereas apomorphine continued to evoke vomiting. In the presence of systemic naloxone, given to counteract self-blockade of vomiting, the narcotics were shown to induce vomiting through excitation of the medullary emetic chemoreceptor trigger zone and emetic receptor tolerance as well as cross-tolerance developed acutely. The present differentiation by naloxone of the emetic and antiemetic properties of narcotic agents placed in the cerebrospinal fluid indicates that the opposing narcotic actions are exercised at different sites in the brain and that the narcotic receptor specificity of the chemoreceptor trigger zone does not encompass the emetic action of apomorphine.     

Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys

The effects of a highly selective alpha-2 adrenergic agonist medetomidine and its antagonist atipamezole were studied on the delayed response task performance of aged monkeys. Medetomidine, at the dose of 1.0 micrograms/kg, improved the memory task performance, whereas atipamezole had no effect on the performance at any dose. It has earlier been shown that alpha-2 adrenergic agonists clonidine and guanfacine improve age-associated memory impairment, but also contradictory effects of clonidine have been reported. There is evidence that the ability of alpha-2 agonists to improve DR task performance is due to its selective action on the alpha-2A receptor subtype. Clonidine and medetomidine are much less selective than guanfacine with respect to alpha-2A and alpha-2B receptor subtypes. Therefore, we also studied the effect of guanfacine on the memory task performance of the same aged monkeys in the same testing conditions to compare the effectiveness of these two alpha-2 adrenergic compounds. Guanfacine improved memory task performance at the dose of 0.0001 mg/kg. The results indicate that alpha-2 agonists, independent of their different selectivity with respect to alpha-2A/2B receptor subtypes, are beneficial drugs in improving the performance in the delayed response task.     

Lactate, lactate/pyruvate ratio and catecholamine interrelations in cord blood at delivery in complicated pregnancies

Fucosyltransferases are the enzymes transferring fucose from GDP-Fuc to Gal in an alpha1,2-linkage and to GlcNAc in alpha1,3-, alpha1,4-, or alpha1,6-linkages. Since all fucosyltransferases utilize the same nucleotide sugar, their specificity will probably reside in the recognition of the acceptor and in the type of linkage formed. A search of nucleotide and protein databases yielded more than 30 sequences of fucosyltransferases originating from mammals, chicken, nematode, and bacteria. On the basis of protein sequence similarities, these enzymes can be classified into four distinct families: (1) the alpha-2-fucosyltransferases, (2) the alpha-3-fucosyltransferases, (3) the mammalian alpha-6-fucosyltransferases, and (4) the bacterial alpha-6-fucosyltransferases. Nevertheless, using the sensitive hydrophobic cluster analysis (HCA) method, conserved structural features as well as a consensus peptide motif have been clearly identified in the catalytic domains of all alpha-2 and alpha-6-fucosyltranferases, from prokaryotic and eukaryotic origin, that allowed the grouping of these enzymes into one superfamily. In addition, a few amino acids were found strictly conserved in this family, and two of these residues have been reported to be essential for enzyme activity for a human alpha-2-fucosyltransferase. The alpha-3-fucosyltransferases constitute a distinct family as they lack the consensus peptide, but some regions display similarities with the alpha-2 and alpha-6-fucosyltranferases. All these observations strongly suggest that the fucosyltransferases share some common structural and catalytic features.     

Learning rate equivalency of two narcotic gases.

Two groups of US Navy divers were tested for (a) digit span forward and backward and (b) simple and difficult paired-associate learning while breathing normal air or a narcotic gas (nitrous oxide or hyperbaric nitrogen). The 1st group of 21 divers (mean age 30.3 yrs) breathed 30% nitrous oxide (N?O), and the 2nd groups of 11 divers (mean age 30.0 yrs) breathed hyperbaric nitrogen (Hyper N?) at a simulated ocean depth of 65 m. The 2 forms of the digit span and paired-associate measures were from the Wechsler Memory Scale and were administered in a counterbalanced fashion between normal and narcotic conditions. Forward and backward digit span remained normal during N?O and Hyper N? narcosis, whereas simple and difficult paired-associate learning was impaired uniformly and significantly by both of the narcotic gases. Results indicate that the long-term memory effects of these 2 narcotic gases are similar and that the narcotic properties of both gases may be equivalent. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blockade of the specific lethal effects of narcotic analgesics in the mouse

The capacity of the narcotic antagonists naloxone and nalorphine and the benzodiazepine derivatives diazepam and oxazepam to increase the LD50s of the narcotic analgesics morphine and methadone administered at convulsant doses was eveluated in the mouse. Naloxone produced a dose-related increase in the LD50s of both morphine and methadone. Iiazepam and oxazepam were also effective in increasing the LD50s of the narcotics; this effect was additive with that of naloxone. However, the maximal increase in the LD50s of the narcotics produced by pretreatment with naloxone alone was not increased further by the combined pretreatment of naloxone and a benzodiazepine. The anticonvulsant trimethadione did not elevate the LD50s of methadone, nor did it potentiate the effects of naloxone. These results suggest that the benzodiazepines may reduce the lethality of narcotic analgesics administered at high doses by a mechanism other than by an anticonvulsant effect alone. Therefore, the present results support the conclusion that the capacity to increase the convulsant LD50 of the narcotic analgesics is a general property of the narcotic antagonists.     

Phencyclidine-induced deficits in prepulse inhibition of startle are blocked by prazosin, an alpha-1 noradrenergic antagonist

Prepulse inhibition (PPI) is a form of plasticity of the startle response in which presentation of a weak stimulus immediately before an intense startling stimulus reduces the resultant startle response. Deficits in PPI, an operational measure of sensorimotor gating, are observed in schizophrenia patients and can be modeled in rats by the psychotogen phencyclidine (PCP). PCP-induced deficits in PPI in rats are resistant to dopamine and serotonin antagonists but can be antagonized by antipsychotics such as clozapine, olanzapine and Seroquel. These latter antipsychotics have antagonistic actions at several receptors, including alpha-1 and alpha-2 adrenergic, M1 muscarinic and gamma-aminobutyric acid (GABA)-A receptors. Although the direct actions of PCP are thought to be mediated by noncompetitive antagonism of N-methyl-D-aspartate sites, PCP thereby indirectly activates multiple neurotransmitter systems, including those affected by the aforementioned antipsychotics. The present studies examined the possibility that an antagonist action at a particular receptor subtype might be responsible for the interaction between PCP and the clozapine-like antipsychotics by testing whether a selective antagonist at alpha-1, alpha-2, M1 or GABA-A receptors would prevent the PCP-induced deficit in PPI in rats. Animals were pretreated with either the alpha-1 antagonist prazosin (0, 0.5, 1.0 or 2.5 mg/kg), the alpha-2 antagonist RX821002 (0, 0.2 or 0.4 mg/kg), the M1 muscarinic antagonist pirenzepine (0, 10 or 30 mg/kg) or the GABA-A antagonist pitrazepin (0, 1.0 or 3.0 mg/kg) and then treated with either saline or PCP (1.5 mg/kg). Because prazosin was effective in blocking the effects of PCP, an additional experiment tested the possibility that prazosin (0, 1.0 or 2.5 mg/kg) would block the PPI deficits produced by the dopamine agonist apomorphine (0 or 0.5 mg/kg). After drug administration, animals were tested in startle chambers. PCP was found repeatedly to decrease PPI. Prazosin (1.0 and 2.5 mg/kg) blocked this deficit in two separate experiments but did not increase base-line PPI levels. The effects on PPI were dissociable from changes in startle reactivity. Furthermore, prazosin did not antagonize apomorphine-induced disruptions of PPI, which suggests that the antagonism of the PCP effect was not simply due to a generalized improvement of deficient PPI. The antagonists for alpha-2, for M1 and for GABA-A receptors had no effect on base-line PPI or on PCP-induced disruptions in PPI. These findings indicate that the PPI-disruptive effect of PCP may be mediated in part by alpha-1 adrenergic receptors and that antagonism of alpha-1 receptors may play a major role in mediating the blockade of PCP-induced deficits in PPI by certain antipsychotics.     

Expression of alpha-1,3-galactose and other type 2 oligosaccharide structures in a porcine endothelial cell line transfected with human alpha-1,2-fucosyltransferase cDNA

The binding of xenoreactive natural antibodies to the Galalpha1-3Galbeta1-4GlcNAc (alpha-galactose) oligosaccharide epitope on pig cells activates the recipient's complement system in pig to primate xenotransplantation. Expression of human alpha-1, 2-fucosyltransferase in pigs has been proposed as a strategy for reducing the expression level of the alpha-galactose epitope, thereby rendering the pig organs more suitable for transplantation into humans. The aim of this study was to examine how the cell surface expression of alpha-galactose, H, and related fucosylated and sialylated structures on a pig liver endothelial cell line is affected by transfection of human alpha-1,2-fucosyltransferase cDNA. Nontransfected and mock-transfected cells expressed alpha-galactose, alpha-2,3-sialylated, and alpha-2,6-sialylated epitopes strongly, with low level expression of type 2 H and LewisX. By contrast, expression of the H epitope was increased 5-8-fold in transfected cells with a 40% reduction in the expression of alpha-galactose epitope and a 50% decrease in sialylation, as measured by binding of Maackia amurensis and Sambuccus nigra agglutinins. LewisX expression was reduced to background levels, while the LewisY neoepitope was induced in human alpha-1,2-fucosyltransferase-expressing pig cells. The activities of endogenous alpha-1,3-galactosyltransferase, alpha-1,3-fucosyltransferases, and alpha-2,3- and alpha-2, 6-sialyltransferases acting on lactosamine were unaffected. Our results show that a reduction in alpha-galactose epitope expression in porcine endothelial cells transfected with human alpha-1, 2-fucosyltransferase cDNA may be achieved but at the expense of considerable distortion of the overall cell surface glycosylation profile, including the appearance of carbohydrate epitopes that are absent from the parent cells.     

Inguinal hernia repair: a comparison between local and general anaesthesia

BACKGROUND: A comparative analysis of outcomes of inguinal hernia repair performed under local (LA) and general anaesthesia (GA) by a single surgeon using a standardized technique of anterior transversalis repair was performed. Ninety-three cases were examined, 56 of which were cases of LA hernia repair. METHODS: A retrospective analysis of the patient hospital record was performed with particular attention to intra-operative and post-operative analgesia requirements. RESULTS: An overall series complication rate of 6.5% (6/93) is reported. Only one of 56 LA patients (2%) required more than 24 h of narcotic analgesic injections compared to 11% (4/37) in the GA group (P < 0.05). The mean total postoperative parenteral narcotic requirement in the LA group was 86+/-14 mg of pethidine as compared to the GA group who had a mean total requirement of 121+/-17 mg of pethidine (P > 0.08). CONCLUSIONS: The LA infiltration technique is an effective method for inguinal hernia repair. This series demonstrates benefits in terms of length of hospital stay and a lower incidence of postoperative parenteral narcotic analgesic requirement although when post-operative parenteral narcotics were required by the LA group of patients, the difference in mean total pethidine requirement was not statistically significant.     

Major cytochrome P450 enzyme responsible for oxidation of secondary alcohols to the corresponding ketones in mouse hepatic microsomes. Oxidation of 7-hydroxy-delta8-tetrahydrocannabinol to 7-oxo-delta8-tetrahydrocannabinol

The oxidative activities of 7alpha- and 7beta-hydroxy-Delta8-tetrahydrocannabinol (7alpha- and 7beta-hydroxy-Delta8-THC) to 7-oxo-Delta8-THC in hepatic microsomes of mice were significantly increased by the treatment of mice with dexamethasone or phenobarbital. A cytochrome P450 enzyme, named P450MDX-B, was purified from hepatic microsomes of dexamethasone-treated mice, and its apparent molecular mass was estimated to be 51,000. The NH2-terminal amino acid sequence of P450MDX-B was the same as that of CYP3A11. The oxidative activities of 7alpha- and 7beta-hydroxy-Delta8-THC were 2.55 and 4.92 nmol/min/nmol P450, respectively. The antibody against P450MDX-B almost completely inhibited the oxidative activities of 7alpha- and 7beta-hydroxy-Delta8-THC in mice. These results indicate that P450MDX-B (CYP3A11) is a major enzyme responsible for the oxidation of 7alpha- and 7beta-hydroxy-Delta8-THC to 7-oxo-Delta8-THC in mouse liver.     

Systemic administration of recombinant interferon alfa in carcinoma patients upregulates the expression of the carcinoma-associated antigens tumor-associated glycoprotein-72 and carcinoembryonic antigen

PURPOSE: The ability of interferons (IFNs) to enhance tumor-associated antigen expression may be an important approach to enhance the efficacy of some monoclonal antibody (MAb)-based protocols for tumor diagnosis and/or therapy. The present study was designed to determine whether systemic IFN alpha-2a administration (via the intramuscular [IM] route) could upregulate the expression of tumor-associated glycoprotein-72 (TAG-72) and/or carcinoembryonic antigen (CEA) at histologically confirmed sites of carcinoma. PATIENTS AND METHODS: Eighteen patients diagnosed with gastrointestinal (GI) carcinoma received systemic IFN alpha-2a according to four dose schedules. In cohorts I and II, patients received two injections of 3 or 6 x 10(6) U IFN alpha-2a per injection, respectively. Patients in cohorts III and IV received the same doses of IFN alpha-2a, 3 and 6 x 10(6) U, respectively, but three injections were given. Tumor and normal colonic mucosa biopsies were obtained from each patient by endoscopy before IFN alpha-2a and after IFN alpha-2a at surgery. The levels of TAG-72 and CEA expression were measured by (1) immunohistochemistry and reported as percent antigen-positive tumor cells, as well as the relative staining intensity, and (2) a quantitative radioimmunoassay. RESULTS: TAG-72 and CEA levels were consistently increased in tumor biopsies taken from patients in cohorts III and IV. For example, of 10 patients treated in cohorts III and IV, eight had enhanced TAG-72 expression when measured either as percentage TAG-72-positive tumor cells or as an increased MAb staining intensity following IFN alpha-2a. CEA expression in tumor biopsies from seven of 10 patients in cohorts III and IV was also elevated following IFN alpha-2a treatment. Quantitative analysis of TAG-72 and CEA levels in tumor biopsies confirmed higher tumor antigen levels following IFN alpha-2a administration. No such increases in TAG-72 or CEA levels were observed in tumor samples taken from patients in cohorts I and II. CEA or TAG-72 expression in samples of histologically confirmed normal colonic mucosa showed little or no change after IFN alpha-2a treatment. CONCLUSION: Systemic IFN alpha-2a administration can upregulate TAG-72 and CEA expression at distal tumor sites, which may play an important role in immunodiagnosis and therapy.     

Actions of A-131701, a novel, selective antagonist for alpha-1A compared with alpha-1B adrenoceptors on intraurethral and blood pressure responses in conscious dogs and a pharmacodynamic assessment of in vivo prostatic selectivity

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.     

Self-concept of white, middle socioeconomic status addicts: a controlled study

Commonalities in the developmental patterns of both narcotic addiction and negative self-attitudes motivated this controlled study of 70 White, middle socioeconomic status (WMSES) addicts and 70 WMSES nonaddicts. The hypothesis that measures of self-attitudes would distinguish addicts from nonaddicts was confirmed with highly significant differences. The hypothesis that antecedent conditions purported to result in positive self-attitudes would distinguish addicts from controls was also supported. Developmental conditions posited as indices of early self-attitudes further discriminated the two groups. A self-reported profile of the WMSES addict was compiled describing drug-use patterns and childhood situations.     

N-methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, markedly reduced infarct size in rabbit hearts

BACKGROUND: N-methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase of glycogen-debranching enzyme in the liver, in addition to possessing an antihyperglycemic action by blocking alpha-1,4-glucosidase in the intestine. Because the reduction of the glycogenolytic rate may be one of the mechanisms of myocardial protection in ischemic preconditioning, the compounds inhibiting myocardial alpha-1,6-glucosidase may be protective against ischemic damage. Thus, we investigated whether MOR-14 could inhibit alpha-1,6-glucosidase and reduce the infarct size in rabbit hearts without collateral circulation. METHODS AND RESULTS: MOR-14 dose-dependently decreased the alpha-1,6-glucosidase activity in rabbit heart extract. A tracer study demonstrated the myocardial uptake of a considerable amount of MOR-14 sufficient to fully inhibit alpha-1,6-glucosidase. To assess the infarct size-reducing effect of MOR-14, 54 rabbits were subjected to 30-minute coronary occlusion followed by 48-hour reperfusion. Preischemic treatment with 25, 50, and 100 mg/kg of MOR-14 dose-dependently reduced the infarct size (to 26+/-4%, 19+/-3%, and 14+/-2% of the area at risk, respectively), compared with the saline control (45+/-5%) without altering the blood pressure or heart rate. Another 40 rabbits given 100 mg of MOR-14 or saline 10 minutes before ischemia were euthanized at 10 or 30 minutes of ischemia for biochemical analysis. MOR-14 decreased the alpha-1,6-glucosidase activity to approximately 20% in vivo, reduced the glycogen breakdown, and attenuated the lactate accumulation at both 10 and 30 minutes of ischemia. CONCLUSIONS: Preischemic treatment with MOR-14 preserved glycogen, attenuated the accumulation of lactate, and reduced the myocardial infarct size by 69%. This cardioprotective effect was independent of changes of blood pressure and heart rate or regional blood flow. It may be associated with alpha-1,6-glucosidase inhibition, because MOR-14 markedly decreased the alpha-1,6-glucosidase activity in the heart.     

Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase

OBJECTIVE: In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure. METHODS: Sprague-Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2, Gi alpha-3) and G beta proteins were determined by immunoblotting, whereas the levels of Gi alpha-2 and Gi alpha-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques. RESULTS: The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Gi alpha-2, Gi alpha-3 and G beta proteins and Gi alpha-2 and Gi alpha-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF4-23 were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gs alpha were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5'-[gamma-thio]triphosphate (GTP gamma S), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DOCA-salt treatment but not in rats treated for 1 or 2 weeks. CONCLUSIONS: These results indicate that the enhanced expression of Gi alpha-2 and Gi alpha-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension.     

Alpha-1 adrenoceptor subtypes involved in mediating adrenergically induced antinatriuresis and antidiuresis in two kidney, one clip Goldblatt and deoxycorticosterone acetate-salt hypertensive rats

This study characterized the alpha-1 adrenoceptor subtypes involved in adrenergically induced antinatriuresis and antidiuresis in pentobarbital-anesthetized deoxycorticosterone acetate (DOCA)-salt and two kidney, one clip (2K1C) Goldblatt hypertensive rats. In the DOCA-salt rats, phenylephrine infusion (100 microgram kg(-1) hr(-1) close renal arterially) caused increases in blood pressure of 5 to 10%, decreases in renal blood flow of 5 to 12%, whereas there were large reversible decreases in urine flow and absolute and fractional sodium excretions of 55 to 70%. The presence of chloroethylclonidine (10 microgram kg(-1) hr(-1) to block alpha-1B adrenoceptors) had no effect on the magnitude of the phenylephrine-induced excretory responses, but after 5-methylurapidil (10 microgram kg(-1) hr(-1) to block alpha-1A adrenoceptors) they were abolished. Infusion of phenylephrine in the 2K1C hypertensive rats caused small hemodynamic and renal blood flow responses with marked 55 to 70% reductions in urine flow and absolute and sodium excretion. The phenylephrine-induced antinatriuresis and antidiuresis, which was probably due to activation of alpha-1 adrenoceptors present on the renal tubular epithelial cells, and the fact that these tubular responses were blocked by 5-methylurapidil but not by chloroethylclonidine in both DOCA-salt and 2K1C Goldblatt hypertensive models, means that the alpha-1A adrenoceptors was the major functional subtype present.