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Biomedical subjects

J A Kennedy

Publications and source records attributed to J A Kennedy.

At least 19 recordsLinked to original sources
PubMed1992

Novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles are described. A number of the compounds inhibit the release of histamine from anti-IgE stimulated basophils obtained from allergic donors. Optimal inhibition is exhibited in benzothiophenes with a 3-alkoxy substituent in combination with a 5-methoxy, 6-methoxy, or a 5,6-dimethoxy group. Compound 13c (CI-959) also inhibited respiratory burst of human neutrophils and the release of mediators from anti-IgE-stimulated human chopped lung.

Antibodies, Anti-Idiotypic↗
PubMed1992

Effect of fatty acids on rat liver nuclear T3-receptor binding.

The effects of selected fatty acids (linoleic, oleic, and palmitic) on triiodothyronine (T3)-receptor binding were compared in isolated rat hepatocytes, rat liver nuclei, and receptor protein. Scatchard analysis indicated that the inhibition of T3-receptor binding by fatty acids was characterized by an increase in Kd and no change in maximum binding capacity (MBC). In isolated receptors, the rank order of potency for inhibition was linoleic acid greater than oleic acid greater than palmitic acid. The Ki for oleic acid in isolated receptors was the same as that for whole nuclei (15.4 +/- 1.3 v 16.3 +/- 1.9 mumol/L, respectively), indicating that the inhibition of nuclear T3 binding is probably at the level of the receptor protein itself. In isolated hepatocytes, linoleic acid was more potent than oleic acid in inhibiting T3 binding to nuclear receptors. Cell-associated T3 was not affected by the presence of fatty acids, implying that cellular uptake of T3 was not inhibited. High concentrations of fatty acids were necessary for inhibition of T3-receptor binding in isolated hepatocytes, with linoleic acid being one to two orders of magnitude less potent in isolated hepatocytes compared with isolated receptors (Ki, 179 +/- 12 v 4.4 +/- 0.5 mumol/L, respectively). It is concluded that the inhibitory effect of fatty acids on T3-receptor binding in isolated rat hepatocytes probably occurs at the level of the nuclear receptor, and does not involve an inhibition of the access of T3 to the receptor. However, in vivo it seems unlikely that fatty acids will have access to the nuclear receptors in sufficiently high concentrations to affect T3-receptor binding in liver cells.

Animals↗
PubMed1991

Distribution of extraneuronal uptake1 in reproductive tissues: studies on cells in culture.

Cultures of stromal cells from pregnant mouse uterus, and an FL cell line derived from human amnion, displayed significant capacities to O-methylate noradrenaline. O-methylation was inhibited in the stromal cells by uptake1-inhibitors, and in the FL cell line by uptake2 inhibitors. These findings are discussed in terms of the distribution and possible functional importance of catecholamine metabolising systems in the female reproductive system.

Amnion↗
PubMed1991

Effect of catechol oestrogens on extraneuronal metabolism of noradrenaline by rabbit uterine endometrium and myometrium.

The effects of 2-hydroxy and 2-methoxy oestrogens on the extraneuronal O-methylation of 3H-(-)-noradrenaline were examined in progesterone-dominated, monoamine oxidase (MAO)-inhibited, rabbit uterine tissues in vitro. Both the corticosteroid-sensitive system in myometrium and the cocaine-sensitive system in endometrium were examined. In myometrial slices preincubated with nialamide to inhibit MAO and incubated with cocaine to inhibit neuronal uptake, 3H-normetanephrine (3H-NMN) formation was inhibited in the order of potency 2-hydroxy oestrone greater than or equal to 2-hydroxy oestradiol = 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone. In myometrial slices not exposed to cocaine and nialamide, inhibition of 3H-NMN formation by both 2-hydroxy and 2-methoxy oestradiol did not affect the formation of deaminated metabolites of 3H-(-)-noradrenaline by the alternative metabolising pathway. In endometrial slices preincubated with nialamide to inhibit MAO, only 2-hydroxy oestrogens inhibited 3H-NMN formation, but they were one to two orders of magnitude less potent in this regard than in the myometrium. The uptake of 3H-(-)-noradrenaline by MAO- and COMT-inhibited myometrial slices was inhibited by 2-hydroxy and 2-methoxy oestrogens in the order of potency 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone greater than or equal to 2-hydroxy oestrone greater than 2-hydroxy oestradiol. Uptake of 3H-(-)-noradrenaline by endometrial slices was not affected by either 2-hydroxy or 2-methoxy oestrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗
PubMed1991

Novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated human basophils. Optimal inhibition is exhibited in compounds with a 3-alkoxy, a 4-halo, and a 5-methyl, 5-methoxy, or 5-bromo on a thiophene-2-carboxamidotetrazole.

Basophils↗
PubMed1991

Successful intracardiac electrical conversion of atrial flutter in patients with complex congenital heart disease.

Sixteen patients presenting on 21 occasions with atrial flutter in association with complex congenital heart disease were treated by intracardiac stimulation techniques combined with activation mapping. Nineteen episodes of atrial flutter were successfully converted to sinus rhythm. In the remaining two episodes atrial fibrillation was induced with spontaneous conversion to sinus rhythm within 12 hours in one episode and immediate DC cardioversion to sinus rhythm in the other. Intracardiac stimulation techniques were highly successful in this group and allowed reliable conversion to sinus rhythm without general anaesthesia and high energy cardioversion. In patients with atrial flutter associated with congenital heart disease intracardiac stimulation techniques should be tried first.

Adolescent↗
PubMed1991

A comparison of the efficacy and safety of ramipril and digoxin added to maintenance diuretic treatment in patients with chronic heart failure.

The efficacy and safety of ramipril were compared with that of digoxin in a prospective, randomized, double-blind, crossover study of 35 patients with congestive heart failure (CHF), New York Heart Association (NYHA) grades II to IV, stabilized on diuretic maintenance therapy. Major assessments were conducted at baseline and at the end of each 10-week treatment period: primary efficacy variables were total exercise duration (modified Bruce, treadmill), NYHA grade, and clinical signs and symptoms (by visual analogue score) of heart failure. Twenty-seven patients completed the study. There were two deaths (one on each study drug) and six patient withdrawals (one on ramipril and five on digoxin). Although the NYHA grade was significantly better on ramipril than on digoxin, there were no other important differences in the relief of either signs or symptoms of heart failure. A significant order effect was observed with the exercise testing data and therefore only data in the first active treatment period were analyzed; no significant differences were noted. There were fewer reports of adverse effects, and no clinically significant episodes of hyperkalemia or renal impairment on ramipril. We conclude that ramipril seems to be better tolerated and marginally more effective than digoxin in the management of patients with moderate to severe chronic CHF, stabilized on maintenance diuretic therapy.

Adult↗
PubMed1990

Chronic pain and substance abuse: a pilot study of opioid maintenance.

Recent reports suggest that opioid maintenance may be appropriate for treatment-resistant patients with chronic nonmalignant pain syndromes. However, a history of substance abuse is thought to be a contraindication for such treatment. We present a pilot study of a methadone maintenance-type treatment for patients with both chronic pain and substance abuse, evaluating the ability to attract and hold patients, the methodology for assessing change, and the potential problems and pitfalls. Weekly random urinalysis, weekly psychotherapy, and quarterly self-report tests of pain, mood, and function were used to evaluate change. Three out of 4 patients remained in treatment for 19-21 months, stopped needle use, and/or markedly decreased substance abuse, and appear to have improved functionally. Surprisingly, all 3 patients had significant psychopathology requiring treatment with psychotropic medication. This treatment may warrant further research.

Adult↗
PubMed1990

Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949.

The novel antiallergy compound, 5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide, L-arginine salt (CI-949), inhibited mediator release from human basophilic leukocytes and from human chopped lung mast cells challenged with anti-IgE. In leukocytes, CI-949 was a more potent inhibitor of leukotriene C4/D4 and thromboxane B2 release (concentration of drug that inhibits mediator release by 50% [IC50] 0.5 and 0.1 mumol/L, respectively) than of histamine (IC50, 11.4 mumol/L) when anti-IgE was the challenging stimulus. In human lung, inhibition of release of all three mediators occurred at approximately equal concentrations (IC50s for histamine, 16.6 mumol/L; for leukotriene C4/D4, 7.1 mumol/L; and for thromboxane B2, 6.2 mumol/L). The inhibition of histamine release from basophils by CI-949 was further characterized using a variety of stimuli. Challenge with anti-IgE, histamine-releasing factor derived from lymphocytes, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, and concanavalin A revealed potent inhibition (IC50, 10 to 15 mumol/L). CI-949 was less potent versus calcium ionophore A23187, phorbol myristate acetate (12-o-tetradecanoylphorbol-13-acetate), and C5a (IC50s, 30, 54, and 60 mumol/L, respectively). These results suggest that diverse pathways of cell activation-excitation coupling exist for different stimuli in basophils. Furthermore, the activity and potency of CI-949 in inhibiting release of histamine, leukotrienes, and thromboxane from both human basophils and mast cells suggest that the compound will be effective clinically for indications in which these mediators are implicated, including asthma and allergic rhinitis.

Basophils↗
PubMed1990

Metyrapone-induced withdrawal symptoms.

The metyrapone test is widely used in endocrinological testing to assess the integrity of hypothalamic-pituitary-adrenal axis function; we have used it to study the metabolic basis of addictive disease and opioid dependence. In recent studies, we have observed that metyrapone administration in long-term methadone-maintained patients and in patients undergoing slow dose reduction to drug-free status following chronic treatment may induce a narcotic withdrawal-like syndrome. Although metyrapone is known to produce mild adverse reactions in non-opiate dependent subjects, narcotic withdrawal-like symptoms have not been previously observed or reported. The metyrapone test was administered to 15 former heroin addicts: 10 (8 male, 2 female) in steady-state methadone maintenance therapy (30 to 90 mg/d) and 5 (3 male, 2 female) in the final phase of a slow methadone dose reduction procedure (0 to 10 mg/d). Eight out of 15 methadone maintenance subjects exhibited a narcotic withdrawal-like syndrome ranging from 'moderate' to 'severe' and four additional subjects had 'mild' symptoms, occurring within 1 h after metyrapone administration, and resolving within 2 h of onset. No significant symptoms were seen in 3 methadone maintained subjects nor in any of 9 normal volunteers (7 male, 2 female). The mechanism by which metyrapone induces symptoms resembling narcotic withdrawal in opiate-dependent individuals is unknown but physicians performing this test should be aware of this possible response.

Adult↗
PubMed1989

Live donor renal transplantation--the experience of the Belfast Renal Unit.

Live donor renal transplants are often preferred to cadaver grafts because of better graft survival. In a retrospective study of 41 live donor transplants performed in the Belfast Renal Unit from 1971 until November 1988, actual graft survival at 2 and 5 years was 84% and 69% respectively. Corresponding patient survival rates were 87% and 81%. These results are no better than those of cadaver grafts. A subdivision of patients considered to be relatively poor risk for transplantation showed less favourable results than those who were good risk. 15% of the donors suffered post-operative complications, which occurred more often in older donors. Live donor transplantation is not necessarily preferable to cadaver organ graft, and is not recommended for poor risk recipients or donors aged over 50 years.

Graft Survival↗
PubMed1989

Novel indolecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic potential of a series of novel indolecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated basophilic leukocytes obtained from allergic donors. Optimal inhibition is exhibited by compounds with 3-alkoxy, 5-methoxy, and 1-phenyl substituents on the indole core structure. Compound 8d (5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide; designated CI-949) is a potent inhibitor of histamine release from human basophils and from guinea pig and human chopped lung.

Animals↗
PubMed1989

Ten-year results of renal transplantation using only azathioprine and low-dose prednisolone as immunosuppression.

This paper describes the results of renal transplants carried out in a single center more than 10 years ago. One hundred fifty-five recipients received 170 grafts; 164 from cadavers and 6 from living-related donors. All patients received the same immunosuppressive therapy with azathioprine and low-dose steroid. 1. The total actual patient survival was 67.1% at 10 years; 104 patients survived and 51 died. 2. The actual first cadaver graft survival was 54.7% at 10 years; 82 grafts survived and 68 were lost. Death with a functioning graft was the commonest cause of graft loss. 3. Ninety-seven patients and 70 first cadaver grafts survived in the 12th year. Two patients survived with first cadaver grafts into the 21st year. 4. Tissue match grade was not related to cadaver graft survival at 10 years. 5. Five of the 6 recipients of living-related donor kidneys survived but only 3 of their grafts were functioning after 10 years.

Adolescent↗
PubMed1988

Ten-year results of renal transplantation with azathioprine and prednisolone as only immunosuppression.

93 patients received 102 renal transplants between 1968 and 1977. 99 grafts were from cadavers and 3 were from live donors; 93 were first grafts, 7 were second, and 2 were third. At 10 years total actual patient survival was 66.6%. 50 (55.5%) of 90 first cadaver grafts, and 52.2% of all cadaver grafts, survived at 10 years. Cardiovascular disease was the commonest cause of death, being responsible for 18 of 31 deaths (58%).

Adolescent↗
PubMed1988

Catecholamine inactivation in uterine tissues: changes in pregnancy in the rat.

1. In vitro metabolism of [3H]-(-)-noradrenaline (3H-NA), 0.2 mumol/l, was measured in rat endometrial and myometrial slices at different stages of gestation and compared with that in dioestrous rats. Metabolism of 3H-NA, 0.2 mumol/l, was measured in rat placental slices from day 14 of gestation onwards. 2. 3H-NA was metabolized mainly by deamination in rat myometrium, with [3H]-3,4-dihydroxyphenylethylene glycol, (3H-DOPEG) being the major metabolite. Cocaine, 30 mumol/l, inhibited 3H-DOPEG formation and the amount of 3H-NA remaining in the tissue. O-methylated metabolite formation was unaffected by cocaine. 3. O-methylation and deamination were equally active pathways for metabolizing 3H-NA in rat endometrium. O-methylation to [3H]-normetanephrine (3H-NMN) predominated in the placenta. In both tissues O-methylated metabolite formation was inhibited by 30 mumol/l cocaine. 4. In myometrium, metabolite formation per gram was constant in the first half of pregnancy and was similar to that in dioestrous animals. By day 17 of gestation, however, [3H]-O-methylated deaminated metabolites (3H-OMDA), comprising 3-methoxy, 4-hydroxy-phenylethylene glycol and vanillylmandelic acid, and 3H-NMN formation were less than in dioestrous animals. 5. Endometrial 3H-NMN and 3H-DOPEG formation per gram were higher in rats at day 5 of gestation than in dioestrous rats but metabolite formation per gram declined thereafter to reach values equal to (3H-DOPEG) or less than (3H-OMDA and 3H-NMN) those in dioestrous rats. 6. 3H-NMN and 3H-OMDA formation per gram decreased from day 14 to day 20 of gestation in rat placentae.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Specific inhibition of phorbol ester and DiC8-induced histamine release from human basophils by the protein kinase C inhibitors, H-7 and H-9.

The release of histamine and other inflammatory mediators from human basophils is triggered by numerous stimuli, including chemical, physical and receptor-mediated activators. Several mechanisms of cell activation including protein kinase C activation have been proposed to operate in these cells. We used phorbol ester and DiC8 to induce histamine release from human basophils and the protein kinase C inhibitors H-7 and H-9 to inhibit this release. Both DiC8 and TPA induced histamine release were inhibited by H-7 (ID 50 = 37 mcM) and H-9 (IC 50 = 20 mcM). However, anti-IgE, fmlp and A23187-induced histamine release were unaffected. In contrast, the calmodulin antagonists W-7 and perphenazine effectively inhibited histamine release by all five stimuli. Therefore, different biochemical pathways appear to be critical for basophil activation depending on the nature of the stimulus used.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗