Impact resistance of drinking glasses.
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Glass↗
Biomedical subjects
D Grimes
Publications and source records attributed to D Grimes.
Caudate nucleus pathology in Parkinson's disease: ultrastructural and biochemical findings in biopsy material.
Ultrastructural and biochemical properties of caudate nucleus (CN) biopsies in two patients with advanced Parkinson's disease (PD) were compared with three CN specimens removed during surgery for intracranial tumors. An additional two specimens from neurologically intact patients (59 and 86 years old) were removed during autopsy (performed 3 and 4 h post mortem, respectively) for electron microscopic studies. Dopamine levels in PD were reduced to less than 15% of control values. Both PD patients showed frequent dystrophic neurites and transsynaptic degeneration of neurons and neuritic processes. These changes were not found in CN from the four control individuals. Only a few dystrophic neurites were noticed in one 67-year-old control patient. The development of neuroaxonal dystrophy in CN is consistent with a dying-back process, probably accompanying abnormalities of axonal transport in PD. Transsynaptic degeneration of neurons in CN very likely represents a morphological marker of disease severity. The occurrence of this change may account for the poor clinical response of patients with advanced PD to intracerebral implantation of dopaminergic tissues.
3,4-Dihydroxyphenylacetic Acid↗
Deprenyl in Parkinson's disease: mechanisms, neuroprotective effect, indications and adverse effects.
Deprenyl is a synthetic, selective inhibitor of the monoamine oxidase-B enzyme system. The mechanism of its beneficial effect in early and advanced Parkinson's disease is not settled. Increased striatal dopamine accumulation, sensitization of surviving dopamine neurons with increased dopamine production and reduced nigro-striatal toxicity may all contribute. The standard daily dose of deprenyl is 10 mg. Selectivity may be lost at higher doses. Deprenyl is especially indicated in untreated patients, improving up to 50 percent of patients with mild motor fluctuations. Major symptomatic benefit also occurs in occasional levodopa treated patients. Adverse effects are common, however. Increase dyskinesias, confusion and hallucinations, nausea and postural hypotension may necessitate drug withdrawal or the use of low dose regimens. Caution should be exercised with older patients, those with ulcer disease, which may be worsened by deprenyl, and individuals with active ischemic heart disease where the safety of this drug is not yet clear.
Humans↗
Non-seminomatous germ cell tumours of the testis: game and set but not match.
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Antineoplastic Combined Chemotherapy Protocols↗
Rat peritoneal neutrophils selectively relax vascular smooth muscle.
A vascular relaxing factor from oyster glycogen-elicited rat peritoneal neutrophils has been shown previously to possess a pharmacologic profile similar to that described for endothelium-derived-relaxing factor. The present experiments were designed to determine the in vitro tissue and species selectivity effects of the neutrophil-derived nitric oxide. Neutrophils (1 x 10(5) to 1 x 10(8) cells/10-ml organ chamber) were added to organ chambers filled with a physiological salt solution (37 degrees C; pH 7.4; 21% O2; 100 U/ml of superoxide dismutase) containing a ring or strip of an isolated tissue contracted with an appropriate contractile agent. Neutrophils caused relaxations in all vascular tissues tested, with the dog coronary artery being the most sensitive (IC50 approximately 1 x 10(5) cells), followed by the dog femoral artery, rabbit aorta and dog saphenous vein, respectively. In the rabbit fundic strip, approximately 1 x 10(7) cells were required to induce 50% relaxation, with 1 x 10(8) cells producing less than 35% relaxation in the dog, guinea pig and rat tracheas. In contrast, nitroprusside- and cromakalim-induced relaxations in all the smooth muscle tissues tested. The response to cromakalim was similar in all tissues with nitroprusside being more active in the vascular tissues. Methylene blue (1 x 10(-5) M) abolished the neutrophil induced relaxations in the rabbit aorta and dog femoral artery but had no effect on the responses to nitroprusside or cromakalim in the rabbit aorta, dog femoral artery or guinea pig trachea. Neutrophils, nitroprusside and cromakalim had limited effects on the spontaneously beating guinea pig right atria.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
WY-50, 295 tromethamine: an orally active 5-lipoxygenase inhibitor with anti-allergic activity.
WY-50,295 tromethamine inhibited antigen-induced peptidoleukotriene (pLT) release from fragmented sensitized guinea pig lung (IC50 = 0.63 microM), antagonized LTD4-induced contractions of isolated guinea pig trachea (pA2 = 6.06), and suppressed antigen-induced contraction of sensitized guinea pig trachea over the 0.1-10 microM concentration range. In vivo, WY-50,295 tromethamine inhibited LTD4-induced bronchoconstriction (ED50 = 1.3 mg/kg i.v. and 6.6 mg/kg p.o.) and antigen-induced bronchoconstriction (ED50 = 2.5 mg/kg i.v. and 7.3 mg/kg p.o.) in anesthetized guinea pigs. Peak activity vs antigen was noted at 4-6 h after oral dosing and remained significant through 18 h. These studies demonstrate that WY-50,295 tromethamine possesses the complimentary actions of 5-LO inhibition and LTD4 receptor antagonism.
Administration, Oral↗
WY-50,295 tromethamine: a novel inhibitor of leukotriene-mediated reactions.
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Animals↗
Bronchial vs. cardiovascular activities of selective phosphodiesterase inhibitors in the anesthetized beta-blocked dog.
This study was undertaken to determine whether isozyme-specific inhibitors of cAMP-selective phosphodiesterases (PDEs) induce bronchodilation without the cardiovascular side effects known to be produced by nonselective PDE inhibitors. The abilities of PDE inhibitors to reverse the bronchoconstriction induced by serotonin in a beta-blocked anesthetized dog were compared simultaneously with their effects on cardiac contractile force (+dP/dt), heart rate and blood pressure. Aminophylline and enprofylline, two antiasthma drugs with nonselective PDE inhibitory activity, produced dose-dependent (ED50S = 2.3 and 0.58 mg/kg, respectively) and complete (95-100%) bronchodilation accompanied by profound increases in cardiac force, tachycardia and decreases in blood pressure. Similar effects were observed with forskolin, a potent adenylate cyclase activator. Imazodan and CI-930 (inhibitors of the cGMP-inhibitable cAMP-selective PDE isozyme designated PDE-III) induced pulmonary and cardiovascular effects virtually identical to the nonselective PDE inhibitors, but with greater potency (ED50S = 0.02 and 0.04 mg/kg). In contrast, rolipram and Ro 20-1724 (inhibitors of a cGMP-insensitive cAMP-selective PDE isoform commonly designated PDE-IV) induced bronchodilation in the dog (ED50S = 0.007 and 0.63 mg/kg, respectively) without causing significant changes in cardiac force or heart rate, even after predosing dogs with forskolin. However, rolipram and Ro 20-1724 were less efficacious than the other inhibitors in that they induced only partial (50-60%) bronchodilation. The results suggest that canine respiratory muscle tension is regulated by both PDE-III and PDE-IV. Inhibitors of PDE-IV produce bronchodilation in the described model with minimal concomitant cardiac side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Anesthesia↗
N-[(arylmethoxy)phenyl] carboxylic acids, hydroxamic acids, tetrazoles, and sulfonyl carboxamides. Potent orally active leukotriene D4 antagonists of novel structure.
Four series of N-[(arylmethoxy)phenyl] compounds were prepared as leukotriene D4 (LTD4) antagonists. In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg. Compound 20 also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg. In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08. In the sulfonyl carboxamide series, N-[(4-methylphenyl)sulfonyl]-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist. Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively. In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78. In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99% at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79). In the tetrazole series, the most potent inhibitor was 2-[[3-(1H-tetrazol-5-ylmethyl)phenoxy]methyl]quinoline (Wy-49,451, 41). The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin. In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.
Animals↗
Potential regulatory role of inflammatory cells on local vascular smooth muscle tone.
A neutrophil-derived relaxing factor (NDRF) from oyster glycogen (OG)-elicited rat PMN, which causes an endothelium independent relaxation of rat aorta, and which is pharmacologically indistinguishable from endothelium-derived relaxing factor (EDRF) has been described. Experiments were designed to evaluate the presence of NDRF in PMN from rat -whole blood, -carrageenan pleurisy, -OG peritonitis, and guinea pig (GP) -OG peritonitis, as well as in OG-elicited rat macrophages (M phi). Significant vascular relaxing activity was found using rat PMN from OG peritonitis and carrageenan pleurisy, as well as from OG-M phi. Little or no activity was found in rat whole blood PMN or PMN from GP-OG peritonitis. These results suggest that NDRF activity may be expressed upon cellular migration to an inflammatory site in the rat, and may not be present in all species. Also, all inflammatory cells examined were capable of reversing EDRF-dependent relaxations when stimulated to produce superoxide anion suggesting a dual regulatory role for these cells on local vascular tone.
Animals↗
Structure-activity relationships of 1H-indole-7-carboxamides as a novel series of selective alpha 1-adrenoceptor agonists.
The present isolated tissue study was designed to quantitate the alpha-adrenoceptor agonist activity of AY- 30,191 (5-(1-hydroxy-2-amino-ethyl)-1H-indole-7-carboxamide) and a series of related compounds. AY-30,191 induced contractions in the rabbit aorta, which were blocked by prazosin. In the rat vas deferens, while clonidine inhibited the electrically induced twitch response, AY-30,191 caused a prazosin-sensitive augmentation. In the dog saphenous vein, rauwolscine was less effective than the combination of rauwolscine and prazosin in inhibiting the contractions induced by AY-30,191. Pretreatment of the dog saphenous vein with phenoxybenzamine reduced the response to AY-30,191. The addition of rauwolscine to phenoxybenzamine-treated tissues had no effect on the contractions to AY-30,191 remaining after phenoxybenzamine treatment. These results suggest that AY-30,191 is a selective alpha 1-adrenoceptor agonist. Optimal alpha 1-adrenoceptor agonist activity in the 1H-indole-7-carboxamide series was seen in compounds in which a) the indole ring and the ethylamine side chain were intact; b) the indole nitrogen was unsubstituted; and c) the carboxamide was present at the 7-position in the indole ring. Removal of the carboxamide decreased alpha 1-adrenoceptor activity and, more importantly, resulted in a loss of alpha 1-adrenoceptor selectivity. Replacement of the carboxamide in the 7 position with methanesulfonamide resulted in a decrease in activity but a retention of alpha 1-adrenoceptor selectivity, whereas the dimethylamino analog was nonselective and the phosphoramidic acid diethylester analog was inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
Comparison of the beta-adrenoceptor affinity and selectivity of cetamolol, atenolol, betaxolol, and ICI-118,551.
The objective of the present study was to compare the quantitative differences in the beta 1- vs. beta 2-adrenoceptor affinity and selectivity of cetamolol and its enantiomers to the reference compounds atenolol, betaxolol, and ICI-118,551, using isolated tissues obtained from the dog, guinea pig, and rat. Cetamolol antagonized the beta-adrenoceptor-mediated responses induced by isoproterenol, epinephrine, norepinephrine, and salbutamol, in tissues from both the dog and guinea pig, in a concentration-dependent manner. For a given tissue, the beta-adrenoceptor antagonist activity of cetamolol (measured as a pA2 or pKB value) was independent of the agonist used. In the dog tissues, cetamolol was more potent at inhibiting responses in the coronary artery (beta 1-adrenoceptors) than in the saphenous vein (beta 2-adrenoceptors). In the guinea pig tissues, the potency of cetamolol was approximately the same in the trachea (mixed beta 1- and beta 2-adrenoceptors) and atria (predominately beta 1-adrenoceptors), but lower in the soleus muscle (beta 2-adrenoceptors). Studies with the S-(-) and R-(+) enantiomers of cetamolol demonstrated that the S-(-) enantiomer was approximately 100-fold more potent at beta 1-adrenoceptors than the R-(+) enantiomer. In rat brain, cetamolol displaced [3H]-dihydroalprenolol bound to homogenates of cortex (beta 1-adrenoceptor binding sites) and cerebellum (beta 2-adrenoceptor binding sites). The potency of cetamolol at beta 1-adrenoceptors was found to be similar to that of betaxolol but greater than that of atenolol. However, the magnitude of the beta 1-adrenoceptor selectivity displayed by atenolol and betaxolol was greater than that displayed by cetamolol. In contrast, ICI-118,551 was found to possess potent and selective affinity for beta 2-adrenoceptors.
Acetamides↗
Antisecretory and antiulcer activities of a potent new histamine H2-receptor antagonist with an intermediate duration of action.
The antisecretory activities of 4-(dimethylamino)- N-[2-[3-[3-(1-piperidinyl)methyl]phenoxy]propyl]amino]- 1,2,5-thiadiazol-4-yl]amino]ethyl]-butanamide, S-oxide (AY-29,315) and ranitidine were determined in the rat, dog and monkey. In conscious, chronically cannulated rats, AY-29,315 was 10 and 208 times more potent than ranitidine as an inhibitor of spontaneous gastric acid secretion by the p.o. and i.v. routes, respectively. Tolerance did not develop in the conscious rat with either compound when administered for 8 consecutive days at doses equivalent to 4 times their antisecretory ED50. In lumen-perfused, anesthetized rats, AY-29,315 i.v. was 44 times more potent than ranitidine as an inhibitor of dimaprit-induced acid secretion. In the gastric fistula dog, AY-29,315 was 7.5 times more potent than ranitidine as an inhibitor of dimaprit-induced secretion by the i.v. route but 3 times less potent by the oral route. In the monkey, against dimaprit, AY-29,315 was 3 and 12 times more potent than ranitidine by the oral and i.v. routes, respectively. p.o./i.v. ratios indicate that, relative to ranitidine, the bioavailability of AY-29,315 by the oral route was low, particularly in the dog. In the dog, at 4 times the oral ED50 dose, the antisecretory effect of ranitidine lasted 190 +/- 3 min, while that of AY-29,315 lasted more than 9 h. AY-29,315 was 8 times more potent than ranitidine as an inhibitor of acetylsalicylic acid-induced ulcers in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Anesthesia↗
Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor.
Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%. The neutrophil-induced smooth muscle relaxation occurred in rings with and without endothelium and in rings precontracted with increasing concentrations of phenylephrine, prostaglandin F2 alpha or KCI. Catalase (1000 U/ml) and mannitol (1 X 10(-3) M) did not block the neutrophil-induced relaxation, whereas phenazine methosulfate (1 X 10(-5) M), hydroquinone (3 X 10(-5) M) and methylene blue (1 X 10(-5) M) reversed the neutrophil-induced relaxation. Pre-exposure of endothelium-rubbed rings to neutrophils (2 X 10(7) cells/organ chamber; 15 min) depressed the subsequent concentration-response curve to phenylephrine but augmented the relaxation induced by the phosphodiesterase inhibitor zaprinast (1 X 10(-5) M). The effluent from a column restraining the neutrophils induced a relaxation of endothelium-rubbed aortic rings that was prevented by methylene blue (1 X 10(-5) M). These results demonstrate that rat neutrophils release a factor that has a pharmacologic profile similar to that previously reported for the relaxing factor released from the vascular endothelium.
Animals↗
Demonstration of the beta 2-adrenoceptor intrinsic efficacy of AY-28,925 using the PGF2 alpha-contracted guinea-pig trachea.
The abilities of AY-28,925, labetalol and medroxalol to relax the PGF2 alpha-contracted isolated guinea-pig trachea have been investigated to compare their activities at beta 2-adrenoceptors. Maximum relaxation induced by AY-28,925 was significantly greater than that induced by either labetalol or medroxalol. This relaxation occurred in a concentration-dependent manner over a range of concentrations consistent with the previously determined affinity of AY-28,925 for beta-adrenoceptors. ICI-118,551 inhibited AY-28,925-induced relaxation in a concentration-dependent manner with a pA2 value similar to that determined for ICI-118,551 inhibition of the selective beta 2-adrenoceptor agonist salbutamol, but not the selective beta 1-adrenoceptor agonist norepinephrine. The Schild plot slope for ICI-118,551 inhibition of AY-28,925 or salbutamol did not differ significantly from unity, while that for inhibition of isoproterenol (a non-selective beta-adrenoceptor agonist) did. It is concluded that AY-28,925 is a more efficacious relaxant of tracheal smooth muscle than either labetalol or medroxalol, and that this relaxant activity is the result of its greater intrinsic efficacy at the beta 2-adrenoceptor.
Adrenergic beta-Agonists↗
In vitro isolated tissue studies with atiprosin (AY-28,228): a new antihypertensive compound.
Using in vitro isolated tissue and binding studies we have defined a receptor activity profile for atiprosin. The most prominent action of the compound was significant alpha-adrenoceptor antagonist activity (pA2 = 8.11) that was less potent than prazosin (pA2 = 8.78) but more potent than either ketanserin (pA2 = 7.34) or indoramin (pA2 = 7.85). In addition, atiprosin was selective for alpha 1-adrenoceptors, since the compound was over 100-fold less potent as an antagonist at alpha 2-adrenoceptors (pA2 = 6.04). Atiprosin also displayed selective serotonin 5-HT2-receptor antagonist activity similar to that seen with ketanserin, but with a lesser potency (pA2 atiprosin, 6.87; ketanserin, 8.61). Although atiprosin also displayed significant histamine H1-antagonist activity (pA2 = 7.32), it was less potent as an H1-antagonist than as an alpha 1-adrenoceptor antagonist. In contrast, both indoramin and ketanserin displayed H1-antagonist activity (pA2 8.77 and 8.83, respectively) greater than their respective alpha 1-adrenoceptor antagonist activities. Atiprosin had little or no activity at either beta 1- or beta 2-adrenoceptors, muscarinic or histamine H2-receptors, nor any marked ability to produce smooth muscle relaxation either by a direct effect or via calcium entry blockade.
Adrenergic alpha-Antagonists↗
Co-regulation of tracheal tone by cyclic AMP- and cyclic GMP-dependent mechanisms.
The regulation of guinea pig tracheal muscle tone by cyclic AMP-dependent and cyclic GMP-dependent relaxant mechanisms was investigated by studying the tracheal relaxant activities of forskolin, nitroprusside, N6-2'-O-dibutyryl-cyclic AMP and 8-bromoguanosine-cyclic GMP. In carbachol (3 X 10(-6) M)-contracted isolated tracheal rings, N6-2'-O-dibutyryl-cyclic AMP and 8-bromoguanosine-cyclic GMP each caused biphasic relaxation responses, which consisted of an acute relaxation followed by a sustained but lesser degree of relaxation. The biphasic nature of this response is suggested to result from a functional counter-balancing of cyclic nucleotide-dependent relaxant mechanisms and the contractile mechanisms stimulated by carbachol. The sensitivity of carbachol-contracted tracheal rings to forskolin and nitroprusside (activators of adenylate and guanylate cyclase, respectively) was generally not influenced by N6-2'-O-dibutyryl-cyclic AMP or 8-bromoguanosine-cyclic GMP in concentrations that induced up to 50% relaxation of the trachea. Furthermore, the partial relaxation of tracheal tension with one cyclic nucleotide analog did not alter the sensitivity of the tracheal rings to the other. These results demonstrate that cyclic AMP- and cyclic GMP-dependent mechanisms induce relaxations of the trachea that are functionally additive, each neither potentiating nor depressing the effects of the other. In the presence of 3 X 10(-6) M carbachol, the effectiveness of cyclic AMP- and cyclic GMP-dependent relaxant mechanisms appears to be fixed, and independent of the amount of active tension being maintained by the tracheal muscle itself.
Animals↗