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D Grimes

Publications and source records attributed to D Grimes.

At least 37 records · Page 2Linked to original sources
PubMed1998

Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD Study Group.

BACKGROUND: The value of antibiotic prophylaxis before insertion of an intrauterine device (IUD) remains uncertain. We undertook a triple-masked, randomised, placebo-controlled trial to find out whether such prophylaxis reduces the rate of IUD removal within 90 days. METHODS: 11 clinic sites in southern California enrolled women who requested IUD insertion and were at low risk of sexually transmitted infection according to self-reported medical history. We randomly assigned 1985 participants either 500 mg azithromycin or placebo capsules of identical appearance taken about 1 h before insertion of a Copper T 380A IUD. 118 women did not have an IUD inserted. We followed up 1833 of the remaining 1867 (98%) participants for at least 90 days after insertion. FINDINGS: The rate of IUD removal for any reason other than partial expulsion was 3.8% (35/918) in the antibiotic group and 3.4% (31/915) in the placebo group (relative risk 1.1 [95% CI 0.7-1.8]). The two treatment groups sought medical attention with equal frequency (mean 38 visits per 100 women). During the 90 days after IUD insertion, only one woman from each assignment group had salpingitis, as defined by established criteria. INTERPRETATION: Prophylaxis with azithromycin did not affect the likelihood that a woman would retain her IUD at 90 days or the frequency of postinsertion medical attention. In appropriately screened women, the risk of upper-genital-tract infection is negligible after IUD insertion, with or without the administration of prophylactic antibiotics.

Adult↗
PubMed1998

Can intrauterine device removals for bleeding or pain be predicted at a one-month follow-up visit? A multivariate analysis.

From 4%-14% of intrauterine device (IUD) users have their IUD removed due to bleeding or pelvic pain in the first year of use. Past studies have analyzed whether baseline patient information can help predict such removals, but no previous analysis has examined whether information provided at the recommended 1-month follow-up visit could improve such predictions. Using data from an international multicenter randomized controlled trial, 89 women with removals for bleeding and pain after the 1-month visit were compared with 2536 continuing users. Logistic regression indicated several significant predictors of removal. Women reporting intermenstrual bleeding since last menses were nearly three times more likely to have removals for bleeding or pain (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.4-5.9). Similarly, those complaining of excessive menstrual flow were 3.5 times more likely to have removals within 12 months (95% CI 1.4-9.2). Women reporting these menstrual problems during scheduled revisits may benefit from counseling and treatment with nonsteroidal anti-inflammatory drugs (NSAID).

Adolescent↗
PubMed1997

Modern oral contraceptives and cardiovascular disease.

We reviewed evidence that bears on the cardiovascular safety of combined oral contraceptives containing second- and third-generation progestogens and < 50 micrograms of estrogen. Recent epidemiologic studies indicate that current use of these formulations is associated with a smaller increase in the incidence of venous thromboembolism than earlier formulations. In some studies the increase for third-generation formulations containing desogestrel or gestodene was about 1.5 to 2 times that for second-generation formulations, but there is evidence that differences between users in underlying risk and likelihood of being diagnosed contributed to this result. Recent studies of myocardial infarction suggest a smaller increase in risk associated with modern formulations than with earlier ones; one study suggests a threefold increase for second-generation formulations and no increase for third-generation formulations, but the finding requires confirmation. Recent studies of stroke indicate little or no increase in risk for modern formulations among women without risk factors. We conclude that modern combined oral contraceptives are safer than earlier formulations with respect to cardiovascular disease, which occurs rarely in young women.

Cardiovascular Diseases↗
PubMed1996

Azole phenoxy hydroxyureas as selective and orally active inhibitors of 5-lipoxygenase.

Azole phenoxy hydroxyureas are a new class of 5-lipoxygenase (5-LO) inhibitors. Structure-activity relationship studies have demonstrated that electronegative substituents on the 2-phenyl portion of the oxazole tail increased the ex vivo potency of these inhibitors. Similar substitutions on the thiazole analogs had only minor contribution to the ex vivo activity. The trifluoromethyl-substituted oxazole 24 was the best compound of the oxazole series in both the ex vivo (6 h pretreated rats) and in vivo (3 h pretreated rats) RPAR assay with ED50 values of approximately 1 and 3.6 mg/kg, respectively, but was weakly active in the allergic guinea pig assay. Oxazole 50 was equally active in both the RPAR and guinea pig in vivo models and was similar to zileuton. The unsubstituted thiazole 52 was the best compound of the thiazole series, by inhibiting the leukotriene B4 biosynthesis in the RPAR assay (3 h pretreated rats) by 99%, at an oral dose of 10 mg/kg, and the bronchoconstriction in the allergic guinea pig by 50%, at an intravenous dose of 10 mg/kg. Oxazole 24 demonstrated high and selective 5-LO inhibitory activity in the in vitro assays, with IC50 values ranging from 0.08 microM in mouse macrophages to 0.8 microM in human peripheral monocytes to 1.2 microM in human whole blood. This activity was selective for 5-LO, as concentrations up to 15 microM in mouse macrophages did not affect prostaglandin formation. Oxazole 59 was the most active inhibitor in the human monocyte assay with an IC50 value of 7 nM.

Animals↗
PubMed1993

WY-50,295 tromethamine, a novel, orally active 5-lipoxygenase inhibitor: biochemical characterization and antiallergic activity.

WY-50,295 tromethamine demonstrates significant 5-lipoxygenase inhibitory activity with IC50 values ranging from 0.055 microM in rat peritoneal exudate cells, to 0.16 microM in mouse macrophages, 1.2 microM in human peripheral neutrophils and 8.1 microM in rat blood leukocytes. This activity appeared selective for 5-lipoxygenase as concentrations up to 10 microM in rat peritoneal exudate cells, and 1 microM in mouse macrophages did not effect prostaglandin generation. In non-cellular enzyme assays, WY-50,295 tromethamine displayed inhibitory activity against a soluble 5-lipoxygenase from guinea pig peritoneal exudate cells (IC50 = 5.7 microM), while it was essentially inactive against 12-lipoxygenase, 15-lipoxygenase, or prostaglandin H synthetase at concentrations up to 500 microM, or against human phospholipase A2 at concentrations up to 50 microM. In purified human blood neutrophils the inhibitory activity was reversible but did not appear dependent upon substrate concentration. IN contrast, in the guinea pig cell-free 5-lipoxygenase assay changing the arachidonic acid substrate concentration from 5 to 500 microM produced a concentration-dependent reduction in inhibitory activity. WY-50,295 tromethamine inhibited the release of peptidoleukotrienes from fragmented guinea pig lung with an IC50 of 0.63 microM. When administered p.o. with a 4 h pretreatment time, WY-50,295 tromethamine inhibited ex vivo leukotriene B4 production in rat blood leukocytes with an ED50 of 19.6 mg/kg. Against an ovalbumin-induced leukotriene dependent bronchoconstriction in anesthetized sensitized guinea pigs, WY-50,295 tromethamine inhibited the ovalbumin-induced bronchoconstriction with an i.v. ED50 of 2.5 mg/kg (5 min pretreatment) and a p.o. ED50 of 7.3 mg/kg (4 h pretreatment). Significant activity was also evident with an 18 h pretreatment. Thus WY-50,295 tromethamine is an potent and selective 5-lipoxygenase inhibitor in a number of in vitro systems. Additionally the compound is orally efficacious and has a long duration of action in an allergic bronchoconstriction model. This data suggests that WY-50,295 tromethamine may have utility in the treatment of asthma and other leukotriene-dependent pathologies.

Administration, Oral↗
PubMed1993

Anti-leukotriene effects of WY-50,295 tromethamine in isolated guinea pig pulmonary tissues.

The abilities of WY-50,295 tromethamine, a 5-lipoxygenase inhibitor, to inhibit antigen-induced leukotriene (LT) release from guinea pig lung fragments, and to prevent LTD4 or antigen-induced contraction of isolated guinea pig tracheal muscle were compared with the activities of zileuton and MK-886 (two selective 5-lipoxygenase inhibitors), and LY171883 (a LTD4 receptor antagonist). In fragmented guinea pig lung, WY-50,295 tromethamine inhibited antigen-induced LT release with an IC50 of 0.63 microM, and was 4.6- and 5.2-fold more potent than zileuton and MK-886, respectively. WY-50,295 tromethamine differed from these 5-lipoxygenase inhibitors, however, in that WY-50,295 tromethamine competitively antagonized LTD4-induced tracheal contractions (pA2 = 6.06) at concentrations that inhibited LT release. LY171883 was an effective LTD4 receptor antagonist (pA2 = 6.96), that only inhibited antigen-induced LT release at higher concentrations (IC50 = 7.9 microM). WY-50,295 tromethamine almost completely inhibited antigen-induced leukotriene-dependent tracheal contractions, whereas high concentrations of zileuton, MK-886, or LY171883 produced only partial inhibition. This partial inhibition was likely to result from 'breakthrough' 5-lipoxygenase activity, because combinations of zileuton plus MK-886 or zileuton plus LY171883, were more effective than zileuton, MK-886, or LY171883 alone. The greater efficacy of WY-50,295 tromethamine in the antigen-challenged guinea pig trachea is likely to result from its combined abilities to prevent LT biosynthesis and block LTD4 receptors.

Acetophenones↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1991

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↗
PubMed1991

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↗