The potential of specific COX-2 inhibition.
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Journal Article↗
Biomedical subjects
I Ho
Publications and source records attributed to I Ho.
Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.
BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.
Acetylcholine↗
Diabetic retinopathy and nephropathy in Fiji: comparison with data from an Australian diabetes centre.
BACKGROUND: As part of a project to improve diabetes care in Fiji, we assessed the magnitude of problems posed by diabetic retinopathy in that country and compared the findings with those from an Australian diabetes centre. The relationship between diabetic retinopathy and nephropathy was also examined in a subset of patients. METHODS: A medical team from Australia screened a total of 446 type 2 diabetic patients (ethnicity: Fijian/Indian 16/84%) for diabetic retinopathy in five towns from the Division of Viti Levu, Fiji. The findings were compared with data obtained from 1659 type 2 diabetic patients who had attended an Australian diabetes centre (ethnicity Indian/ Anglo-Celtic 12/88%). In both cohorts, retinopathy was assessed by direct fundoscopy and a spot urine sample was collected for determination of albuminuria (defined as a concentration > 50 mg/L). RESULTS: The prevalence of diabetic retinopathy increased linearly with duration of diabetes. It was higher in Fiji, even when cases from the same ethnicity (i.e. Indians) and duration were compared (P < 0.05). Extrapolation of the data points suggests a delay in the diagnosis of diabetes in Fiji. Of those patients with retinopathy in Fiji, more than half had moderate to severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy, significantly higher than patients in the Australian cohort (chi2 = 29.2; P < 0.0001). Retinopathy was not a predictor of albuminuria in Fijian Indians (chi2 = 0.4; P = 0.5). In contrast, Australian Indians with retinopathy had significantly more albuminuria (chi2 = 10.2; P = 0.001). CONCLUSIONS: Severe diabetic retinopathy is common in both ethnic groups in Fiji. A delay in the diagnosis of diabetes as well as poor glycaemic control are possible factors. The availability of laser therapy is important to prevent loss of vision, but it is also essential that appropriate training of health professionals is integrated with a programme of diabetic complication screening to support this form of therapy.
Adult↗
Tumor-associated sialylated antigens are constitutively expressed in normal human colonic mucosa.
Immunohistochemical studies have indicated that sialylated carbohydrate antigens such as sialyl-Tn, sialyl-Le(a), and sialyl-Le(x) are expressed in a tumor-associated fashion in human colon. Since sialic acid residues are O-acetylated more extensively in normal colonic epithelium than in colon cancer cells, we examined whether deacetylation of colonic tissues might enable monoclonal antibodies to recognize these tumor-associated sialylated antigens. In normal colon, deacetylation turned most cases (82%) positive with anti-sialyl-Tn mAb TKH2; and in colon cancers, it increased the number of TKH2-positive cells. Sialyl-Le(a) and sialyl-Le(x) detection was also increased after deacetylation of normal and malignant colonic tissues so that the frequency of positive cases in normal tissues was similar to that in the cancers. However, in the stomach and pancreas, the same treatment rarely increased the detection of the sialylated epitopes in normal or cancerous tissues. Thus, the same sialylated epitopes can be expressed in a tumor-associated fashion by different mechanisms in different gastrointestinal organs; in the colon, these antigens are constitutively expressed and O-acetylated, whereas in the upper gastrointestinal tract, they are rarely O-acetylated, suggesting that other mechanisms such as differences in glycosylation account for the cancer-associated expression.
Adenocarcinoma↗
Simplified experimental human dermatophytosis model.
The authors have improved and simplified previous methods for producing localized mycotic skin infections in an attempt to compare topical antifungal agents for their bioequivalency. Healthy human volunteers who had negative results for commercial, purified Trichophyton antigen (Trichophytin) were inoculated with Trichophyton mentagrophytes on two sites on each forearm in a randomized study designed to compare the antifungal activities of two ciclopirox olamine formulations. The lesions, easily induced by the authors' method, were localized and did not spread under the occlusive dressings. Infections established at the four sites on 26 subjects were treated twice daily for 14 days with the two active drug formulations and their vehicles. There were no significant differences in culture-documented cure rates or alleviation of clinical signs and symptoms between ciclopirox olamine lotion and cream. Each drug was significantly better than its vehicle. The authors' method seems to be effective and suitable for therapeutic studies.
Adult↗
Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a potential therapeutic agent for Alzheimer's disease.
The pharmacokinetics, safety, and tolerance of 1,2,3,4-tetrahydro-9-aminoacridin-1-olmaleate (HP 029) a potential therapeutic agent for Alzheimer's disease, were assessed after multiple oral doses in a randomized double-blind, placebo controlled, ascending dose study in 56 healthy elderly men (14 per dose group). The subjects in the first three groups received 25, 50, or 100 mg two times a day and a fourth group was administered 100 mg velnacrine tid for 28 days. All subjects received a final dose on day 29. Subjects were confined for continuous observation during the 36-day study period. Blood and urine samples were collected for the pharmacokinetic assessment. There were no clinically important changes in the safety variables in both age groups after any dose. There was no evidence of hepatotoxicity when elderly men were given 100 mg tid for 28 days. Nine subjects reported one or two episodes of gastrointestinal (diarrhea) side effects (6 in the 100 mg bid group and 3 in the 100 mg tid dose group) during a 29-day trial. None required treatment or were discontinued from study. These results indicate that the safety and tolerance up to 100 mg tid for 28 days in healthy elderly men are acceptable. Velnacrine was rapidly absorbed after oral administration. There were dose-related increases in Cmax, AUCs, and amount of drug excreted in urine. During multiple dosing, the Cmax increased as a function of dose. The tmax and t1/2 were not affected by dosage nor multiple dosing. Steady state levels of velnacrine were reached between days 2 and 3 with no evidence of further accumulation of velnacrine thereafter. Approximately 11-30% of the administered dose was excreted in the urine over the course of the study. The favorable pharmacokinetic characteristics and acceptable safety and tolerance of multiple dosing oral doses of velnacrine support further testing of this compound for efficacy and safety in Alzheimer's patients.
Administration, Oral↗
Disposition of roxithromycin in patients with normal and severely impaired renal function.
The disposition of roxithromycin, an investigational macrolide antibiotic, was evaluated in 20 subjects, 10 with normal renal function (creatinine clearance [CLCR] of 116 +/- 17 ml/min [mean +/- standard deviation]) and 10 with severely impaired renal function (CLCR of 10.2 +/- 2.6 ml/min) after a single 300-mg oral dose. Plasma concentration-time data were analyzed in terms of a one- or two-compartment oral absorption model utilizing nonlinear regression analysis. The terminal elimination half-life was significantly prolonged in the group with severely impaired renal function (15.5 +/- 4.7 h) compared with that of the group with normal renal function (7.9 +/- 2.5 h). Apparent total body clearance was significantly reduced in the renally impaired (25.3 +/- 10.5 ml/min) in relation to the group with normal renal function (48.8 +/- 11.1 ml/min). The first-order absorption rate constants and apparent volumes of distribution did not differ between the two groups. These data indicate that the disposition of roxithromycin is significantly delayed in subjects with CLCRs of less than 15 ml/min and suggest that the roxithromycin dosing interval be doubled for these patients.
Absorption↗
The effect of food on the bioavailability of velnacrine (HP 029) in healthy elderly men: a potential Alzheimer agent.
Velnacrine (HP 029; 1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is an investigational drug being studied in patients with Alzheimer's disease. In this open, randomized, crossover study, 24 healthy, elderly men were given 100 mg of velnacrine on two different study days to assess the influence of food on the bioavailability of velnacrine. On the first day, subjects received drug either after an overnight fast or 15 minutes after completing a standard breakfast. Seven days later, the treatments were crossed over. Blood and urine samples were collected at specific times and various intervals, respectively, from all subjects before and after drug administration for up to 24 hours. Plasma and urine concentrations of velnacrine were determined by an HPLC method. Administration of velnacrine with food resulted in slightly lower peak plasma levels of unconjugated velnacrine, (175 vs 213 ng/ml) and delayed times-to-peak plasma levels, (2.5 vs 1.5 h) without affecting the AUCs and the t 1/2 of the drug. The amount of unconjugated velnacrine excreted in urine was slightly higher when the drug was taken with food (19 vs 17 mg), but renal clearance was not altered. These results indicate that food delayed the rate but not the extent of velnacrine absorption. The minor differences in Cmax and tmax may not be clinically meaningful. Therefore, velnacrine can be administered with or without food.
Aged↗
Single dose safety, tolerance, and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent.
1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Whole plant senescence of sunflower following seedhead removal.
This study was undertaken to further clarify the relationship between seed development and monocarpic senescence of sunflower (Helianthus annuus L.). Field-grown plants with and without seedheads were evaluated for rate and duration of accumulation of dry weight, reduced N, and P by whole shoots, and for partitioning of these constituents within the individual plant parts. Concurrent with seedhead removal, [(15)N]nitrate was applied to the plants in a selected area of the experimental plot. Whole plants (above ground portions) were harvested seven times during the seed-filling period and analyzed for dry weight, reduced N, and P. Although seedhead removal depressed the rates of dry weight, reduced N, and P accumulation by whole shoots, it extended the duration of accumulation of these constituents, relative to headed control plants. As a result, the final whole shoot dry weight and N and P contents at seed maturity were similar for deheaded and headed plants. Seedhead removal also affected the partitioning of dry matter, reduced N, and P but the relative proportions varied as a function of constituent and growth stage. Analysis of (15)N present in whole shoots at physiological maturity showed that similar amounts of nitrate were absorbed during the postflowering period by headed and deheaded plants. These data indicate that the absence of seeds does not affect the total accumulation of dry matter, reduced N, or P, by sunflower plants, but does alter the rates of accumulation and partitioning of these constituents.
Journal Article↗
Pharmacokinetics of roxithromycin (RU 965).
This report contains the findings of five studies performed to evaluate the pharmacokinetics of roxithromycin (RU 965), a new macrolide antibiotic. Roxithromycin was given as 150- and 300-mg film-coated tablets. The drug is rapidly absorbed after oral administration. Peak plasma levels following 150- and 300-mg doses occur within two hours. Steady state is reached within four days with doses of 150 mg twice a day or 300 mg once daily. The plasma half-life is approximately 12 hours. About 10% of the dose is excreted in urine. Although dose dependency was observed for the various pharmacokinetic parameters, dose proportionality could be demonstrated only in terms of the percentage of the dose excreted in urine. The rate of absorption is not affected by age. The rate of elimination and renal clearance are decreased in healthy elderly subjects, however, these differences should not be clinically meaningful. The bioavailability of the drug is not affected to a clinically meaningful extent when it is given with milk. Less than 0.05% of the administered dose is excreted in the breast milk of lactating women. Roxithromycin was safe and well tolerated with no clinically meaningful changes in any of the safety variables in any of the five studies reported.
Adult↗
The pharmacodynamics and pharmacokinetics of multiple doses of the new H2-receptor antagonist, roxatidine acetate, in healthy men.
Roxatidine acetate (HOE 760, TZU 0460) is a new H2-receptor antagonist which is more potent than cimetidine and ranitidine. A randomised, double-blind, placebo-controlled study was conducted in healthy men to determine the effects of multiple oral doses of roxatidine acetate on unstimulated gastric acid secretion, and to assess the preliminary multiple-dose pharmacokinetics of its active desacetyl metabolite. The subjects were randomised to receive either roxatidine acetate 150 mg or placebo daily at 9 pm for 14 days. Gastric secretions were collected by aspiration using a nasogastric tube placed in the distal part of the stomach. Gastric fluid volume, pH, and acid concentrations were determined for 2 hours before drug administration and over 24 hours after administration on days 1, 7, 14 (the last day of dosing), and 17 (3 days after the last dose). Plasma and urine samples were collected throughout the study for the pharmacokinetic assessment. All subjects completed the study without side effects or clinically significant changes in any of the safety variables. Subjects receiving roxatidine acetate had substantial increases in gastric pH and decreases in acid secretion compared to baseline and to placebo-treated subjects. The duration of effect was approximately 12 hours. Nocturnal pH was greater than or equal to 6.0 in 80% of the roxatidine acetate-treated subjects. When sampled 3 days after the last dose (day 17) no differences in pH, acid secretion, or gastric volume were observed between the roxatidine acetate- and placebo-treated groups. The gastric pH increased with the mean plasma concentrations of the desacetyl metabolite. Mean plasma levels at steady state were attained between the 4th and 7th days after which there was no evidence of appreciable accumulation of the desacetyl metabolite. Roxatidine acetate 150 mg administered orally at 9 pm for 14 days to healthy men was safe, well tolerated, and produced clinically relevant increases in gastric pH, and decreases in gastric acid concentration, without affecting gastric fluid volume.
Adult↗
Effect of head removal on leaf senescence of sunflower.
Greenhouse and field studies examined the effect of flower or seedhead removal on leaf senescence and associated changes in sunflower (Helianthus annuus L.) plants. At intervals during seed development, selected leaves (leaves 6 through 8 from the top in the greenhouse and leaf 7 from the top in the field) were harvested and analyzed for chlorophyll, specific leaf weight, N, P, soluble protein, and electrophoretic gel profiles of soluble polypeptides. In both the greenhouse and the field, the leaves of headless plants retained or accumulated more N, P, soluble protein, and dry weight than leaves of plants with heads. Obviously, head removal affected the partitioning of these metabolites during seed development. None of the treatments resulted in the formation of new polypeptides (electrophoretic gel profiles). Comparisons of the rates and extent of loss of chlorophyll, soluble protein, and polypeptide bands (especially ribulose 1,5-bisphosphate carboxylase) from the leaves of headed and deheaded plants showed that head removal delayed the rate of development of leaf senescence for the greenhouse-grown but had much less effect on field-grown plants. These findings illustrate the variability in different parameters commonly associated with the leaf senescence processes of headed and deheaded sunflower plants grown under different environments.
Journal Article↗
Pharmacokinetics of orally administered pentoxifylline in humans.
The pharmacokinetics of pentoxifylline was studied in healthy male volunteers following single oral doses of 100, 200 and 400 mg of the drug in solution. Concentrations of the drug and three of its metabolites were determined in plasma. The major urinary metabolite was also determined for 24 hours after dosing. Pentoxifylline was rapidly and extensively absorbed at all doses. Peak plasma concentrations of pentoxifylline occurred between 0.29 and 0.41 hours after dosing. Its metabolites, a secondary alcohol and two homologous carboxylic acids showed tmax values from 0.72 to 1.15 hours. Cmax and AUC values increased in a dose-dependent manner for pentoxifylline and its metabolites over the three dose levels though strict dose proportionality could only be demonstrated for the principal carboxylic acid metabolite. The apparent plasma half-life of pentoxifylline varied between 0.39 and 0.84 hours for the various doses while the apparent half-lives of the metabolites were in the range of 0.96 to 1.61 hours. The major circulating metabolites, the secondary alcohol and carboxypropyl derivative, were at consistently higher plasma concentrations than the parent drug. Two major pathways account for the circulating metabolites of pentoxifylline though oxidation of the parent drug to a carboxylic acid accounts for the formation of the principal urinary elimination product. Because of the pharmacological activities of pentoxifylline, studies are proposed of the pharmacokinetic-pharmacodynamic correlations of pentoxifylline and its metabolites. The present pharmacokinetic results further support the use of a controlled-release dosage form of pentoxifylline for therapy.
Administration, Oral↗
The pharmacokinetics and bioavailability of nomifensine maleate in healthy men.
Two studies were conducted in normal male volunteers to establish the pharmacokinetic parameters for nomifensine maleate and to determine the bioavailability of the drug from the Merital capsule intended for U.S. marketing. Single oral doses of 25, 100, and 200 mg of nomifensine maleate as aqueous solutions were administered to 24 men in the open-label Latin-square design pharmacokinetic study. In the bioavailability study, 24 men received single oral 50 mg doses of nomifensine maleate in a capsule or as an aqueous solution. Plasma levels of nomifensine were determined by radioimmunoassay and urinary levels of total nomifensine and its metabolites were assayed by thin-layer chromatography. There was a proportional increase in the area under the curve (AUC) with increasing dose, while peak plasma levels and amounts of total nomifensine and its metabolites excreted in the urine rose as dose increased. The pharmacokinetics of nomifensine are considered linear over the dose range tested. Nomifensine maleate was equally bioavailable from the 50 mg aqueous solution and the Merital capsule formulation.
Administration, Oral↗
Cefotaxime: pharmacokinetics and in vitro antibacterial activity of serum and urine in normal human volunteers.
The pharmacokinetic and antibacterial properties of cefotaxime were determined in normal adult volunteers. Single doses of 250, 500, 1,000 and 2,000 mg were evaluated following 5- and 20-min intravenous (i.v.) infusions and intramuscular (i.m.) administration. Cefotaxime was well tolerated and mean peak serum levels exceeded the minimum inhibition concentration (MIC) values for a wide spectrum of potential bacterial pathogens. Approximately 48% of the i.v. doses was excreted renally; average volume of distribution was 30% of body weight and the t 1/2 was about 1 h. Cefotaxime was rapidly absorbed following i.m. injection with maximum serum concentrations occurring at approximately 0.6 h. Serum and urine antibacterial activity reflected the concentration of cefotaxime and MIC of the bacterial pathogens tested.
Bacteria↗
Clobazam kinetics: intrasubject variability and effect of food on adsorption.
The kinetics of single 20-mg oral doses of clobazam was determined on two occasions in 12 healthy male volunteers. Clobazam was given in the fasting state on one occasion and following a standard breakfast on another. Compared with the fasting state, administration of clobazam with food reduced mean peak plasma concentrations (465 vs. 333 ng/ml, P less than 0.01), and prolonged the time to reach peak concentration (1.7 vs. 2.5 hours after dosage, P less than 0.1). Total area under the curve nor the extent of formation of desmethylclobazam, the major metabolite. Clobazam AUC and elimination half-life each were highly correlated within subjects between the two trials (r = 0.97 and 0.95, respectively). Thus, administration of clobazam with food slows the rate of clobazam absorption but does not alter the completeness of absorption. The rate of drug elimination is highly replicable upon repeated administration clobazam to the same individual.
Adult↗
Interaction between a Bacillus cereus spore hexosaminidase and specific germinants.
A purified coat-associated hexosaminidase from spores of Bacillus cereus was studied to determine whether it could promote germination of dormant spores. Spores of a coat-deficient mutant as well as chemically extracted spores were used as substrate. Both of these spore preparations responded poorly to most germinants. However, absorbance loss was accelerated when the hexosaminidase was added in the presence of L-alanine. Enzyme alone was not effective. The addition of D-alanine inhibited completely the absorbance loss caused by hexosaminidase and L-alanine. Calcium dipicolinate and L-alpha-aminobutyric acid activated the hexosaminidase to some extent, but these chemicals were much less effective than L-alanine. In addition to the absorbance loss, the spores treated with enzyme and germinants released hexosamine and lost heat resistance and phase whiteness. The results suggest that this particular enzyme might have a role in germination.
Alanine↗