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Biomedical subjects

I James

Publications and source records attributed to I James.

At least 19 recordsLinked to original sources
PubMed1997

The acute effects of exercise on bone turnover.

Exercise is known to have long-term benefits on bone mass, but little is known about the short-term effects of exercise on bone turnover. The purpose of this study was to investigate whether acute effects of exercise on bone remodelling could be detected by measuring blood and urinary markers of bone turnover. We measured biochemical markers of bone turnover in ten healthy, young men before and up to 32 hours after 30 minutes of brisk treadmill walking. Blood samples were taken before, immediately after and at 0.5, 1, 8, 24 and 32 hours after the exercise. These were assayed for osteocalcin and bone specific alkaline phosphatase. Twenty-four hour urine samples were taken over three days (day before, day of and day after exercise) and measured for pyridinoline and deoxypyridinoline crosslinks. Crosslink excretion was standardised for total body bone mineral content (TBBMC) and urinary creatinine. Total body bone mineral density (and content) and body composition were measured by dual energy X-ray absorptiometry. No changes in the levels of either osteocalcin or alkaline phosphatase were seen at any time point following the exercise. Both urinary crosslinks exhibited an increase in levels on the day of the exercise and a further significant increase the day after (pyridinoline 38.7%, p = 0.05; deoxypyridinoline 42.3%, p = 0.025; median, corrected for TBBMC). There were significant negative correlations between the crosslinks, osteocalcin and body fat percentage. In conclusion, the exercise appears to have stimulated bone resorption within 32 hours of moderate exercise, but there was no measurable effect on bone formation after 32 hours. A longer study period may be necessary to detect changes in bone formation.

Absorptiometry, Photon↗
PubMed1997

A longitudinal study of markers of bone turnover in Graves' disease and their value in predicting bone mineral density.

Whether biochemical markers can predict improvement in reduced bone mineral density (BMD) associated with thyrotoxicosis in unclear. We investigated the relationship between serum osteocalcin (OC), bone-specific alkaline phosphatase (b-ALP), serum deoxypyridinoline (Sdpd) and pyridinoline (Spyr), 24-hour urinary deoxypyridinoline (Udpd), and BMD in 17 thyrotoxic patients during 1 yr of treatment. Coinciding with euthyroidism at 4-8 weeks, there was a peak in b-ALP and OC and a prompt fall into the normal range in Udpd and Sdpd, but not Spyr, levels. Mean b-ALP continued to be raised at week 52 when it was inversely correlated with BMD. Mean BMD rose approximately 6%, P < 0.01, over 1 yr. Coupling indices were calculated as a measure of bone balance and, at diagnosis, was [minus4.26 in favor of bone resorption and rose with treatment in favor of bone formation: weeks 2: -0.23; 4: +4.01; 8: +4.37; 12: +4.44; 24: +2.32; and 52: +1.56. Bone turnover is balanced within 2 weeks of starting treatment for thyrotoxicosis. Udpd accurately indicates thyrotoxic bone resorption. Serum b-ALP indicates continuing bone formation and, at 1 yr, may provide a marker for low BMD. OC, Sdpd, and Spyr are less sensitive in documenting bone remodeling during treatment of thyrotoxicosis.

Adult↗
PubMed1996

Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. 4. Potent, orally active analgesics.

Structural features of three regions of the capsaicin molecule necessary for agonist properties were delineated by a previously reported modular approach. These in vitro agonist effects were shown to correlate with analgesic potency in rodent models. Combination of optimal structural features from each of these regions of the capsaicin molecule have led to highly potent agonists (eg., 1b). Evaluation in vivo established that 1b had analgesic properties but poor oral activity, short duration of action, and excitatory side effects which precluded further development of this compound. Preliminary metabolism studies had shown that the phenol moiety of 1b was rapidly glucuronidated in vivo, providing a possible explanation for the poor pharmacokinetic profile. Subsequent specific modification of the phenol group led to compounds 2a-j, which retained in vitro potency. The in vivo profiles of two representatives of this series, 2a,h, were much improved over the "parent" phenol series, and they are candidates for development as analgesic agents.

Administration, Oral↗
PubMed1996

Pharmacokinetics and food interaction of MK-462 in healthy males.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.

Absorption↗
PubMed1995

The effect of tenidap on the anti-hypertensive efficacy of thiazide diuretics in patients treated for mild to moderate hypertension.

1. This randomised, placebo-controlled, double-blind, parallel-group study was conducted to assess the effect of tenidap sodium 120 mg, a novel anti-arthritic cytokine modulating drug, on the hypotensive efficacy of the thiazide diuretics hydrochlorothiazide or bendrofluazide. 2. Twenty-three male and female patients, aged 41-78 years, with mild to moderate, uncomplicated, essential hypertension controlled with thiazide diuretic therapy, received either a single daily dose of tenidap sodium 120 mg or matched placebo for 22 days in addition to their diuretic therapy. Changes between baseline and endpoint in supine and standing systolic and diastolic pressures and pulse rate were compared between treatment groups. 3. Daily treatment with tenidap reduced the anti-hypertensive efficacy of the thiazide diuretics. Blood pressure tended to increase marginally and the increase in mean standing diastolic pressure observed with tenidap was significantly greater than the change in the placebo group. All pressures tended to decrease in the placebo group and all endpoint measurements were within 7 mm Hg of baseline in both groups. 4. Treatment-related side effects of mild to moderate severity were reported in two subjects receiving tenidap, but in neither case was treatment discontinued. Two subjects receiving placebo also experienced side effects considered to be treatment-related and both were withdrawn from the study. 5. The results of this study suggest that tenidap may be given to patients treated for mild to moderate essential hypertension controlled with thiazide therapy; however, the patient's blood pressure should be regularly monitored.

Adult↗
PubMed1995

The effect of tenidap on the anti-hypertensive efficacy of ACE inhibitors in patients treated for mild to moderate hypertension.

1. A randomised, placebo controlled, double-blind, parallel group study was conducted to assess the effect of tenidap sodium, a novel cytokine modulating drug, on the stable hypotensive response to the angiotension converting enzyme (ACE) inhibitor enalapril in subjects with mild to moderate, uncomplicated, essential hypertension. 2. Twenty-four male and female hypertensives, aged 33-77 years, received either 120 mg tenidap sodium or matched placebo daily for 22 days concomitantly with enalapril. 3. Mean endpoint supine and standing, systolic and diastolic pressures remained within 10% of baseline in each treatment group. However, the endpoint values were marginally above baseline during double-blind treatment with tenidap and marginally below baseline in the group receiving placebo. The increases in supine and standing systolic pressures in the tenidap group differed significantly from the changes in the placebo group. There were no significant differences between groups in changes in pulse rate. 4. Gastrointestinal side effects of mild to moderate severity attributed to treatment with tenidap were experienced by five subjects, one of whom was withdrawn during the third week of treatment. One subject receiving placebo was withdrawn because of a moderate headache attributed to study treatment. 5. The results of this study suggest that treatment with tenidap may interfere with the anti-hypertensive efficacy of ACE inhibitors. It is recommended that blood pressure should be monitored when tenidap is administered concomitantly with an ACE inhibitor.

Adult↗
PubMed1994

The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin.

Capsaicin and resiniferatoxin are natural products which act specifically on a subset of primary afferent sensory neurons to open a novel cation-selective ion channel in the plasma membrane. These sensory neurons are involved in nociception, and so, these agents are targets for the design of a novel class of analgesics. Although synthetic agonists at the capsaicin receptor have been described previously, competitive antagonists at this receptor would be interesting and novel pharmacological agents. Structure-activity relationships for capsaicin agonists have previously been rationalized, by ourselves and others, by dividing the capsaicin molecule into three regions--the A (aromatic ring)-, B (amide bond)-, and C (hydrophobic side chain)-regions. In this study, the effects on biological activity of conformational constraint of the A-region with respect to the B-region are discussed. Conformational constraint was achieved by the introduction of saturated ring systems of different sizes. The resulting compounds provided agonists of comparable potency to unconstrained analogues as well as a moderately potent antagonist, capsazepine. This compound is the first competitive antagonist of capsaicin and resiniferatoxin to be described and is active in various systems, in vitro and in vivo. It has recently attracted considerable interest as a tool for dissecting the mechanisms by which capsaicin analogues evoke their effects. NMR spectroscopy and X-ray crystallography experiments, as well as molecular modeling techniques, were used to study the conformational behavior of a representative constrained agonist and antagonist. The conformation of the saturated ring contraint in the two cases was found to differ markedly, dramatically affecting the relative disposition of the A-ring and B-region pharmacophores. In agonist structures, the A- and B-regions were virtually coplanar in contrast to those in the antagonist, in which they were approximately orthogonal. A rationale for agonist and antagonist activity at the capsaicin receptor is proposed, based on the consideration of these conformational differences.

Animals↗
PubMed1994

L-692,429, a nonpeptide growth hormone (GH) secretagogue, reverses glucocorticoid suppression of GH secretion.

The reversal of glucocorticoid-induced negative nitrogen balance by GH supports a possible therapeutic role for GH treatment in patients receiving these catabolic steroids. A GH secretagogue might be of similar utility. However, stimulated GH secretion is generally suppressed by glucocorticoids. To test whether L-692,429, a nonpeptide mimic of GH-releasing peptide-6, can overcome such suppression, a double blind, placebo-controlled, three-period, cross-over study was performed in nine healthy young men who received 0.2 mg/kg L-692,429, i.v., preceded by 4 days of prednisolone (20 mg, orally, three times daily) or placebo, and 0.75 mg/kg L-692,429 preceded by prednisolone only. The mean (SE) GH peak and area under the curve between 0-240 min after administration of 0.2 mg/kg L-692,429 in the absence of steroid were 53.8 (7.2) micrograms/L and 3481 (1005) micrograms/min.L, which were reduced to 25.1 (3.4) micrograms/L and 1342 (285) micrograms/min.L (P < or = 0.01) when treatment was preceded by 4 days of prednisolone. However, the suppressive influence of the steroid was attenuated by the high dose of L-692,429, which achieved a GH peak and area under the curve between 0-240 min of 42.6 (5.8) micrograms/L and 2298 (425) micrograms/min.L, respectively (P < 0.01 vs. 0.2 mg/kg L-692,429 plus prednisolone). L-692,429 stimulates GH secretion even in the setting of short term, high dose, concomitant glucocorticoid treatment, suggesting that such compounds might provide an alternative means of increasing circulating GH and reversing the catabolic effects of these steroids.

Adult↗
PubMed1993

Assay of pyridinium crosslinks in serum using narrow-bore ion-paired reversed-phase high-performance liquid chromatography.

The pyridinium crosslinks are important biomarkers of mature hard tissue collagen degradation. This paper describes an isocratic ion-paired reversed-phase high-performance chromatographic assay using narrow-bore columns and high-sensitivity fluorescence detection to enable for the first time the determination of pyridinium crosslinks in both serum and synovial fluid samples. Extracted freeze-dried acid hydrolysates were re-suspended in 20 mM pentafluoropropionic acid (PFPA). Separations were carried out using an Exsil 100 5-microns ODS2 column (100 mm x 2.1 mm I.D.) eluted with 10 mM PFPA in water at 0.15 ml/min and detected using a Jasco 821-FP detector (xenon lamp: excitation 290 nm, emission 400 nm). Fluorescent response was linear from 269 to 8620 fmol for pyridinoline (Pyr) and 85 to 2710 fmol for deoxypyridinoline (dPyr). The limits of detection were 28 and 57 fmol, respectively. The coefficient of variation for extraction and analysis of normal serum was 7.96% for Pyr and 6.30% for dPyr (n = 6). The mean +/- S.D. concentration of Pyr in normal serum was 3.26 +/- 0.83 nM.

Biomarkers↗
PubMed1993

A single-blind, randomised, comparative study of clarithromycin and amoxycillin suspensions in the treatment of children with lower respiratory tract infections.

One hundred and forty-five children with signs and symptoms of lower respiratory tract infections were entered into this multicentre, General Practice, investigator-blind study, designed to demonstrate equivalent efficacy between clarithromycin and amoxycillin suspensions. Seventy one children were randomised to treatment with clarithromycin suspension 7.5 mg/kg bodyweight twice daily and 74 to treatment with amoxycillin suspension 125 mg (bodyweight < 25 kg) or 250 mg (bodyweight > or = 25 kg) three times a day according to bodyweight. Duration of therapy was 5-10 days as determined by the investigator. Clinical evaluations were performed pretreatment, during treatment and post-treatment within 72 hours of cessation of therapy. Fifty two children in the clarithromycin group and 57 in the amoxycillin group were clinically evaluable. Both study medications were effective and there were no significant differences between the groups with respect to clinical cure rate (60% for clarithromycin and 63% for amoxycillin), clinical success rate (cure plus improvement, 96% for clarithromycin and 95% for amoxycillin) or rate of resolution of clinical signs and symptoms in clinically evaluable patients. The intention to treat analysis for all patients entered similarly showed no significant differences in efficacy. The two treatment groups did not differ significantly with respect to incidence or severity of adverse events which were generally mild and associated with the gastrointestinal system. Therapy was withdrawn because of adverse events in three children on clarithromycin and one on amoxycillin. Bacteriological cure rates could not be determined because of an insufficient number of evaluable pre-treatment sputum samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗
PubMed1992

Longitudinal study of serum thyroid hormone levels during normal pregnancy.

We undertook a prospective longitudinal study of thyroid function in 60 normal pregnant women and measured serum concentrations of T4, triiodothyronine (T3), T-uptake, thyroxine binding globulin (TBG), free thyroxine index (FTI), free T4, albumin and thyrotropin (TSH). From these data we established reference ranges for each of these analytes for each trimester and examined the inter-relationships between laboratory measurements of thyroid function tests. We observed significant increases in serum concentrations of thyrotropin and decreases in free T4, assays commonly used as first line investigations of thyroid activity during pregnancy. However, the 95th centile intervals for both analytes remained within the reference range for nonpregnant women.

Female↗
PubMed1992

Preliminary results of the use of urinary excretion of pyridinium crosslinks for monitoring metastatic bone disease.

The collagen crosslinks, pyridinoline and deoxypyridinoline, are recently described markers of the rate of bone resorption. The urinary excretion of these compounds, expressed as a ratio to urinary creatinine, has been measured using ion-pair reversed phase high-performance liquid chromatography in 20 patients receiving oral pamidronate for bone metastases from breast cancer. Before treatment the ratio of pyridinoline and deoxypyridinoline to creatinine in urine (UPCR and UdPCR respectively) were each above normal in 16/20 (80%) patients. Urinary calcium excretion (UCCR) was elevated in 15/20 (75%). There was a strong correlation between UPCR and UdPCR, but neither of the crosslink measurements correlated well with UCCR. Urinary excretion of all three indices of bone resorption fell significantly during pamidronate treatment. The median values after 4 weeks treatment were 63% of baseline for UPCR, 45% for UdPCR and 26% for UCCR. From this preliminary study urinary pyridinoline and deoxypyridinoline excretion appear to be promising markers of bone resorption in advanced malignancy. Their role in response assessment and the advantages over UCCR measurements merit further study.

Administration, Oral↗