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Biomedical subjects

P Strange

Publications and source records attributed to P Strange.

At least 19 recordsLinked to original sources
PubMed1999

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.

Adult↗
PubMed1999

Repaglinide versus glyburide: a one-year comparison trial.

This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naïve patients suggest that patients given repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.

Adult↗
PubMed1999

Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes.

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Aged↗
PubMed1999

Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects.

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic profile of insulin aspart (a new fast-acting human insulin analog) after subcutaneous administration in the deltoid, abdominal, and thigh sites and to compare this profile with regular human insulin (Novolin; Novo Nordisk A/S, Copenhagen). RESEARCH DESIGN AND METHODS: A total of 20 healthy subjects were studied in a single-center six-period double-blind randomized crossover trial with 6 study days and a washout period of 1 week between each single daily dose of the trial drug. Subjects were randomized to receive a single dose of 0.2 U/kg of insulin aspart or regular insulin on each of the 6 study days in three different sites (the deltoid, the abdomen, and the thigh) during a 10-h euglycemic clamp (two drugs and three injection sites). Pharmacokinetic and pharmacodynamic measurements were derived from blood sample measurements of glucose, insulin, and C-peptide during these clamps. RESULTS: The pharmacodynamic data from the euglycemic clamp study showed that, regardless of injection site, the maximal glucose infusion rate (GIR Cmax) was greater and occurred at an earlier time (GIR Tmax) after administration of insulin aspart than regular insulin (GIR Cmax: abdomen 813 vs. 708, deltoid 861 vs. 736, and thigh 857 vs. 720 g/min, P < 0.05 for all; GIR Tmax: abdomen 94 vs. 173, deltoid 111 vs. 192, and thigh 145 vs. 193 g/min, P < 0.05 for all). Pharmacokinetic parameters were also consistent with faster absorption and higher peak insulin concentrations after insulin aspart administration. From all sites, the peak insulin concentration (Cmax) was higher and occurred earlier (Tmax) after administration of insulin aspart than of regular insulin (Cmax: abdomen 501 vs. 260, deltoid 506 vs. 252, thigh 422 vs. 220 pmol/l, P < 0.001 for all sites; Tmax: abdomen 52 vs. 109, deltoid 54 vs. 98, and thigh 60 vs. 107 min, P < 0.01 for all sites). The absorption and glucose-lowering action of insulin aspart did not differ between sites (similar GIR Cmax, Tmax, and area under the curve parameters). However, the duration of the glucose-lowering effect was up to 34 min shorter (P < 0.01) for the abdomen injections than for the deltoid or thigh injections (lower time of 50% glucose disposal). In addition, the amount of glucose infused was significantly lower by 10-14% in the abdomen than in other sites. CONCLUSIONS: Subcutaneous administration of insulin aspart causes a more rapid and intense maximal effect compared with regular insulin during euglycemic clamp studies in nondiabetic subjects. Abdominal administration of insulin aspart has a shorter duration of glucose-lowering effect compared with administration in the deltoid or thigh.

Absorption↗
PubMed1998

A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes.

OBJECTIVE: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded. RESULTS: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated. CONCLUSIONS: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

Adult↗
PubMed1997

Lesional alopecia areata T lymphocytes downregulate epithelial cell proliferation.

Alopecia areata is characterized by peribulbar infiltration by activated T cells. The function of these T cells in the pathogenesis is unknown. To elucidate the potential role of lesional T cells in the regulation of hair growth, T-cell clones from the margin of involved alopecia areata lesions from three patients were obtained by cloning, using the limiting dilution method. Of these T-cell clones, 31 were CD4+CD8-, 15 were CD8+CD4- and 2 were CD4-CD8-. The T-cell clones were activated and the supernatant harvested 24 h later and tested for its capacity to regulate proliferation of neonatal keratinocytes. The majority of the T-cell clone supernatants inhibited epithelial cell proliferation in a dose-dependent fashion. When the cytokine profiles of conditioned T-cell medium were compared with the growth-regulatory capacity, it was found that T-cell clones that released high amounts of interferon gamma and/or tumour necrosis factor alpha inhibited keratinocyte growth. In conclusion, T cells derived from the margin of active alopecia areata lesions are able to downregulate epithelial cell proliferation. This points to an important role of the immune system, especially the T cells, in this disease.

Alopecia Areata↗
PubMed1997

Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy.

We performed proton magnetic resonance spectroscopy (1H-MRS) in patients with motor neuron disease (MND) to determine the absolute in vivo concentrations in the brain of the metabolites N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr/PCr). We examined the spectra acquired from a 20 x 20 x 20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients with both upper and lower motor neuron signs had a significantly decreased concentration of NAA (9.13 +/- 0.28 mM, mean +/- SEM) in the primary motor cortex when compared with healthy controls (10.03 +/- 0.22 mM). In conclusion, the slightly decreased concentration of NAA in the primary motor cortex from ALS patients may represent a loss of neurons in this region.

Adult↗
PubMed1996

Staphylococcal enterotoxin B applied on intact normal and intact atopic skin induces dermatitis.

BACKGROUND AND DESIGN: Colonization of inflammatory skin diseases with Staphylococcus aureus is a frequent phenomenon and may cause exacerbation of the skin disease. Staphylococcus aureus strains present on atopic dermatitis are capable of releasing staphylococcal enterotoxins, a group of superantigens that are very potent T-cell activators. To determine whether the superantigen staphylococcal enterotoxin B can induce inflammation when applied on the skin, staphylococcal enterotoxin B was applied with and without occlusion on the volar aspect of the skin on the forearm of 10 subjects without skin disease and six subjects with atopic dermatitis of minimal activity and no eczema on the volar aspect of the skin on their forearm. The main outcome measures were clinical rating; determination of the increase of the thickness of the skin-fold; and determination of skin blood flow. RESULTS: Clinically, staphylococcal enterotoxin B induced skin changes of erythema and induration in 10 of 10 healthy volunteer subjects and six of six subjects suffering from atopic dermatitis, while the vehicle induced clinically evident skin changes in only one of 10 healthy subjects and none of six subjects with atopic dermatitis. On day 3 after the application of an occluded patch containing 10 micrograms/cm2 of staphylococcal enterotoxin B in the healthy subjects, the thickness of the skinfold increased 0.47 +/- 0.49 mm (mean +/- SD) (n = 9; P < .02) relative to the increase in the thickness of the skinfold following application of the vehicle. The Doppler laser-measured skin blood flow index had increased from 1.0 +/- 0.4 to 5.3 +/- 3.7 (mean +/- SD) (n = 10; P < .002). On day 3 after the application of occluded patchs containing 10 micrograms/cm2 of staphylococcal enterotoxin B in the subjects suffering from atopic dermatitis, the increase in the thickness of the skinfold increased 0.20 +/- 0.24 mm (n = 6; P, not significant) relative to the increased thickness in the skinfold following application of the vehicle. The Doppler laser-measured skin blood flow index had increased from 1.1 +/- 0.4 to 3.7 +/- 2.2 (n = 6, P, not significant). Three of six subjects suffering from atopic dermatitis experienced a flare of their disease in the elbow flexure ipsilaterally to where the staphylococcal enterotoxin B patch was applied. CONCLUSIONS: The superantigen staphylococcal enterotoxin B applied on intact skin from both normal subjects and patients with atopic dermatitis induces an inflammatory reaction. This finding suggests that superantigens released from S aureus present on the skin in inflammatory skin diseases may exacerbate and sustain the inflammation.

Adult↗
PubMed1994

Interferon gamma-treated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules.

During inflammation in the skin keratinocytes can express major histocompatibility complex class II molecules but are unable to present nominal antigens to resting T cells. Certain bacteria including staphylococci produce a new class of antigens termed superantigens that are very potent T-cell activators. Using an in vitro model with cultured normal human keratinocytes and purified allogeneic T cells, we demonstrated that major histocompatibility complex class II+ keratinocytes can activate T cells in the presence of the superantigen staphylococcal enterotoxin B. Major histocompatibility complex class II+ keratinocytes activated T cells at concentrations of staphylococcal enterotoxin B as low as 100 pg/ml. The activation required contact between keratinocytes and T cells, was inhibited with a monoclonal antibody to human leukocyte antigen DR, -DQ, and was not affected by fixation of the keratinocytes. These data show that major histocompatibility complex class II+ keratinocytes activate T cells in the presence of the superantigen staphylococcal enterotoxin B.

Antibodies, Monoclonal↗
PubMed1993

T-lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation.

To investigate whether growth factors derived from T cells in psoriatic lesions are able to stimulate keratinocyte growth, T-cell lines were initiated from lesional psoriasis skin and cloned by limiting dilution. Eight clones with good proliferative capacity out of 40 clones from one patient were stimulated. After 24 h, the conditioned medium was harvested and the growth modulatory effect of the conditioned medium on keratinocytes was assessed. Seven of the eight T-cell clones stimulated keratinocyte growth to an extent ranging from 22% +/- 19 to 64% +/- 9 (mean +/- SD of three experiments) of maximal inducible keratinocyte growth, and one T-cell clone had no effect (-5% +/- 2) on keratinocyte growth. Keratinocyte growth was also induced by T-cell clones obtained from two other patients. Several cytokines were tested in this system to determine which T-cell growth factor may induce the keratinocyte growth. None of the cytokines interferon-g, transforming growth factor-beta, interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, or granulocyte-macrophage colony stimulating factor alone was found to possibly be responsible for the T-cell-induced keratinocyte growth. Thus the nature of the T-cell keratinocyte growth-promoting stimulus remains to be elucidated.

Cell Division↗
PubMed1991

Irreversible effects in rats of toluene (inhalation) exposure for six months.

The irreversible CNS effects of six months' exposure to toluene (0, 500, and 1500 p.p.m.) in rats was studied applying a multi-disciplinary approach. After an exposure-free period, neurobehavioural, morphometric, pathological, and biochemical examinations were performed. No neurobehavioural or gross pathological changes were found. Morphometric measurements did not show loss of neurones. At 500 p.p.m. the mean nuclear volume and mean perikaryonal volume and the variation of the values of these parameters was increased in the exposed groups compared to the controls. Noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) levels were significantly changed in various brain regions. It is concluded that this investigation failed to reveal overt toluene-induced CNS-neurotoxicity, however, certain irreversible effects were found which further add to the accumulating evidence of the chronic CNS-neurotoxicity of toluene.

Administration, Inhalation↗