Biomedical subjects

R Huupponen

Publications and source records attributed to R Huupponen.

At least 37 records · Page 2Linked to original sources

PubMed1999

Pharmacokinetics and safety of deramciclane during multiple oral dosing.

UNLABELLED: Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers. SUBJECTS, MATERIAL AND METHODS: A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events. RESULTS: The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram. CONCLUSIONS: In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.

Administration, Oral↗

PubMed1998

Differential regulation of uncoupling proteins by chronic treatments with beta 3-adrenergic agonist BRL 35135 and metformin in obese fa/fa Zucker rats.

The expressions of uncoupling proteins 2 and 3 (UCP2; UCP3) mRNA were studied in obese (fa/fa) Zucker rats treated with two weight gain reducing agents for three weeks. The specific beta 3-adrenoceptor agonist BRL 35135 (0.5 mg/kg/day orally) increased the expression of UCP3 mRNA by 3.8-fold (P < 0.0001; two-way ANOVA) and that of UCP1 mRNA by 2.6-fold (P = 0.014) in brown adipose tissue, but had no effect on expression of UCP3 mRNA in white fat or in the soleus muscle, or on UCP2 mRNA expression in brown or white fat. The antihyperglycemic metformin (300 mg/kg/day orally) had no effect on expressions of UCP1, UCP2 or UCP3 in any tissue studied. Concentrations of plasma insulin were significantly correlated with the levels of white fat UCP2 mRNA (in the control group: r = 0.89, P = 0.0015) and UCP3 mRNA (in the control group: r = 0.80, P = 0.009) suggesting that insulin may play a role in the control of UCP2 and UCP3 mRNA expressions in white adipose tissue.

Adipose Tissue↗

PubMed1998

Effects of ZD7114, a selective beta3-adrenoceptor agonist, on neuroendocrine mechanisms controlling energy balance.

Selective beta3-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The aim of this study was to investigate how changes in energy balance affect energy intake and interaction of peripheral metabolic feedback signals with central neuroendocrine mechanisms participating in the control of body energy balance. Expression of preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus and preprocorticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus were measured by in situ hybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl)phenoxyacetamide, 3 mg kg(-1) day(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expression of leptin mRNA in epididymal fat and serum levels of leptin were analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. Treatment with ZD7114 significantly reduced weight gain and activated brown adipose tissue thermogenesis, but had no effect on food intake. Expressions of preproNPY or preproCRF mRNAs were similarly not changed by treatment with ZD7114. Furthermore, ZD7114 had no effect on plasma insulin or leptin and the expression of leptin mRNA in epididymal fat. However, statistically significant correlations were found between preproNPY and preproCRF mRNA expressions and brown fat thermogenic activity and plasma insulin levels in the ZD7114 treated rats, but not in the control rats. It is concluded that treatment with ZD7114 markedly activated brown fat thermogenesis, but did not affect neuropeptide Y (NPY) and CRF gene expression per se. However, the correlation analyses suggest that ZD7114 may modulate feedback connections of brown adipose tissue thermogenesis and plasma insulin with the hypothalamic neuroendocrine mechanisms integrating body energy balance.

Adipose Tissue, Brown↗

PubMed1998

Aqueous humour concentration and the intraocular pressure-lowering effect of topical betaxolol before cataract surgery.

OBJECTIVE: The aim was to study the relationship between aqueous humour betaxolol concentration and intraocular pressure (IOP). METHODS: In this double-blind, randomized study, we administered betaxolol (a) or placebo (b) ocularly to 131 patients scheduled for cataract surgery. The patients were randomly divided into ten groups. In groups 1a and 1b, the drug was scheduled to be instilled 1-2 h, in groups 2a and 2b 12 h, in groups 3a and 3b 24 h, and in groups 4a and 4b 48 h before surgery. The pupil was dilated in all eyes prior to surgery. The IOP was measured with Perkins' applanation tonometer before the instillation of the drug and just before the peribulbar block. Twenty microlitres of 0.5% betaxolol or placebo solution was instilled into the eye. IOP was also measured before instillation of the drug and after 1 2 h in undilated eyes of 20 patients, whose contralateral eye was to be operated on, to rule out the effect of pupil dilation on IOP (groups 5a and 5b). Aqueous humour betaxolol concentrations were analysed using a radioreceptor assay. RESULTS: Betaxolol did not decrease IOP significantly in eyes with pupillary dilation. Both betaxolol and placebo decreased IOP significantly in patients without pupillary dilation, the effect of betaxolol being slightly more pronounced. The betaxolol concentration in aqueous humour was 731 ng m-1 in group la, 2.4 h after drug instillation. Measurable concentrations of betaxolol were also detected in aqueous humour in group 4a 47.7 h after drug administration. CONCLUSION: No correlation between aqueous humour concentration of betaxolol and the effect on IOP was found in eyes where the pupil was dilated before surgery. A single betaxolol dose did not decrease IOP significantly in patients undergoing cataract surgery, but the IOP decreasing effect was, however, clearly seen in patients who did not receive mydriatic drugs. The routine use of topical betaxolol prior to cataract surgery to decrease IOP is not recommended.

Adrenergic beta-Antagonists↗

PubMed1998

Hormonal effects of MPV-2213ad, a new selective aromatase inhibitor, in healthy male subjects. A phase I study.

AIMS: A novel non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, was entered into an open dose-escalation study. The objective of this study was to investigate the tolerability and efficiency of this new compound with assessment of the hormonal effects after study drug administration. METHODS: MPV-2213ad was given to 39 healthy male volunteers. Single increasing oral doses of 0.003, 0.03, 0.3, 3, 9, 30 and 100 mg were given to three subjects at each dose level, after which ten subjects received the 300 mg dose and eight subjects the highest 600 mg dose of MPV-2213ad. RESULTS: Serum oestradiol levels were suppressed by 58-65% when MPV-2213ad was given at doses between 0.3 and 30 mg. A reduction in serum oestradiol levels by 83% from baseline was achieved with the 300 mg dose. No additional decrease was seen with the highest dose. The suppression lasted longer with higher doses of MPV-2213ad. After the 300 and 600 mg doses serum oestradiol returned to baseline within 4 days. Marked increases in serum concentrations of testosterone, androstenedione, 17-OH-progesterone, LH and FSH were also observed at doses between 100 and 600 mg of MPV-2213ad. The drug was well-tolerated and the adverse events were mild or moderate including hot flushes, mild vertigo, nausea, acne and gastrointestinal discomfort. CONCLUSIONS: MPV-2213ad has a potent, dose-dependent inhibitory effect on serum oestradiol. It was selective for the aromatase enzyme with no signs of adreno-cortical suppression or haematological or biochemical toxicity.

Adult↗

PubMed1998

Insulin sensitivity in a long-term crossover trial with celiprolol and other antihypertensive agents.

The effects of a vasodilating beta-blocker, celiprolol, on insulin sensitivity and cardiovascular risk factors were compared with those of another beta1-selective adrenoceptor blocker, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. A randomized 21-month crossover trial was carried out with 25 patients with dyslipidemia receiving antihypertensive monotherapy. The study consisted of a 3-month active run-in period and two treatment periods, during which the patients received celiprolol (200-400 mg daily) or the control drug for 12 and 6 months in a crossover manner. A hyperinsulinemic euglycemic clamp and an oral glucose tolerance test (OGTT) were performed every 6 months. According to the clamp tests, the insulin-sensitivity index increased on average by 32% (p < 0.0001) during celiprolol treatment compared with that with the other antihypertensive agents, including ACE inhibitors. In OGTT, area under the incremental glucose curve decreased by 36% (p = 0.002) during celiprolol treatment, whereas insulin secretion diminished on average by 26% (p = 0.006). The mean decrease in fasting serum triglycerides was 11% (NS), whereas the high-density lipoprotein to low-density lipoprotein (HDL/LDL) ratio increased by 15% (p = 0.012). The results suggest that celiprolol improves insulin sensitivity of hypertensive patients with dyslipidemia in long-term therapy.

Adult↗

PubMed1998

Inverse correlation between serum testosterone and leptin in men.

Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P < 0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.

Adult↗

PubMed1998

Biological day-to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17beta in healthy men.

Information on biological day-to-day variation is needed for detecting within-subject changes over time. In this study the daytime changes and the biological day-to-day variation of serum testosterone, follitropin, lutropin and oestradiol-17beta concentrations were investigated in 31 healthy males. To analyse daytime changes, blood specimens were taken at 0800 h, 1200 h, 1600 h and 2000 h during one day (n=31) and two days (n=8). The day-to-day variation was analysed from blood specimens collected at 0800 h on days 1 and 2 (n=31) and additionally on days 3, 4, 6 and 9 (n=8). The evaluation of the day-to-day variation was based on calculations of the within-subject (CVA+I) and between-subject (CV(G)) coefficients of variation. When the within-subject day-to-day variances were not too heterogeneous, they were used for the calculation of 95 % reference change limits. Serum testosterone and oestradiol-17beta concentrations showed a significant daytime variation; testosterone had higher serum concentrations at 0800 and 1200 h. A peak in the serum concentration of oestradiol-17beta occurred at 1200 h with a decrease towards the evening. There were no clear daytime changes in the serum concentrations of follitropin or lutropin. For different analytes the reference change limits were: serum testosterone +/- 32.0 %, serum follitropin +/- 24.1 % and serum oestradiol-17beta +/- 38.3 %. The reference change limit was not calculated for serum lutropin, as a high degree of heterogeneity and individuality was found. The interpretation of the results of hormone measurements requires recognition of the biological daytime and day-to-day changes of hormones. The reference change limits determine what changes are significant when monitoring the patient.

Adult↗

PubMed1998

Correlation between circulating leptin and luteinizing hormone during the menstrual cycle in normal-weight women.

OBJECTIVE: Leptin is the hormonal product of the ob gene. It is expressed in adipocytes and participates in the regulation of food intake and metabolism. Since leptin also seems to signal metabolic information to the reproductive system, we studied the association between reproductive hormones and plasma leptin in normal-weight young women. DESIGN: Eight young women with normal menstrual cycles (body mass index (BMI) 21.2 +/- 1.6 kg/m2) and eight young women using hormonal contraception (BMI 21.4 +/- 1.1 kg/m2) were studied. Furthermore, six women with normal menstrual cycles and no hormonal therapy (BMI 20.7 +/- 1.2 kg/m2) were studied around the time of the anticipated ovulation. METHODS: Serum leptin, estradiol, progesterone and luteinizing hormone (LH) concentrations were measured with radioimmunoassays. RESULTS: Serum leptin concentrations were similar at the beginning of the cycle, at the time of the anticipated ovulation and at the end of the menstrual cycle (10.2 +/- 7.1, 10.7 +/- 7.0 and 11.8 +/- 6.9 microg/l respectively). There was an association between leptin and LH concentrations (r= 0.37, P< 0.01) when values recorded during different time points during the cycle were plotted with each other. There was no change in serum leptin in samples taken at different times of the cyclic treatment with an oral contraceptive. There was no significant difference in mean serum leptin concentrations between women using oral contraceptives and women with no hormonal therapy. CONCLUSIONS: There is a link between serum leptin and LH concentrations during the menstrual cycle. Variations in circulating estrogen and/or progesterone concentrations have no major influence on circulating leptin in young female subjects.

Adipose Tissue↗

PubMed1997

Chronic treatment with BRL 35135 potentiates the action of insulin on lipid metabolism.

The effects of a beta 3-adrenoceptor agonist on insulin-induced changes in lipid metabolism were studied in obese male Zucker (fa/fa) rats during euglycaemic clamp. Rats were treated with BRL 35135 (R*, R*-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)-ethyl-amino]-propyl] phenoxyacetate hydrobromide) (0.5 mg/kg per day in drinking water) for three weeks before an euglycaemic hyperinsulinaemic clamp was performed. Insulin infusion lowered serum non-esterified fatty acids and plasma glycerol more efficiently in BRL 35135-treated than in control rats although plasma insulin remained significantly lower in the BRL 35135-treated than in the control rats during the clamp. In conclusion, chronic treatment with BRL 35135 potentiates the effect of insulin on lipid metabolism.

Adrenergic beta-Agonists↗

PubMed1997

Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity.

MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.

Adipose Tissue, Brown↗

PubMed1997

Lack of adverse interactions between concomitantly administered selegiline and citalopram.

We have evaluated the risk for pharmacokinetic and/or pharmacodynamic interactions of concomitantly administered selegiline, a selective monoamine oxidase type B inhibitor, and citalopram, a widely used selective serotonin uptake inhibitor antidepressant. Two parallel groups of healthy volunteers received 20 mg of citalopram (n = 12) or placebo (n = 6) once daily for 10 days in a randomized, double-blind fashion, followed by concomitant selegiline 10 mg once daily for 4 days. The safety of this drug combination was assessed by measurements of blood pressure, heart rate, body temperature, and inquiries for adverse events. Blood samples were taken for the analysis of serum concentrations of both study drugs and their metabolites and plasma prolactin, adrenaline, noradrenaline, and 3,4-dihydroxyphenylglycol (DHPG); urinary excretion of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were assessed. After a 5-week washout, the 12 subjects who took citalopram in the first part of the study received 10 mg of selegiline once daily for 4 days to compare the pharmacokinetics of selegiline with and without concomitant citalopram. The safety analysis showed no significant differences in vital signs or the frequency of adverse events between the study groups. Plasma prolactin concentrations were increased by 40% after 10 days' treatment with citalopram (p = 0.03); this was not potentiated by concomitantly administered selegiline. The comparison of plasma concentrations of noradrenaline, adrenaline, and DHPG and the amount of serotonin and 5-HIAA excreted into urine between the study groups indicated no signs of subclinical pharmacodynamic interaction between selegiline and citalopram. The relative bioavailability of selegiline was slightly reduced (by 29%; p = 0.008) when citalopram was coadministered compared with selegiline alone. However, no indication of a pharmacokinetic interaction was found in the analysis of serum concentrations of the three main metabolites of selegiline. The pharmacokinetics of citalopram remained unaffected by concomitant selegiline. The present results indicate lack of clinically relevant pharmacodynamic or pharmacokinetic interactions between selegiline and citalopram.

Adult↗

PubMed1997

Comparison of cyclophilin binding assay and radioimmunoassay in monitoring of blood cyclosporine.

Cyclosporine binds with cyclophilin, an abundant protein found in almost all tissues, and the resulting complex interacts with calcineurin diminishing T-cell activation. Cyclophilin can be regarded as a cellular "receptor" for cyclosporine. Measuring cyclosporine binding to cyclophilin may offer a link between pharmacokinetics and pharmacodynamics that could improve monitoring of cyclosporine therapy. The authors investigated the feasibility of the cyclophilin binding assay and compared the results with a standard specific monoclonal radioimmunoassay in 100 blood samples taken for therapeutic drug monitoring. The results obtained with these methods were related closely with each other (r = 0.96; p < 0.001) but the mean (+/-SEM) concentrations were approximately two-fold higher in cyclophilin binding assay than in radioimmunoassay (520.4 +/- 49.9 ng/ml versus 257.7 +/- 28.6 ng/ml, respectively, p < 0.001). The shapes of the cyclosporine concentration versus time curves in two patients after a liver and heart transplantation, respectively, were similar after both methods but cyclophilin binding assay gave higher values than radioimmunoassay. Before firm conclusions on the clinical value of cyclophilin binding assay can be made, comparative studies in patients linking cyclosporine concentrations measured with cyclophilin binding assay and standard methods to the therapeutic outcome are needed.

Amino Acid Isomerases↗

PubMed1997

Serum leptin concentrations in women with polycystic ovary syndrome.

The role of gonadotropins, androgens, and insulin in the regulation of circulating leptin levels is obscure. In order to clarify the relationships of these parameters we studied serum leptin levels in 19 healthy control subjects and in 35 hyperandrogenic and hyperinsulinemic patients with polycystic ovary syndrome (PCOS). Serum leptin concentrations did not differ significantly between PCOS patients and control subjects. When PCOS and control groups were analyzed together by univariate analysis, serum leptin was positively correlated with body mass index (BMI), body weight, serum insulin, serum triglyceride, and serum free testosterone concentrations. Serum leptin was inversely correlated with serum sex hormone binding globulin (SHBG) concentrations. There were no significant correlations between serum leptin and testosterone, androstenedione, or gonadotropin concentrations. Serum insulin, triglyceride, and free testosterone concentrations were positively correlated, and serum SHBG was negatively correlated with BMI. However, when BMI on one hand and serum insulin, triglyceride, free testosterone, or SHBG on other hand were used as independent variables in the partial correlation analysis with leptin, BMI turned out to be the variable primarily responsible for all of the correlations with leptin. In conclusion, the concept that circulating leptin levels would be different in PCOS patients than in regularly menstruating control subjects is not supported by our data.

Adult↗

PubMed1996

Muscarinic receptors and insulin concentration in the rat pancreas after chronic alcohol intake and cholinergic stimulation.

The effects of chronic alcohol intake and carbachol stimulation on pancreatic muscarinic receptor binding and insulin concentrations were studied in the rat pancreas. There was a strong correlation between the number of muscarinic receptors and the concentration of insulin in the pancreas. The concentration of insulin decreased in the pancreas after long-term ethanol exposure and increased after carbachol stimulation. These results indicate that the secretion of insulin is mediated via the muscarinic receptor pathway, and that the changes in the number of muscarinic receptors may have a role in insulin deficiency after long-term alcohol consumption.

Animals↗

PubMed1995

Anorectic effect of metformin in obese Zucker rats: lack of evidence for the involvement of neuropeptide Y.

The hypothalamic neuropeptide Y content and preproneuropeptide Y mRNA expression were studied in metformin-treated (300 mg/kg orally for 12 days), in pair-fed and in ad libitum-fed obese Zucker rats in order to elucidate possible mechanisms involved in the anorectic and body weight reducing effect of chronic metformin treatment in genetically obese Zucker rats. In addition the acute influence of metformin on food intake was studied by comparing its effects after oral and parenteral administration. The concentration of neuropeptide Y in the hypothalamic paraventricular nucleus was significantly higher in the metformin-treated and pair-fed rats when compared to the control animals. The expression of preproneuropeptide Y mRNA in the arcuate nucleus was similar in all three treatment groups. Both chronic metformin treatment and pair-feeding markedly lowered hyperinsulinaemia in these animals. A single subcutaneous dose of metformin (300 mg/kg) reduced food intake only in obese animals, while the same dose of metformin given orally did not affect food intake in either lean or obese animals. It is concluded that the treatment with metformin and pair-feeding, which results in comparable reductions in food intake, body weight gain and hyperinsulinaemia, similarly increase neuropeptide Y concentrations in the paraventricular nucleus while not affecting preproneuropeptide Y mRNA expression in the arcuate nucleus. The increase in hypothalamic neuropeptide Y content may be secondary to the reduction in hyperinsulinaemia during metformin treatment and pair-feeding. Thus, the anorectic effect of chronic metformin treatment cannot be explained by changes in content or expression of hypothalamic neuropeptide Y.

Administration, Oral↗

PubMed1995

Buccal delivery of an alpha 2-adrenergic receptor antagonist, atipamezole, in humans.

OBJECTIVE: To evaluate the pharmacokinetics, systemic effects and clinical applicability of buccally administered atipamezole in healthy volunteers. METHODS: The study was carried out in two parts. In the first part, spray preparations of atipamezole hydrochloride in water/alcohol (50/50) solution were applied on buccal mucosa of six volunteers. Single doses of 5, 10, 20, and 40 mg atipamezole hydrochloride were administered in ascending order during separate sessions. In the second part, nine subjects received single 20 mg doses as buccal spray, intravenous infusion, or oral solution in randomized order. RESULTS: Values for area under the concentration-time curve for atipamezole (mean +/- SD) ranged from 26 +/- 4 ng x hr/ml after 5 mg to 112 +/- 21 ng x hr/ml after 40 mg and peak concentrations ranged from 11 +/- 3 ng/ml after 5 mg to 38 +/- 9 ng/ml after 40 mg. Individual peak concentrations were mainly measured at 30 and 60 minutes after administration. Mean elimination half-lives were approximately 1 1/2 hours after every treatment. In part two, a mean bioavailability of 33% was calculated for buccal administration (compared with intravenous), whereas systemic availability after an oral dose was < 2%. After intravenous administration the mean total clearance, apparent volume of distribution, and elimination half-life were 1.2 L/hr/kg, 2.9 L/kg, and 1.8 hours, respectively. The intravenous administration of 20 mg atipamezole hydrochloride produced a fivefold elevation in mean plasma norepinephrine concentration, a slight and short-lasting elevation in blood pressure and, in most subjects, increased tension, alertness and restlessness, and sweating. After buccal administration, some subjects reported short-lasting restlessness or tension after the 20 and 40 mg doses. No significant changes in heart rate, blood pressure, or plasma catecholamines were observed. No effects were observed after swallowing of 20 mg atipamezole hydrochloride. The spray caused local reactions at buccal mucosa. Superficial white spots or areas were observed for several hours; these disappeared gradually. Subjects also reported transient numbness at the application site. CONCLUSION: Atipamezole hydrochloride is well absorbed systemically through oral mucosa. The oral bio-availability of atipamezole is negligible, probably because of extensive first-pass metabolism.

Administration, Buccal↗

PubMed1995

Effects of metformin treatment on glucose transporter proteins in subcellular fractions of skeletal muscle in (fa/fa) Zucker rats.

1. The present study was designed to clarify the cellular mechanism through which the antihyperglycaemic drug, metformin, exerts its effects. For this purpose the contents of glucose transporter protein isoforms GLUT1 and GLUT4 were measured in plasma membrane and intracellular membrane fractions of skeletal muscle obtained from genetically obese, insulin-resistant Zucker rats. 2. Hindlimb muscles were dissected from metformin-treated (300 mg kg-1 day-1, p.o., for 12 days) and control rats in basal treatment state, and after acute stimulation with insulin (22 u kg-1, i.p.). Since metformin treatment reduces food intake, we also used a pair-fed control group to investigate the effects of altered insulinaemia per se. Glucose transporter levels were analysed by Western blot and slot blot-techniques. In addition, 2-deoxy-[14C]-glucose uptake in isolated muscle strips was evaluated. 3. No changes were noted in the contents of GLUT1 proteins in any of the subcellular fractions after metformin treatment. The contents of GLUT4 in subcellular fractions were not altered in the basal treatment state. After acute insulin exposure the content of GLUT4 in the intracellular membrane fraction declined significantly in the metformin-treated group, while no significant effect was seen in the plasma membrane fraction. In agreement with these results, metformin treatment did not alter 2-deoxyglucose uptake into isolated muscle strips. 4. In conclusion, the present study does not support the concept that metformin would enhance translocation of glucose transporter proteins from the intracellular compartment to the plasma membrane in skeletal muscle in vivo.

Animals↗