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Biomedical subjects

R Huupponen

Publications and source records attributed to R Huupponen.

At least 73 records · Page 4Linked to original sources
PubMed1992

Systemic absorption of ocular cyclopentolate in children.

Cyclopentolate plasma levels were quantitated and heart rate and pupil size were monitored after ocular application of the drug to juveniles. In all, 12 children were given one 35-microliters eyedrop of either 1% cyclopentolate (n = 6) or placebo (n = 6) in randomized order in the lower cul-de-sac of one eye. A sensitive radioreceptor assay was used to determine the systemic drug absorption. With the exception of one child, detectable cyclopentolate concentrations were seen in plasma at as early as 3 min after the ocular drug application. There was a marked interindividual variation in peak plasma cyclopentolate concentrations ranging from undetectably low to 5.8 ng/ml (median, 2.9 ng/ml). In some children a second drug concentration peak was detected. Cyclopentolate increased the pupillary diameter from 4.8 +/- 1 mm before drug application to 8 +/- 0.9 mm at 30 min after administration, but the children's heart rate did not alter.

Absorption↗
PubMed1991

Effects of repeated administration of mifepristone and 8-OH-DPAT on expression of preproneuropeptide Y mRNA in the arcuate nucleus of obese Zucker rats.

Neuropeptide Y (NPY) is an important hypothalamic regulator of feeding behavior. In this study we have investigated the regulation of the expression of preproNPY mRNA in male obese and lean Zucker rats by in situ hybridization. These animals represent a model of genetic obesity with hyperphagia, hyperinsulinemia and altered endocrine functions. Obese Zucker rats, treated for 12 days with 0.9% saline, had about 210% higher level of basal preproNPY mRNA expression in the arcuate nucleus when compared to their lean littermate controls. Repeated administrations of 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a serotonergic 5-HT1A agonist, or mifepristone, a glucocorticoid receptor antagonist, did not modify the basal expression of preproNPY mRNA in the Zucker phenotypes. The 8-OH-DPAT treatment significantly reduced hyperinsulinemia in obese Zucker rats without changing plasma glucose levels. The mifepristone treatment significantly increased plasma corticosterone levels in lean animals, but not in obese animals. The present study demonstrates enhanced expression of preproNPY mRNA in the arcuate nucleus in obese Zucker rats suggesting an involvement of NPY in the pathophysiology of the hyperphagic syndrome and genetically determined obesity in Zucker rats. Neither the antagonism of glucocorticoid receptors by mifepristone, nor repeated treatment with 8-OH-DPAT resulting in reduced insulin levels in obese Zucker rats, modified the basal expression of preproNPY mRNA in the arcuate nucleus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Beta-blocking effects of timolol at low plasma concentrations.

The concentration-effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double-blind, crossover study design. Blockade of cardiac beta-adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR-1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 +/- 0.11 (+/- SD; n = 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac beta-blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The beta-blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.

Adult↗
PubMed1991

Systemic absorption of ocular timolol in poor and extensive metabolizers of debrisoquine.

The oxidation of timolol exhibits genetic polymorphism of debrisoquine type. After oral administration, poor metabolizers have high timolol concentrations in plasma and show an intensified systemic beta-blockade. Since the contribution of debrisoquine metabolizer status on timolol eyedrop therapy is not known we determined the systemic absorption of ocularly applied timolol in healthy subjects classified either extensive or poor metabolizers. Unlike after oral timolol ocular drug administration caused higher peak drug concentrations in plasma in extensive metabolizers. The variation in the systemic absorption of ocular timolol contributed more than the debrisoquine oxidation phenotype to timolol plasma levels after a single ocular timolol application.

Absorption↗
PubMed1991

Activity of xenobiotic metabolizing liver enzymes in Zucker rats.

The activity of four liver enzymes participating in the xenobiotic metabolism was determined in male and female obese hyperinsulinemic Zucker rats. When compared to lean normoinsulinemic control animals the obese male rats had lower hepatic aryl hydrocarbon hydroxylase and the female animals lower 7-ethoxycoumarine O-deethylase and N-nitrosodimethylamine N-demethylase activities. The results contrast those reported in the literature for hypoinsulinemic streptozotocin diabetic rats.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics of chlorpropamide.

The pharmacokinetics and urinary metabolite pattern of a single oral dose of chlorpropamide 250 mg have been studied in 6 extensive and 5 poor metabolizers of debrisoquine. Ammonium chloride was given orally to acidify the urine in order to make elimination of the parent drug dependent on metabolism alone. The concentration profile in serum and the pharmacokinetic parameters of the parent drug were similar in both groups. However, the ratio in urine of unchanged chlorpropamide to its hydroxylated metabolites was higher in poor than in extensive metabolizers.

Adult↗
PubMed1990

Insulin and sulphonylurea in the therapy of type 2 diabetes.

The role of insulin in the therapy of NIDDM is still under discussion. To clarify the problem we performed a randomized double-blind placebo controlled crossover study of insulin treatment for 4 weeks in diabetic patients (n = 18, age 52-74 years) who were unsatisfactorily controlled by oral antidiabetic agents. The patients continued to use these agents during the study. Special attention was given to informing the patients about the trial and, in particular, about self-monitoring the blood glucose by the use of a reflectance meter. Insulin treatment produced the following significant changes: decreases in blood glucose (at 7.00, 10.00, 16.00), mean daily blood glucose, HbA1, urinary glucose and low density lipoprotein (LDL) cholesterol and increased postglucose immunoreactive insulin (IRI) levels. Significant changes were also observed during the placebo periods: decreases in HbA1 urinary glucose and LDL cholesterol (but not in blood glucose). Therapy with insulin increased the body weight, whereas the placebo insulin had the opposite effect. The finding emphasizes the importance of using not only a run-in period but also a placebo design when the metabolic effects of antidiabetes therapy are to be evaluated. The study indicates that insulin therapy for patients with type 2 diabetes can be initiated at home.

Aged↗
PubMed1990

Reduced glucose-6-phosphorylase and NADPH generating enzyme activities associated with glibenclamide induced hypoglycemia and hypoinsulinemia in genetically obese mice.

Addition of phenobarbital, an inducer of the liver mixed function oxidase system, to sulphonylurea regimen improves insulin sensitivity and intracellular glucose handling in patients with non-insulin dependent diabetes mellitus. The inducer also activates liver NADPH synthesis and its availability for mono-oxygenase reactions. In this study we further evaluated the mutual relationship between glucose and drug metabolism and the effect of sulphonylurea therapy by using genetically obese female mice. The mice were treated with glibenclamide, phenobarbital or both. Glibenclamide reduced blood glucose and plasma insulin levels indicating improved insulin sensitivity in the mice. Total glucose phosphorylating, delivering and NADPH generating enzyme activities were reduced together with decreased microsomal protein content and the amount of smooth endoplasmic reticulum in the liver. Phenobarbital had an opposite effect: the drug induced liver drug metabolism and increased hepatic glucose phosphorylating and NADPH generating enzyme activities. Treatment with glibenclamide seems to reduce serum immunoreactive insulin levels, microsomal enzyme function and NADPH generating enzyme activities in genetically obese mice.

Animals↗
PubMed1990

Hypothalamic 5-hydroxytryptamine metabolism is not influenced by streptozotocin-diabetes induced at neonatal age.

Rats were rendered diabetic at neonatal age by an intraperitoneal injection of streptozotocin (90 mg/kg). At 8-10 weeks of age, their 5-HT and 5-HIAA levels in different hypothalamic nuclei (ventromedial, paraventricular, periventricular, supraoptical and suprachiasmatic nuclei) were similar to control animals which received vehicle only. It is concluded that the combination of mild hyperglycemia and hypoinsulinemia does not affect hypothalamic 5-HT metabolism in rats.

Animals↗
PubMed1990

Systemic absorption of ocular scopolamine in patients.

The systemic absorption of scopolamine 0.25% eyedrops given unilaterally was quantitated in eight patients following therapeutic drug application. Another set of eight patients received placebo drops to study the effect of scopolamine on heart rate, blood pressure and salivation. Scopolamine was rapidly and efficiently absorbed after its ocular administration. The peak plasma scopolamine concentration of 550 +/- 60 pg/ml was reached within 15 minutes in all but two patients. Ocular scopolamine did not affect patients blood pressure or heart rate when compared to patients in the placebo group. Thirty minutes after administration of scopolamine the salivary secretion was slightly but insignificantly reduced.

Absorption↗
PubMed1990

The effects of beta-adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine.

The in vivo inhibitory effect of five beta-adrenoceptor antagonists and levomepromazine on debrisoquine metabolism was assessed in 37 subjects. The debrisoquine phenotyping test was performed before and after 7 days' treatment with oxprenolol (40 mg three times daily), propranolol (20 mg three times daily), timolol (10 mg twice daily), pindolol (5 mg twice daily), metoprolol (50 mg twice daily) or levomepromazine (10 mg daily), each of which was given to six-seven subjects. No clear change in the urinary metabolic ratio of debrisoquine/4-OH-debrisoquine (MR) was seen with any of the single beta-adrenoceptor antagonist treatments, but the MR value increased significantly when all beta-adrenoceptor blocker treatments were considered together. Debrisoquine metabolism was clearly impaired after levomepromazine 10 mg daily for 7 days; the mean MR increased from 1.24 +/- 1.6 to 4.70 +/- 5.23 (P = 0.018) and the excretion of 4-hydroxydebrisoquine decreased from 0.92 +/- 0.46 mg to 0.31 +/- 0.19 mg (P = 0.043). Thus, levomepromazine changes MRs towards those characteristic of phenotypically poor metabolizers, but beta-adrenoceptor antagonists at the doses examined have only a marginal effect.

Adrenergic beta-Antagonists↗
PubMed1990

Hypothalamic neurochemistry and feeding behavioral responses to clonidine, an alpha-2-agonist, and to trifluoromethylphenylpiperazine, a putative 5-hydroxytryptamine-1B agonist, in genetically obese Zucker rats.

Genetically obese Zucker rats are hyperphagic, hyperinsulinemic and hyperlipemic. In order to investigate pathophysiological mechanisms underlying hyperphagia in these animals, monoamine metabolism and turnover were studied in discrete hypothalamic nuclei known to participate in the control of feeding behavior. Neurochemical studies in genetically obese Zucker rats and in their lean littermate controls were complemented by investigating feeding behavioral responses to the acute administration of clonidine (15 and 30 micrograms/kg i.p.), an alpha 2-adrenoceptor agonist, and to trifluoromethylphenylpiperazine (TFMPP; 1, 2 and 5 mg/kg s.c.), a putative serotonergic 5-hydroxytryptamine-1B receptor agonist. Obese Zucker rats had significantly lower concentrations of 5-hydroxyindoleacetic acid, the main deaminated metabolite of 5-hydroxytryptamine, in the nucleus paraventricularis (PVN) and in the nucleus ventromedialis (VMN), when compared to their lean littermate controls. The rate of accumulation of 5-hydroxytryptophan after decarboxylase inhibition was reduced in the PVN, nucleus supraopticus, nucleus periventricularis and nucleus suprachiasmaticus of the obese rats. No differences were observed in basal concentrations of norepinephrine, dopamine or 3,4-dihydroxyphenylacetic acid between obese and lean Zucker rats in the brain areas studied. However, the rate of accumulation of 3,4-dihydroxyphenylalanine was lower in the VMN and in the median eminence of the obese rats. The feeding behavioral tests showed significantly augmented hyperphagic responses to clonidine in obese Zucker rats. The anorexic effect of TFMPP was similar in both phenotypes. It is concluded that serotonergic activity is reduced in obese Zucker rats, particularly in the PVN, which plays a key role in the control of feeding behavior. The reduced serotonergic activity may be associated with enhanced alpha 2-adrenoceptor-mediated feeding responses in obese Zucker rats.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1990

Debrisoquine hydroxylation polymorphism in diabetic patients.

Debrisoquine hydroxylation was assessed in 54 type I and in 42 type II diabetic patients. The distribution of metabolic ratio debrisoquine/4-hydroxydebrisoquine (MR) in urine of the patients was compared with a MR-distribution of 176 healthy subjects, and the correlation of glucose balance parameters with the MR was investigated. One poor metabolizer of debrisoquine was found among type I diabetics but no poor metabolizers were found among type II diabetics. Despite the low frequency of the poor metabolizers, the prevalences of debrisoquine hydroxylation phenotypes did not differ from that in healthy volunteers in either diabetic group. No correlation was found between MR and fasting blood glucose or blood glycosylated hemoglobin A1c, whereas a negative correlation was evident between age and the excretion of 4-hydroxydebrisoquine in urine. In summary, debrisoquine hydroxylation is essentially unaltered in type I and type II diabetes mellitus, and no relationship exists between debrisoquine hydroxylation and glucose balance.

Adult↗
PubMed1989

Prevalence of debrisoquine oxidation phenotypes in glaucoma patients.

The oxidation of debrisoquine, a sympatholytic antihypertensive agent, exhibits genetic polymorphism. The debrisoquine/4-OH-debrisoquine metabolic ratio (MR) separates the population to poor (PM, MR greater than 12.6) and extensive (EM, MR less than 12.6) metabolizers. 5-10% of the caucasians belong to the PM phenotype. The oxidation of many other drugs, like timolol, correlates with the debrisoquine phenotype. We determined the debrisoquine phenotype in 102 glaucoma patients. The majority of the patients was treated with ophthalmic timolol. Five patients were classified as PMs. However, two of them were on quinidine, a well known inhibitor of debrisoquine oxidation. The prevalence of debrisoquine PM phenotype in glaucoma patients was 2.9% (excluding patients on quinidine) or 4.9% (with patients on quinidine). The figures are slightly lower than the mean value reported for the normal Finnish population. However, both figures lay within the 95% confidence limits of the prevalence of PM phenotype in the normal Finnish population. The beta-blocking activity of oral timolol is increased in PMs. The significance of timolol oxidation phenotype during ocular timolol therapy warrants further investigation.

Cross-Sectional Studies↗
PubMed1989

Prostaglandin F2 alpha binding to bovine ocular and synthetic melanins in vitro.

The binding of 3H-prostaglandin F2 alpha to bovine iris and synthetic melanin was studied in vitro using a ligand binding assay. Prostaglandin F2 alpha was reversibly bound to both types of melanin. The binding was saturable and the Scatchard analysis revealed the existence of at least two binding sites with the corresponding K(D) values of 3.71 nM and 1.99 microM for natural and 4.99 nM and 0.19 microM for synthetic melanin, respectively. The high affinity Bmax values were 3.4 nM/g for natural and 2.5 nM/g for synthetic melanin. The dissociation of prostaglandin F2 alpha from melanin after dilution of the complex was rapid and uniform.

Animals↗
PubMed1989

Beta-adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria.

S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the beta-adrenoceptor antagonist activities and binding of R- and S-enantiomers of timolol have been examined on rat atrial preparations. The beta-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to beta 1- and beta 2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a beta 1- and ICI 118,551 as a beta 2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between beta 1- and beta 2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective beta-adrenoceptor blocking agent, but may possibly exert a more localized beta-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.

Adrenergic beta-Antagonists↗
PubMed1989

Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus.

We evaluated the effects of phenobarbital, an inducer, on plasma glucose and serum immunoreactive insulin levels and on hepatic glucose and drug metabolism using an animal model of non-insulin dependent diabetes mellitus. Genetically obese (ob/ob) mice, characterized by hyperglycaemia, hyperinsulinaemia, fatty liver and obesity were selected. The impairment of diabetic state with age was associated with increased activities of NADPH producing enzymes, whereas mixed function oxidase system remained unaltered. Phenobarbital reduced serum immunoreactive insulin and plasma glucose levels and decreased gluconeogenesis. Hepatic glucose phosphorylating enzyme activity increased and glucose releasing enzyme activity decreased. The demand for NADPH in drug oxidation reactions, caused by the induction phenomenon, was reflected in the elevated activities of the NADPH producing enzymes in pentose phosphate pathway and in the activities of isocitrate dehydrogenase and malic enzyme from mitochondrial oxidation reactions. Glucose metabolism of lean littermates indicated that phenobarbital induction normalizes impaired intracellular glucose handling but leaves normal glucose metabolism unaltered. Hepatic glucose production rate was related to plasma glucose, NADPH producing enzyme activities and cytochrome P450 content in the obese and lean mice.

Animals↗