PubMed Health⌕ Search

Biomedical subjects

P Männistö

Publications and source records attributed to P Männistö.

At least 19 recordsLinked to original sources
PubMed2001

Quantitation of entacapone glucuronide in rat plasma by on-line coupled restricted access media column and liquid chromatography-tandem mass spectrometry.

A column-switching liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS-MS) method was developed for the direct analysis of entacapone glucuronide in plasma. The plasma samples (5 microl) were injected onto a C18-alkyl-diol silica (ADS) column and the matrix compounds were washed to waste with a mixture of 20 mM ammonium acetate solution at pH 4.0-acetonitrile (97:3). The retained analyte fraction containing (E)- and (Z)-isomers of glucuronides of entacapone and tolcapone glucuronide (internal standard) was backflushed to the analytical C18 column, with a mixture of 20 mM ammonium acetate-acetonitrile (85:15) for the final separation at pH 7.0. The eluate was directed to the mass spectrometer after splitting (1:100). The mass spectrometer was operated in the negative ion mode and the deprotonated molecules [M-H]- were chosen as precursor ions for the analytes and internal standard. Collisionally induced dissociation of [M-H] in MS-MS resulted in loss of the neutral glucuronide moiety and in the appearance of intensive negatively charged aglycones [M-H-Glu]-, which were chosen as the product ions for single reaction monitoring. Quantitative studies showed a wide dynamic range (0.0025-100 microg/ml) with correlation coefficients better than 0.995. The method was repeatable within-day (relative standard deviation, RSD<7%) and between-day (RSD<14%) and the recovery (78-103%) was better than with the traditional, laborious pretreatment method. The use of tandem mass spectrometry permitted low limits of detection (1 ng/ml of entacapone glucuronide). The method was applied for the quantitation of (E)- and (Z)-isomers of entacapone glucuronide in plasma of rats used in absorption studies.

Animals↗
PubMed1993

Effects of intraventricular taurine, homotaurine and GABA on serum prolactin and thyrotropin levels in female and in male rats.

Serum prolactin and thyrotropin levels of conscious, unrestrained male and female rats were compared after intracerebroventricular (i.c.v.) administration of taurine, gamma-aminobutyric acid (GABA) and homotaurine. The amino acids studied had no clear effect on serum basal thyrotropin levels in male or female rats. All amino acids elevated serum prolactin levels in female rats at the dose of 5 mumol/rat; homotaurine by about 18-fold, taurine and GABA by 3-fold. Only homotaurine elevated serum prolactin of male rats at this dose, but its effect was less pronounced (p < 0.01) in male than in female rats. Although homotaurine was clearly more potent than the two other amino acids, at the dose of 10 mumol/rat taurine and GABA also elevated serum prolactin in male rats. These findings show that there are gender-related differences in the responses of serum prolactin levels to homotaurine, taurine and GABA in rats. The tuberoinfundibular dopaminergic pathway, which exerts tonic inhibitory influence on prolactin secretion, is sexually differentiated. Hence the gender-related differences in the effects of the amino acids on prolactin secretion suggest that they might inhibit dopamine release from the median eminence. In case of homotaurine, the gender effect was most pronounced. The less clear dependence of GABA's effect on the gender is in accordance with the suggestions that GABA influences the secretion of serum prolactin by more than one mechanism.

Animals↗
PubMed1989

Target tissue morphology and serum biochemistry following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in a TCDD-susceptible and a TCDD-resistant rat strain.

The mode of action of the highly toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is unknown. It was recently discovered that two strains of rat, Long-Evans (L-E) and Han/Wistar (H/W), differ widely in susceptibility to TCDD. Employing this strain divergence as a probe, the present study set out to assess the role of various biochemical and morphological effects in TCDD lethality. In the main experiment, the rats were treated once ip with 0,5,50, or (H/W) 500 micrograms/kg TCDD and killed 1 to 16 days postexposure. Several target organs were evaluated by light microscopy and a number of serum lipid and carbohydrate parameters as well as a few major regulatory hormones were analyzed. The results demonstrated that most alterations caused by TCDD were essentially similar in both strains. TCDD reduced circulating thyroxine to a slightly greater extent and more permanently in the sensitive L-E strain. Moreover, a highly significant interaction on thyroid-stimulating hormone was found among strain, dose, and time. Serum concentrations of corticosterone and free fatty acids were increased only in the L-E rats given 50 micrograms/kg TCDD, i.e., at an apparent LD100 dose level for this strain. Yet, the most striking interstrain difference was seen in the liver which was distinctly affected after Day 4 in L-E rats given 50 micrograms/kg TCDD but only marginally affected in rats from any H/W group. The lesion, while showing no necrotic cell changes, was suggestive of plasma membrane damage, possibly reflecting the production of free radicals. The relation of the findings to possible mechanisms of TCDD action is discussed.

Animals↗
PubMed1988

Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease.

A selective catechol-O-methyltransferase inhibitor, OR-462, was studied for its ability to affect pharmacokinetic properties of L-dopa after the p.o. administration of the inhibitor to rats and mice. When OR-462 was given to rats at the dose range of 0.3 to 30 mg/kg in conjunction with L-dopa and carbidopa, a dose-related and long-lasting (greater than 5 hr) increase in striatal L-dopa and dopamine levels as well as a reduction in 3-O-methyldopa levels were shown. For a 50% reduction of the 3-O-methyldopa levels a dose of 6 mg/kg of OR-462 was needed. The increase in striatal homovanillic acid, an O-methylated metabolite of dopamine which poorly penetrates the blood brain barrier, indicates that O-methylation was not inhibited in the brain. In order to get the same dopamine levels in striatum the L-dopa dose could be lowered to one-fourth when OR-462 was added. The L-dopa-sparing effect of OR-462 given p.o. was also demonstrated in two behavioral parkinsonian models. OR-462 given at doses of 3 to 30 mg/kg in conjunction with L-dopa and carbidopa, dose-dependently potentiated the L-dopa-induced reversal of hypoactivity in reserpinized mice. Likewise, the same doses of OR-462 caused a marked potentiation of L-dopa-induced contralateral turning behavior in rats with unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The data suggest a possible beneficial effect of OR-462 in the therapy of Parkinson's disease.

Animals↗
PubMed1986

Experimental compound OR-K-242-HCl an anilide derivative slows conduction velocity of the heart in the conscious beagle dog.

OR-K-242-HCl is an antitussive compound. Because it resembles lidocaine structurally, one of its target organs may be the heart. In anaesthetized guinea pigs OR-K-242-HCl depressed function of the heart. The aim of the present study was to test effects of OR-K-242-HCl on the conduction velocity of the heart in the conscious beagle dog. OR-K-242-HCl was administered 6 mg/kg and 12 mg/kg i.v. and 6 mg/kg, 12 mg/kg, 24 mg/kg, and 36 mg/kg orally. The doses for lidocaine (reference substance) were 6 mg/kg, and 12 mg/kg i.v. and 6 mg/kg, 12 mg/kg, and 24 mg/kg orally. Five consecutive noisefree cycles of ECG were used before and every 15 min up to three hours after the drug administrations. For each cycle PQ-, QTC-, RR-interval, as well as, QRS-complex and heart rate were calculated. Both OR-K-242-HCl and lidocaine prolonged the conduction velocity in the atria and ventricles. After i.v. and oral administration OR-K-242-HCl induced stronger and more uniform responses than lidocaine. The oral drug administrations produced more sustained responses than the intravenous injections for both compounds.

Administration, Oral↗
PubMed1986

Ethylenethiourea and nabam induced alterations of function and morphology of thyroid gland in rats.

Male Wistar rats were given 0-200 mg/l of nabam and 0-300 mg/l of ethylenethiourea (ETU) in drinking water ad libitum for 28 d to study their effect on thyroid gland function and morphology. Blood samples for RIA hormone assays (T3, T4, TSH) were taken and thyroids of each rat were dissected out for routine light and electron microscopic analysis after sacrifice performed under CO2 anesthesia. Nabam (8.4-30.5 mg/kg bw/d) inhibited dose-dependently T4-secretion and increased T3-secretion, but had no effect on basal TSH-secretion. ETU (10.6-23.4 mg/kg bw/d) inhibited dose-dependently T4- and T3-secretion. ETU also increased basal TSH-secretion tenfold, obviously due to the lack of negative feedback by T4 and T3. Light microscopic analysis revealed neither nabam nor ETU induced morphological alterations in thyroids. Both but especially ETU induced, ultrastructural changes, namely increased number of myelin bodies, dilatation of the rough endoplasmic reticulum, and increased vacuolization in the epithelial cells of thyroid follicles. The functional alterations are obviously connected with, and preceed slight ultrastructural degenerative changes in thyroid follicle epithelial cells even at low doses of nabam, and ETU, after a short-term oral administration.

Animals↗
PubMed1986

Histopathological and morphometrical analysis applied to skin changes in NMRI mice induced by dithranol (anthranil) and its acyl analogs.

Histology and morphometric changes in skin lesions of NMRI mice caused by dithranol and its acyl analogs, with and without pretreatment with dimethylbenzanthracene (DMBA) are described. The course of neoplastic progression seems to have three distinct phases (normal skin, hyperplasia, papilloma), each characterized by typical architectural and cellular changes. The parameters reflecting the nuclear size increased in the above order and the differences between the groups were highly significant. Nuclear shape changes did not take place, as shown by the almost constant form factor. The study demonstrates the value of the morphometric methodology in characterizing quantitative nuclear changes in mouse skin models.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers.

The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers. The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6-9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.

Adult↗
PubMed1985

A six month dermal irritation test with anthralins in the Göttingen miniature swine.

Anthralins, especially dithranol, have been used for the treatment of chronic dermatoses for many years. Unfortunately dithranol stains the skin yellow or brown. It also irritates healthy skin more than psoriatic areas. A new anthralin derivative, butantrone may be tolerated better. Because the skin of the swine resembles human skin in many respects, the Göttingen miniature swine was selected as the test animal for the present study. 12 Göttingen miniature swines of the uncoloured line were randomized into three groups. The two anthralin derivatives were spread in three separate bases (ointment, stick and gel) and in three concentrations each on the allocated skin sites on the flanks of the animals. The responses of the skin were evaluated daily (except Sundays) for six months. Because there was a separate group for the control animals (bases only), for dithranol and butantrone, it was possible to make observations on systemic toxicity, too. Butantrone and dithranol turned out almost equally irritating to the skin of the miniature swine. The mean primary irritation scores in the butantrone group were slightly higher than in the dithranol group. On the other hand, the concentrations of butantrone were higher. It is possible that the release of the drugs from the gel formula was poorer than from the ointment and stick bases.

Animals↗
PubMed1985

The effect of maneb, zineb, and ethylenethiourea on the humoral activity of the pituitary-thyroid axis in rat.

Ethylenebisdithiocarbamates (EBDCs) maneb and zineb are widely used fungicides the final metabolite of which is ethylenethiourea (ETU). EBDCs distort the humoral activity of the thyroid gland, and ETU is especially active in this respect. Male Wistar rats were exposed either to exogenous (100 ng i.p.) or endogenous (+4 degrees C) TRH stimulation. ETU (100-500 mg/kg i.p.) caused no changes in serum TSH levels whereas zineb (70-500 mg/kg i.p.) significantly decreased the bursts induced by cold or exogenous TRH. Maneb (20-200 mg/kg i.p.) significantly decreased the cold-induced TSH response while it had no effect on the TRH-stimulated TSH secretion. None of the agents caused significant changes in serum T3 or T4 levels. It seems that maneb, and zineb, but not ETU, inhibit rat TSH secretion through an action on the endogenous TRH at the hypothalamic or pituitary level. The mechanism behind this action may be the inhibition of dopamine-beta-hydroxylase.

Animals↗
PubMed1984

Determination of catechol-O-methyltransferase activity by high-performance liquid chromatography with electrochemical detection.

A rapid and simple assay for catechol-O-methyltransferase (COMT) activity by high-performance liquid chromatography with electrochemical detection is described. The method is based on the measurement of 3-O- and 4-O-methylated products (3-methoxy-4-hydroxy- and 4-methoxy-3-hydroxybenzylamine, respectively) of the substrate 3,4-dihydroxybenzylamine. These compounds are determined from the incubation mixture after removal of protein injecting aliquot into the liquid chromatograph. The detection limit is 1 pmol of product. This method is very suitable for screening of COMT activity as well as for determining the meta/para product ratios.

Animals↗
PubMed1984

On-line radiochemical assay for monoamine oxidase utilizing high-performance liquid chromatography.

A fast and sensitive assay for the determination of monoamine oxidase activity was developed. The method is based on the separation and quantitation of 14C-labeled assay products by high-performance liquid chromatography, which is interfaced directly into a flow-through radioactivity detector. This allows on-line quantitation of the radioactive compounds with picomole sensitivity. The method makes possible the complete separation and detection of the deaminated products of monoamine oxidase A and B substrates benzylamine and 5-hydroxytryptamine, respectively. This assay has been applied to the measurement of monoamine oxidase A and B activities in rat brain.

Animals↗
PubMed1984

Skin irritation by dithranol (anthralin) and its 10-acyl analogues in 3 animal models.

The skin irritant properties of a single application of dithranol (anthralin), a typical "delayed irritant", and its 10-acyl analogues in acetone or white petrolatum were compared in 3 animals models. Maximal irritation was reached at about 24 h in mouse ear, 48 h in guinea pig back and 1 week in miniature swine back, the last-mentioned serving as a good model of human skin. In all animal species, butantrone was significantly less irritant than dithranol, 10-acetyl dithranol or 10-propionyl dithranol. 10-acetyl dithranol was the most irritant compound. Clinical trials with butantrone on psoriasis are justified.

Animals↗
PubMed1984

Concentrations of metronidazole and tinidazole in abdominal tissues after a single intravenous infusion and repetitive oral administration.

Concentrations of metronidazole and tinidazole in serum and abdominal tissues were determined after a single 500-mg intravenous infusion or after a 5-day oral dosage of 500 mg three times daily in groups of 10 patients each. In the patients who got the single infusions, the concentrations in tissues (except fat) reached almost the serum levels 10 min after the infusion. At 24 h, the tinidazole concentrations in serum averaged 3.2 micrograms/ml and those of metronidazole 1.3 micrograms/ml. In the patients who got the 5-day oral dosages, the steady-state levels of tinidazole in both serum and tissues were twice as high as those of metronidazole.

Abdomen↗
PubMed1984

Pharmacokinetics of pipemidic acid in healthy middle-aged volunteers and elderly patients with renal insufficiency.

Pipemidic acid in bacteriological screening was more potent than nalidixinic acid, notably against Pseudomonas. In a study in middle-aged female volunteers, the relative bioavailability of a single 500 mg tablet of pipemidic acid was good. The main pharmacokinetic parameters were: tmax, 2.3 h; Cmax, 3.3 micrograms/ml; t1/2, 4.6 h; Varea, 2.04 l/kg; Cltot, 5.48 ml/min per kg; Clren, 3.05 ml/min per kg; Ae(0-24), 55.7% of dose. In elderly inpatients with normal renal function, the main alterations from middle-aged volunteers were: slightly elevated Cmax (+28%) and AUC (+13%) and significantly decreased Varea (-51%), Clren (-34%) and Ae(0-24) (-31%). In elderly inpatients with renal insufficiency, Clren (-58%) was decreased compared with elderly inpatients with normal renal function. Concn. of pipemidic acid in urine still exceeded several-fold the MIC values of the most pathogenic bacteria. Among all the subjects, there was a negative correlation between Clcreat and AUC0-infinity, and a positive correlation between Clcreat and Cltot, Clren and Ae(0-24). In the treatment of urinary-tract infections with pipemidic acid, a mild renal insufficiency (Clcreat 30 ml/min or more) does not necessitate dose adjustments.

Adult↗
PubMed1984

Pharmacokinetics of graded oral doses of sulindac in man.

Pharmacokinetics of graded doses of sulindac were studied on 9 healthy volunteers. Serum concentrations of sulindac (inactive prodrug), sulindac sulfide (active metabolite) and sulindac sulfone (inactive metabolite) were measured both after a single dose of 150 mg, 175 mg or 200 mg and on the 6th and 7th days after b.i.d. administration of the same doses. The peak and minimum concentrations of sulindac were practically not dependent on the dose. The concentration-time curves remained similar after a single dose and after the repetitive dosing. On the contrary, both sulindac sulfide and sulfone gave about twice as high serum levels at steady-state as after a single dose. As judged from several pharmacokinetic parameters, a dose of 150 mg gave significantly smaller values than the higher doses but there was no significant difference between 175 mg and 200 mg in sulindac sulfide and sulfone concentrations. The average half-lives of sulindac, sulindac sulfide and sulfone were 1.7 -4.2 h, 15.3-16.1 h and 16.6-19.6 h, respectively. Both sulindac sulfide and sulfone tended to accumulate at a repetitive dose of 200 mg. The appropriate dose of sulindac appears to be 175 mg twice daily.

Adult↗