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Biomedical subjects

J Tuomisto

Publications and source records attributed to J Tuomisto.

At least 109 records · Page 6Linked to original sources
PubMed1987

Food and guar decrease absorption of trimethoprim.

Absorption of trimethoprim suspension 3 mg/kg has been studied in 12 healthy adult volunteers when given alone, with food or with food and guar, using a randomised Latin-squares study design. Serum and urine trimethoprim concentrations were followed for 24 h. The mean peak serum concentration was higher when fasting subjects were treated (mean: 2.35, 1.84 and 1.97 micrograms/ml for the fasting, food and food + guar groups, respectively; ANOVA p less than 0.001 for the difference between fasting and non-fasting values). The times of the peak serum concentrations did not differ. Food ingestion decreased the area under the curve by 22.2%, as did food + guar. For maximal efficacy trimethoprim should be administered between meals.

Absorption↗
PubMed1987

Conformationally rigid dopamine analogues as inhibitors of dopamine and 5-hydroxytryptamine uptake by synaptosomes.

Derivatives of trans-decalin with a dopamine moiety incorporated in different conformations were studied as inhibitors of dopamine and 5-HT uptake in rat brain synaptosomes. In three derivatives the relation of the catechol ring and the amino function was gauche, in one isomer it was anti. One of the gauche isomers, (+/-)-2(a)-amino-3(e)-3, 4-dihydroxyphenol-trans-decalin had an affinity to the dopamine uptake system which was about one fourth of that of dopamine itself. The inhibition was competitive. The affinity of other isomers was about ten per cent or less of the affinity of dopamine. The active isomer was identical in conformation to the most active isomer in respective noradrenaline-derivatives tested previously. These results favour the view that the dopamine uptake site is able to accept the substrate as the gauche rotamer. This was not true with 5-HT uptake, and requirements for these two uptake sites may be conformationally different.

Animals↗
PubMed1987

Trimethoprim pharmacokinetics in children with renal insufficiency.

We studied the pharmacokinetics of trimethoprim in 14 children (two neonates) with renal insufficiency. They were 1 week to 16.4 years old and had glomerular filtration rates (GFR) between 10.8 to 72.3 ml/min/1.73 m2. The half-life (t1/2) of trimethoprim was inversely related to the GFR. The relation followed a power curve (correlation of t1/2 with GFR: r = -0.86; P less than 0.001). The slower elimination rate was mainly the result of lowered renal clearance of trimethoprim. The volume of distribution (Varea) was, in most patients, in the upper normal range for children. In some of the patients, chiefly infants with severe renal insufficiency, the Varea was larger than normal. In some individuals the pharmacokinetics of trimethoprim deviated from that to be expected from the GRF. We recommend reduced daily doses of trimethoprim if the GFR is less than 30 ml/min/1.73 m2. The reduction should be proportional to the reduction in GFR and primarily take the form of a prolonged dose interval.

Absorption↗
PubMed1987

Microcomputer-aided measurement of puff parameters during smoking of low- and medium-tar cigarettes.

A portable microcomputer-assisted flow transducer was developed for analysing puff parameters during smoking of low- and medium-tar cigarettes. Smoke flow was determined by measuring pressure difference between two sites within an orifice flowmeter. According to the Bernoulli equation, the pressure difference is proportional to the square of flow. For calibration of the method, various sizes of air volumes were puffed through the flowmeter by a piston syringe. The calibration curve, which consisted of the flow as a function of the square root of pressure difference, was linear (r = 0.98). The automatic microcomputer analysis consists of the following variables: mean flow and mean volume of inhaled smoke gas, puff duration, time interval between two puffs, number of puffs and total volume inhaled. Eight volunteers smoked 10 low- and 10 medium-tar cigarettes during the cross-over experiments. The investigation indicated that the total inhalation volume of smokers in the case of low-tar cigarettes is twice as large as in the case of medium-tar cigarettes.

Humans↗
PubMed1987

Han/Wistar rats are exceptionally resistant to TCDD. I.

Adult male Han/Wistar rats were administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intraperitoneally at doses ranging from 125 to 1400 micrograms/kg and monitored for 39 to 48 days. Two rats succumbed in the course of the experiment: one in the group receiving 625 and one dosed 1000 micrograms/kg. Body weights of the animals decreased by 20 to 30% during the first 10 to 14 days and became stable thereafter. Feed consumption decreased to 1/3-1/2 of control levels by Day 4 (calculated per metabolic body mass) and returned gradually to starting values by about 4 weeks after dosing. Water intake displayed a triphasic pattern: at first it was slightly increased (Days 1 to 3), then reduced (on Days 4 to 12) and finally increased again throughout the remainder of the test period. The absolute and/or relative weights of thymus, testicles, ventral prostate and interscapular brown fat were significantly decreased at termination. These results indicate that the LD50-value for TCDD in the male, adult Han/Wistar rat is substantially above 1400 micrograms/kg, and that suppression of appetite is the principal phenomenon responsible for TCDD-induced body weight reduction.

Adipose Tissue, Brown↗
PubMed1986

Microcomputer assisted measurement of inhalation parameters during smoking.

A microcomputer aided, battery operated method for analysing puff parameters during smoking was developed. The equipment included a sensitive, differential pressure transducer, a portable microcomputer and a modified cigarette flowmeter. The method is based on measuring pressure differences between two points within the flowmeter. The pressure difference is linearly proportional to smoke flow according to the Poiseuille-Hagen principle. The calibration curve, the mean flow as a function of (the area of puff curve)/puff duration, showed to be linear (r = 0.99) for calculating flow and volume of smoke. In experiments with 11 male volunteers the total inhalation volume reached the range 296-678 ml, the mean puff volume 19-65 ml, the mean puffing rate 15-26 ml/s, the mean puff duration 1.3-3.5 s, the number of puffs 9-16 and the mean interval between puffs 17-25 s.

Adult↗
PubMed1986

No difference between urinary mutagenicity in smokers of low-tar and medium-tar cigarettes: a double-blind cross-over study.

Urinary mutagenicity, blood carboxyhemoglobin and serum thiocyanate levels were measured in young, healthy volunteers smoking a fixed number of either low-tar (5 mg/cig.) or medium-tar (15 mg/cig.) cigarettes. The experiment was performed in a double-blind cross-over fashion. The volunteers were under daily control, and their diet and environment were standardized. The urinary mutagenic activity responded dose-dependently to the number of cigarettes smoked (0, 5, 10 or 20 per day), but there was no difference between the smokers of low-tar and medium-tar cigarettes. Neither were any significant differences found in blood carboxyhemoglobin nor serum thiocyanate. These results suggest that there is no substantial difference between the low-tar and medium-tar cigarette as to the inhalation of hazardous compounds in the real smoking situation.

Adult↗
PubMed1986

Effects of tranylcypromine enantiomers on monoamine uptake and release and imipramine binding.

Studies were carried out in vitro to determine effects of tranylcypromine enantiomers ([+]- and [-]-TCP) on uptake and release of 5-HT, DA and NA in rat synaptosomes and on imipramine binding to rabbit platelets. (+)-TCP was more potent than (-)-TCP as inhibitor of 5-HT uptake and imipramine binding, whereas (-)-TCP was more potent than (+)-TCP as inhibitor of DA and NA uptake. The enantiomers differed only slightly in their effects on monoamine release. The findings agree with previous reports on the stereo-selectivity of monoaminergic mechanisms toward TCP enantiomers, and support the notion that the 5-HT uptake site may be associated with the imipramine binding site.

Amines↗
PubMed1985

Effect of transition or heavy metals on [3H]haloperidol binding in rat striatal membranes in vitro.

Our previous experiments have shown that several metal cations affect dopaminergic uptake and release processes in synaptosomes in vitro. It is thus possible that other membrane-related steps of neurotransmission, such as receptor binding, are affected as well. We studied the effect of Mn2+, Cu2+, Cd2+, Zn2+, Hg2+, Pb2+ and of two organometals, methyl mercury and triethyl lead, on [3H]haloperidol binding in the striatal P2 fraction assuming that such a study would reveal direct effects of the ions on dopaminergic D2 receptor binding. According to non-linear curve fitting and Scatchard analysis, [3H]haloperidol bound to two sites in striatal tissue. The Kd of the higher affinity site was 0.14 +/- 0.05 nM and the Bmax 226.3 +/- 50.3 fmol/mg protein. The respective values for the lower affinity site were 2.49 +/- 0.56 nM and 678.3 +/- 111.4 fmol/mg protein. Among the divalent cations, Hg2+ (IC50 0.7 microM) and Cu2+ (IC50 2.9 microM) inhibited the high affinity [3H]haloperidol binding most potently. The inhibition by Cu2+ was due to a decrease in the binding affinity (increase in the Kd) while the number of binding sites remained unchanged. Zn2+ inhibited the binding by 41.8% and Cd2+ by 38.7% at 10 microM concentration while Pb2+ and Mn2+ did not affect binding significantly at this or lower concentrations. Methyl mercury (IC50 0.9 microM) and triethyl lead (IC50 2.6 microM) inhibited binding as well. Both these organometallic cations decreased the binding affinity but did not change significantly the number of binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

3H-dopamine uptake and 3H-haloperidol binding in striatum after administration of methyl mercury to rats.

Methyl mercury inhibits dopamine (DA) and serotonin (5-HT) uptake by brain synaptosomes and decreases antagonist binding to striatal dopaminergic D2 receptors in vitro. To assess the effects in vivo, adult rats were given methyl mercury, either as a single dose (10 mg/kg by gavage) or a cumulative total dose of 50 mg/kg in 2 weeks. The repeated dosing decreased body weight and caused neuromuscular dysfunction. In spite of this overt toxicity, neither 3H-DA uptake nor 3H-haloperidol binding changed in striatal synaptosomes. There were no significant alterations in 3H-5-HT uptake by hypothalamic synaptosomes or 3H-flunitrazepam binding in cerebellar synaptosomes. The results suggest that monoaminergic synapses and the benzodiazepine binding sites, associated with cerebellar GABA receptors, remain functionally normal at doses of methyl mercury that are otherwise toxic. The results also emphasize the importance of due care when extrapolating cellular or biochemical data to the level of the whole organism.

Animals↗
PubMed1984

Seizure thresholds and their postictal changes in audiogenic seizure (AGS)-susceptible rats.

The convulsive thresholds for bicuculline and electroshock seizures were studied in audiogenic seizure (AGS)-susceptible and control rats. Electroshock seizure thresholds, determined as the amperage necessary to cause tonic extension of the hindlegs in 50% of the rats (CC50 = convulsive current fifty) were markedly lowered in rats of two stocks, bred for AGS susceptibility. During the clonic phase of electroshock seizure the bicuculline threshold was slightly lowered but started to rise after the convulsion had ceased. After 5 min, the threshold was significantly elevated and the maximal increase was reached in 15 min. In control rats the level normalized curvilinearly within an hour, but in AGS rats it decreased more slowly and was still elevated after 90 min. After an audiogenic seizure, the threshold for bicuculline-induced seizures in AGS rats also rose significantly but declined rapidly after having reached a maximum at 15 min. This rise in seizure threshold for bicuculline might indicate a postictal change in GABAergic transmission.

Acoustic Stimulation↗
PubMed1984

Changes in endogenous monoamine levels of rat brain induced by tetraethyl lead.

Tetraethyl lead (TEL) was given to adult rats at single doses of 30, 90, or 180 mumol/kg in soya bean oil by gavage. 24 h later the concentrations of three monoamines were measured in the hypothalamus, occipital cortex and corpus striatum. Cortical noradrenaline (NA) decreased by 17-31% with increasing TEL dose and hypothalamic NA by 32% at the highest TEL dose. After administration of the cumulative total doses of 3, 10, or 30 mumol/kg TEL over 3 weeks, the corpus striatum was most severely affected: levels of NA and dopamine (DA) decreased by 12-22% while that of 5-HT increased by 11% at the highest TEL dose. The changes of 5-HT levels were opposite to those of catecholamines in other brain regions as well suggesting a reciprocal interaction between serotonergic and catecholaminergic neurones.

Animals↗
PubMed1984

The effect of changes in sound pressure level and frequency on the seizure response of audiogenic seizure susceptible rats.

An apparatus for pure tone stimulation of audiogenic seizure (AGS)-susceptible rats is described, and the effect of change in sound pressure level and frequency on AGS response in Uaz:AGS (SD) rats is shown. By use of pure tone stimulation, the prevalence of AGS response in rats of this strain, which have been bred for seizure-susceptibility, is 77%. With increasing frequency, the intensity-response curves show a shift to lower sound pressure levels, the ED50 for 20 kHz (83.8 dB) being significantly lower than the ED50 for 5 (110.5 dB) and 10 kHz (97.5 dB). Repeated exposure to seizure-inducing sound at weekly intervals leads to more severe seizures in individual rats. This should be taken into consideration as one possible confounding factor when using this method for assaying the efficacy of anticonvulsant drugs.

Acoustic Stimulation↗
PubMed1984

Comparison of gas chromatography and receptor bioassay in the determination of diazepam in plasma after conventional tablets and controlled release capsules.

Plasma levels of diazepam and its metabolites were compared after a controlled release formulation and a regular tablet. Both gas chromatographic analysis of plasma diazepam and desmethyldiazepam and radioreceptor assay of total benzodiazepine activity were used. Also the concentrations of benzodiazepine in saliva samples were analyzed by radioreceptor assay. A typical initial plasma peak was seen after the regular tablet but not after the controlled release capsule. Hence the excessive initial sedation can be avoided and the risk of abuse reduced. Desmethyldiazepam increased for about two days after a single dose of diazepam. The receptor assay correlated in general with the sum of diazepam and its desmethyl derivative. The saliva assay gave about 2.5% of the plasma total benzodiazepine which correlates well with the expected free benzodiazepine. It seems that both the plasma radioreceptor assay and the saliva assay can be used to monitor the total benzodiazepine concentration.

Adult↗
PubMed1984

Reduction of the lethality and the nephrocalcinotic effect of single fluoride doses by magnesium in rats.

Magnesium chloride, administered by gavage to fasting young rats, 30 min prior to sodium fluoride, elevated the LD50 for fluoride from 76 to 104 mg/kg body wt. The LD50 was elevated to greater than 180 mg/kg when magnesium was given in a dose equivalent to 2 or 3 times that of fluoride. In two experiments, a dose of 50 mg F/kg caused a mean 14- and 19-fold increase above the level of the control animals in the renal calcium content. The nephrocalcinotic effect of fluoride was nearly completely prevented by administering magnesium in a dose which is 3-fold the equivalent of the fluoride dose 30 min prior to fluoride.

Animals↗
PubMed1983

Release and inhibition of uptake of 5-hydroxytryptamine in blood platelets in vitro by copper and methyl mercury.

Divalent copper (Cu) and methyl mercury (Met-Hg) are potent inhibitors of the uptake of 5-hydroxytryptamine (5-HT) in rat hypothalamic synaptosomes in vitro. To assess the usefulness of blood platelets as a peripheral model of central serotonergic nerve endings for neurotoxicological studies, for comparison human and rabbit platelets were utilized. Cu inhibited 5-HT uptake into human platelets when platelets were separated from plasma (the IC50 0.7-0.8 microM). Plasma added with platelets abolished the toxic influence of Cu towards platelets. Met-Hg inhibited 5-HT uptake both in washed platelets (the IC50 0.2 microM) and in platelets added in plasma (the IC50s 10-15 microM). The inhibition of uptake by Met-Hg did not depend on buffer Ca and Mg. At low concentrations of Cu, the uptake tended to be more inhibited in the presence of Ca and Mg. Zn and Hg did not affect 5-HT uptake up to 100 microM. Pb inhibited it transiently (28% at 1 microM) in the presence of Ca and Mg. Met-Hg induced the release of endogenous 5-HT from rabbit platelets when they were in a suspension in Ca-free buffer, but Cu did not, even at 100 microM concentration. The results suggest firstly, that blood platelets give results comparable with brain synaptosomes regarding inhibitory effects of metals on 5-HT uptake provided plasma is decanted. Secondly, the inhibition of 5-HT uptake by Cu appears to be purely plasma membrane related but Met-Hg may, in addition, induce release of 5-HT from storage granules.

Adult↗
PubMed1983

Increase in dopamine uptake in rat striatal synaptosomes after an acute in vivo administration of organic and inorganic lead.

Adult male Wistar rats were administered acute toxic doses of lead (Pb), triethyl lead (TriEL) or tetraethyl lead (TEL) by gavage. The ability of striatal, hypothalamic and cortical synaptosomes to take up tritiated monoamines was assayed 24 hours later. Pb, TriEL as well as TEL increased dopamine (DA) uptake into striatal synaptosomes at least at some dose level. Pb increased, but TEL decreased 5-hydroxytryptamine(5-HT) uptake into hypothalamic synaptosomes, while TEL increased noradrenaline (NA) uptake into cortical synaptosomes. After a 3 week administration to initially 4 week old rats of even toxic doses of Pb in drinking water, monoamine uptake was not significantly affected. On the contrary, the neurotoxicity of TEL was cumulative in that a much lower dose decreased 5-HT uptake when divided over a 3 week period than acutely. In vitro TriEL inhibited DA uptake (IC50; 0.8 microM) into striatal and 5-HT uptake (5.0 microM) into hypothalamic synaptosomes but TEL and delta-aminolevulinic acid did not. The results suggest that dopaminergic and serotonergic neurones differ in their response to alkyl lead in vivo. The differences could be due to basic differences in the neurochemical behaviour of these two types of nerve endings.

Animals↗