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Biomedical subjects

E Heinonen

Publications and source records attributed to E Heinonen.

At least 19 recordsLinked to original sources
PubMed1992

The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial.

Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).

Administration, Oral↗
PubMed1991

Fall in intracellular pH mediated by GABAA receptors in cultured rat astrocytes.

The influence of muscimol (a specific gamma-aminobutyric acid-A (GABAA) receptor agonist) on intracellular pH (pHi) was studied in cultured rat astrocytes by means of fluorescence spectrophotometry with BCECF as the H+ indicator. In an HCO3(-)-free medium, muscimol had little effect on pHi. In a solution containing 22 mM HCO3-, muscimol produced a reversible, concentration-dependent fall in pHi with a maximum of about 0.1-0.15 units. The muscimol-induced fall in pHi was antagonized by an increase in the external K+ concentration, which suggest that the acidosis is an immediate consequence of a net efflux of HCO3- through GABAA receptor channels rather than an indirect effect caused by a change in membrane potential. The present results raise the possibility that astrocytes may participate in the regulation of extracellular pH at GABAergic synapses and contribute to activity-induced pH changes in nervous tissue.

Animals↗
PubMed1991

Treatment of epilepsy in mentally retarded patients with a slow-release carbamazepine preparation.

Pharmacokinetic properties and efficacy of a conventional (C) carbamazepine (CBZ) preparation divided into three daily doses and a slow-release CBZ preparation (SR) divided into two daily doses were evaluated in a randomized, double-blind, cross-over study. The trial started with a 8-week baseline period followed by the two treatment periods each 10 weeks long. At the end of each period, a 24-h blood sample series for determination of serum CBZ and carbamazepine-10,11-epoxide (CBZE) was collected. The occurrence of seizures was monitored day and night during the whole study period by experienced nurses. The mean age of the 20 evaluable patients was 24.9 and the duration of epilepsy 19.2 and carbamazepine treatment 7.0 years. The bioavailability of CBZ from the two preparations was similar. The mean fluctuation of serum CBZ concentration (Cmax-Cmin/Css) was 16% smaller during SR. The mean serum CBZ concentration in the morning samples was significantly (P less than 0.001) higher during SR treatment. The mean total number of seizures was approximately four per week and did not differ between the two treatments, but during the last 2 weeks of the study period the occurrence of seizures was significantly smaller during SR (P = 0.02).

Adolescent↗
PubMed1990

Carboplatin and etoposide in advanced lung cancer:--a phase I study.

This phase I study was carried out to determine the maximal tolerated dose of carboplatin (Car) together with a fixed dose of etoposide (E) and to recommend the optimal dose for a phase II study. The dose of E was 100 mg/m2 given i.v. on days 1-3, and the starting dose of Car was 200 mg/m2 given i.v. on day 1. The dose was escalated until WHO grade 4 toxicity developed after two treatment cycles in more than one-third of the patients. A total of 33 patients with advanced lung cancer entered the trial. The maximal tolerated toxicity of the combination was reached at a dose of 500 mg/m2 Car. Myelosuppression was moderate, and hematological toxicity of WHO grade 4 was encountered in one of five patients at 475 mg/m2 and in two out of five patients at 500 mg/m2. The main toxic effects were leucopenia and thrombocytopenia. The frequency of treatment-related infections was low and no deaths were caused by treatment. There was a significant overall correlation between the platelet nadir and creatinine clearance. One complete response and three partial responses were achieved after two treatment cycles. Based on the results of the present study, the dose of carboplatin (combined with 100 mg/m2 eposide given on days 1-3) recommended for phase II studies is 450 mg/m2.

Adult↗
PubMed1990

Low affinity binding to glutamate receptor sites correlates with depolarizing responses induced by glutamate and quisqualate in striatal synaptoneurosomes.

In the present study, binding affinity of glutamate and quisqualate to striatal synaptoneurosome membranes in the guinea-pig was compared with concentration-dependence of depolarizing responses induced by these agents. The displacement of radioactive glutamate from receptor binding site by unlabelled glutamate and quisqualate revealed a nonhomogeneous population of binding sites. A high affinity component of binding was observed with an inhibition constant of 0.04 microM for glutamate and 0.45 microM for quisqualate, as well as a low affinity component with an inhibition constant of 10 microM for glutamate and 87 microM for quisqualate. Changes of the membrane potential in striatal synaptoneurosomes induced by glutamate and quisqualate were detected by measuring the absorbance of a potential sensitive cyanine dye. Glutamate and quisqualate induced constantly a depolarization in synaptoneurosome particles. Concentration-response curves showed that half-maximal depolarization was obtained with 10 microM glutamate and 100 microM quisqualate. The comparison of the displacement data with the changes in the membrane potential in the present investigation indicate that in vitro glutamate and quisqualate depolarize striatal synaptoneurosome particles through low affinity binding to receptor site for glutamate.

Animals↗
PubMed1990

Multiple-dose pharmacokinetic study with a slow-release carbamazepine preparation.

The pharmacokinetics, clinical efficacy and side effects of carbamazepine (CBZ) in the steady-state condition were studied using a slow-release preparation (SR), Neurotol Slow, and a conventional preparation (C), Tegretol. Eighteen adult epileptic patients under CBZ therapy were evaluated in this single-blind, randomized cross-over study. The previous daily CBZ dose was kept unchanged and divided into 2 daily doses during two 2 week study periods. At the end of each period blood samples were drawn at frequent intervals for 12 h after the administration of the morning CBZ dose. Serum concentrations of unchanged CBZ and its main metabolite, carbamazepine-10,11-epoxide (CBZE), were determined by HPLC. Peak concentrations of CBZ and CBZE were significantly lower, and the time-lapse before CBZ reached its peak was significantly longer during SR treatment. The fluctuations in serum CBZ and CBZE were significantly lower during SR treatment. There was no significant difference in bioavailability between the 2 preparations. The number of epileptic seizures was 31 during SR and 57 during C treatment. Side effects were more common during C treatment. The occurrence of dizziness was significantly lower with SR treatment than with C treatment. We conclude that greater stability in serum CBZ and CBZE concentrations can be obtained by using an SR of CBZ, without reducing the bioavailability of the drug.

Adult↗
PubMed1990

Differences in side effects between a conventional carbamazepine preparation and a slow-release preparation of carbamazepine.

The aim of this double-blind cross-over study was to investigate whether side effects of carbamazepine (CBZ) could be reduced by using a slow-release CBZ preparation. Twenty-one adult patients with epilepsy who had side effects related to the use of CBZ took part in the trial. Patients were randomized to receive either a conventional (C) or slow-release (SR) CBZ preparation for 3 months and were then switched over to the other preparation for another 3 months. The daily dose and dosing frequency of CBZ were kept the same as before the study. The quality and severity of side effects were assessed monthly using a scored questionnaire containing questions about systemic toxicity (STRS) and neurotoxicity (NTRS). Twenty patients could be evaluated. The mean total values of NTRS of 3 monthly visits on each drug were significantly less during SR than during C treatment (P less than 0.05). All the items of NTRS scored lower during SR therapy, and the difference was significant for the occurrence of headache, dizziness and disturbances of vision, speech and coordination. The total score of STRS was also lower during SR, but the difference was not significant. Eleven patients preferred SR, 3 preferred C and 6 patients estimated the periods to be equal. In conclusion, a slow-release preparation of CBZ can render fewer side effects than conventional CBZ preparations.

Adult↗
PubMed1990

Oral carmofur in advanced gastrointestinal cancer.

One hundred and twenty-four patients with a diagnosis of metastatic gastrointestinal cancer and no prior therapy were included in this clinical study of carmofur monotherapy, 300-500 mg/m2 daily for 6 weeks. For the 115 evaluable patients, the response rates were 19.4% in gastric cancer, 27.2% in cancer of mobile colon, and 12.5% in rectal cancer. No objective responses were seen in 38 patients with pancreatic cancer, although the disease of 13 of these patients has remained stable over a considerably long period of follow-up. The toxicity profile was interesting; the main adverse effects were urinary bladder symptoms and flush. Hematologic toxicity was minimal. The treatment proved to be safe and could be used for outpatients.

Administration, Oral↗
PubMed1990

Vibration stress and the autonomic nervous system.

Raynaud's phenomenon has been considered to be due to activation of the central sympathetic vasoconstrictor reflex, and may represent part of a larger dysfunction of higher autonomic centers. Symptoms, such as sweating disturbances, orthostatic hypotension, insomnia and impotence have been reported to be more common among vibration exposed workers. We studied 217 male forest workers and selected samples of this population for electromyographic (N = 80), autonomic nervous system function, controlled breathing, tilting bed and valsalva manoeuvre (N = 88) tests, and a full clinical neurological examination. Mean alcohol consumption was estimated to be 3.0 kg absolute alcohol/year. The total mean vibration exposure time was 14,100 hours. The prevalence of Raynaud's phenomenon was 5%. The variations in heart rate (HRV) at rest and during deep breathing were observed. The traditional indexes of HRV (CV, CVS, MEAN) were computerized and calculated. There was a significant difference (p less than 0.001) between the HRV indexes during the deep breathing test in those with the shortest and the longest exposure to vibration. The values of HRV indexes were age dependent; and in multiple regression analysis, the total exposure time to vibration had an independent negative association to HRV. Also association of sensory neural hearing loss to Raynaud's phenomenon among vibration exposed workers indicates that there is an involvement of the central nervous system in the pathogenesis of vibration syndrome. The question, does vibration cause permanent changes in autonomic centers of the brain or do these centers only mediate vibration stress to end organs, remains unsettled.

Adult↗
PubMed1989

Changes of the membrane potential in striatal synaptoneurosome, synaptosome and membrane sac preparations induced by glutamate, kainate and aspartate as measured with a cyanine dye DiS-C2-(5).

The effects of glutamate, kainate and aspartate on the membrane potential of striatal synaptoneurosome, synaptosome and membrane sac preparations were studied by using a potential sensitive cyanine dye DiS-C2-(5). Excitatory amino acids glutamate and aspartate had a depolarizing effect on synaptoneurosomes. 7.9 microM glutamate and 2.8 microM aspartate produced a half-maximal response. Depolarizations induced by glutamate and aspartate were dependent on the concentration of extracellular sodium ions, a maximal response occurred at around 40 mM of external Na+. Kainate induced a dual effect on synaptoneurosomes. In a standard Na+-based medium a hyperpolarization, likely due to inhibition of a presynaptic sodium-dependent glutamate uptake, predominated over a postsynaptic kainate receptor-mediated depolarization that was observed when electrogenic glutamate uptake was inhibited. This interpretation was supported by results obtained with synaptosome and membrane sac preparations. In a standard Na+-based medium kainate had a hyperpolarizing effect on synaptosomes while in the membrane sac preparation kainate induced a depolarization.

Animals↗
PubMed1989

Vincristine treatment of acute lymphoblastic leukemia induces transient autonomic cardioneuropathy.

Reduced respiratory sinus arrhythmia, measured as heart rate variability, is a reliable indicator of autonomic nervous dysfunction, reflecting a damage in vagal cardiac control. The authors studied the heart rate variability (HRV) of nine children treated for acute lymphoblastic leukemia during the different phases of cytostatic treatment utilizing heart rate processing techniques with a computer. The indices of HRV as well as the spectral components of heart rate were examined with special relation to vincristine administration. The heart rate variability was significantly reduced during the vincristine induction phases as compared to the consolidation and maintenance phases without vincristine administration. In particular, the respiratory components of the HRV during deep breathing tests were significantly reduced during vincristine treatment. The authors conclude that the measurement of the HRV is a suitable method for monitoring transient autonomic neuropathy, which these results show to be a frequent complication of vincristine treatment.

Adolescent↗
PubMed1989

Phase II evaluation of peroral carmofur, cyclophosphamide, and hexamethylmelamine as a second-line therapy in advanced epithelial ovarian carcinoma.

A prospective phase II study was performed to evaluate the effect and tolerability of a peroral combination chemotherapy consisting of hexamethylmelamine, cyclophosphamide, and carmofur in patients with epithelial ovarian cancer previously heavily treated by cisplatin-based chemotherapy but no longer responding to it. Of the 27 patients 1 showed a clinical complete remission lasting 15+ months and 4 a partial remission of 6+ to 21 months. A further 7 patients had an unchanged situation of 4 to 13+ months. The median survival of the nonresponders was 3 months. The side effects were tolerable, mostly nausea and vomiting. Only 4 of 27 patients suffered from severe vomiting causing discontinuation of the therapy. The peroral ambulatory chemotherapy prolonged markedly the overall survival of about one-half of the patients with ovarian cancer who previously failed to respond to cisplatin-based chemotherapy.

Administration, Oral↗
PubMed1989

Selegiline and levodopa in early or moderately advanced Parkinson's disease: a double-blind controlled short- and long-term study.

Selegiline 10 mg per day was compared to placebo as an adjunct to levodopa treatment in this double-blind study of early or moderately advanced Parkinson's disease. Thirty-eight patients completed an initial cross-over trial comprising two treatment periods, each of eight weeks, with a four weeks' wash-out period between them. Thirty of the patients continued in a long-term, double-blind parallel trial with a mean duration of 16 months (range 6-30 months). Selegiline treatment allowed a significant reduction of the necessary daily levodopa dose in both parts of the study and of the daily dosing frequency in the long-term investigation. In spite of this reduction of levodopa dose, an improvement was noted in tremor during the short-term selegiline periods. The side-effects were slight and related to dopamine effects and disappeared after reduction of levodopa-dose. The results support the use of selegiline as an early adjunctive treatment in Parkinson's disease.

Aged↗
PubMed1987

Intracellular free magnesium in synaptosomes measured with entrapped eriochrome blue.

The free Mg2+ concentration within synaptosomes has been measured with an entrapped Mg2+ indicator, eriochrome blue. Ionophores gramicidin and A23187 slowly increased the absorbance of the entrapped dye. Calibration of the dye response in a Na+-based medium gave a value around 0.3 mM for the internal free Mg2+ concentration at 1 mM external Mg2+. The replacement of Na+ by choline increased this value to around 0.65 mM. Depolarisation with a high K+ concentration or depletion of intrasynaptosomal ATP with FCCP and iodoacetate did not affect the level of intracellular free Mg2+ concentration. An elevation of the external Ca2+ concentration significantly reduced internal Mg2+ to about 0.1 mM. Ca2+ had no significant effect when Na+ was replaced by choline. The results indicate that the intrasynaptosomal Mg2+ activity is partially regulated by a Na+-Mg2+ exchange mechanism which does not directly require ATP as an energy source.

Adenosine Triphosphate↗
PubMed1987

Ionic dependence of membrane potential and glutamate receptor-linked responses in synaptoneurosomes as measured with a cyanine dye, DiS-C2-(5).

Membrane potentials of particles present in a subcellular brain preparation, called synaptoneurosomes, have been monitored by measurement of changes in the absorbance of a cyanine dye, DiS-C2-5. The membrane potential of the particles seems to be dependent on both Cl- and K+ diffusion potentials, as judged from dependence of the absorbance changes on the K+ equilibrium potential across the membrane in the presence of Ba2+ or when Cl- was replaced with gluconate. The apparent high Cl- permeability of the membrane preparation was reduced in the presence of picrotoxin, a finding suggesting endogenous activation of receptor-linked Cl- channels. Glutamate and kainate caused depolarization of the membranes present in the preparation. This effect was only seen if K+ channels had been blocked in the presence of Ba2+ or 4-aminopyridine. No responses were observed with other glutamate receptor agonists (quisqualate or N-methyl-D-aspartate). The membrane potential of particles present in conventional synaptosomal preparations neither had a high Cl- permeability nor reacted to glutamate or kainate in the present conditions. The results suggest that synaptoneurosome preparations may be used for functional studies on postsynaptic neurotransmitter receptor-linked membrane potential changes with optical probes of membrane potential.

Animals↗
PubMed1986

Quantitative measurements of the cytosolic Ca2+ activity within isolated guinea pig nerve-endings using entrapped arsenazo III and quin2.

The absorbance changes of intrasynaptosomally entrapped arsenazo III have been converted into values of free Ca2+ concentration by correcting for the nonlinear response of arsenazo III at different concentrations of the dye as well as for changes in internal pH. An average resting value for free Ca2+ concentration around 0.4 microM is obtained. Depolarization with veratridine or gramicidin increases this value to around 3 microM. Measurements of cytosolic free Ca2+ with the quin2 method gives much lower values in similar conditions. The release of prelabelled [14C]noradrenaline from the nerve-endings is maximally activated when the internal free Ca2+ concentration rises as measured with arsenazo III to about 4 microM when titrated with increasing concentrations of ionophore A23187.

Aminoquinolines↗
PubMed1985

Dependence of cytoplasmic calcium transients on the membrane potential in isolated nerve endings of the guinea pig.

The relation of changes in internal, free Ca2+, measured with arsenazo III, to the membrane potential, measured with the cyanine dye di-S-C2(5) or 86Rb+ distribution ratio, was studied in isolated guinea pig cortical nerve endings. Depolarization of the plasma membrane with veratridine or gramicidin as well as addition of ionophore A23187 led to an increase in cytosolic Ca2+. Only the response to veratridine was inhibited by tetrodotoxin. The dependence of the depolarization-induced increase in intraterminal, free Ca2+ on the membrane potential between about -50 to 0 mV was sigmoidal. A maximal increase in cytosolic Ca2+ was reached when the membrane potential was depolarized from the resting level, about -64 mV, to about -40 mV. These results show that in isolated nerve endings the activation of voltage-sensitive Ca2+ channels concomitantly leads to an increase in cytosolic, free Ca2+. Comparison of the results of the present study with the previous electrophysiological observations indicate that Ca2+ channels in synaptosomes, presynaptic nerve terminals of the squid giant synapse and cardiac cells have essentially similar voltage dependency.

Animals↗