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Introduction: An increase in brain white matter hyperintensities (WMHs) and a decrease in white matter fractional anisotrophy (FA) have been detected in bipolar I (BPI), II (BPII), and major depressive disorder (MDD) patients. Their relationship, and differences in diagnostic groups are obscure. Longitudinal studies are rare., Objective: After 5-year follow-up, we evaluated WMHs in BPI, BPII, and MDD patients as compared with controls, and studied the effects of clinical variables. We also explored the associations of clinical variables with cross-sectional whole brain FA., Methods: Eight BPI, 8 BPII, 6 MDD patients, and 19 controls participated in magnetic resonance imaging at baseline and follow-up. Diffusion weighted imaging was included at follow-up. WMHs were rated by the Coffey scale, and a tract-based spatial statistics method was used for diffusion data. The general linear model, ANOVA, Fisher's exact, Wilcoxon sign, and Kruskal-Wallis tests were used for statistical analyses., Results: Periventricular WMHs were increased in BPI patients (p = 0.047) and associated with the duration of disorder and lifetime occurrence of substance use disorder (p = 0.018). FA decrease was found in the corpus callosum of BPI patients (p < 0.01). MDD patients showed FA decrease in the right cerebellar middle peduncle (RCMP) (p < 0.01). In BPI patients, the duration of disorder associated with FA increase in RCMP (p < 0.05). No FA decrease was detected in patients with WMHs as compared with those without., Conclusions: Preceding illness burden associated modestly with WMHs, and FA increase in RCMP in BPI patients. MDD patients had FA decrease in RCMP. No association with FA decrease and WMHs was found., (© 2021 S. Karger AG, Basel.)

The energy absorbed from the radio-frequency fields of mobile telephones depends strongly on distance from the source. The authors' objective in this study was to evaluate whether gliomas occur preferentially in the areas of the brain having the highest radio-frequency exposure. The authors used 2 approaches: In a case-case analysis, tumor locations were compared with varying exposure levels; in a case-specular analysis, a hypothetical reference location was assigned for each glioma, and the distances from the actual and specular locations to the handset were compared. The study included 888 gliomas from 7 European countries (2000-2004), with tumor midpoints defined on a 3-dimensional grid based on radiologic images. The case-case analyses were carried out using unconditional logistic regression, whereas in the case-specular analysis, conditional logistic regression was used. In the case-case analyses, tumors were located closest to the source of exposure among never-regular and contralateral users, but not statistically significantly. In the case-specular analysis, the mean distances between exposure source and location were similar for cases and speculars. These results do not suggest that gliomas in mobile phone users are preferentially located in the parts of the brain with the highest radio-frequency fields from mobile phones.

Indications for brain imaging include potentially treatable intracranial causes (e.g. normal-pressure hydrocephalus, tumors, subdural hematoma) and especially characteristic features of memory disorders and differential diagnostics of such conditions. Since the primary structural changes in the most common progressive memory disorder, Alzheimer's disease, are seen in the inner temporal lobe, appropriate imaging of these structures is essential in early diagnosis.

Background: A few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics., Methods: Sixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans., Results: Compared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions., Limitations: Possibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies., Conclusions: A novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.

We assessed a new approach for evaluating the glioma risk among users of mobile phones to focus on the part of the brain most heavily exposed to radiofrequency electromagnetic fields from mobile phones. The tumor midpoint was defined from radiological imaging. A case-case analysis with 99 gliomas was performed using logistic regression. The exposed cases were those with the tumor mid-point within 4.6 cm from the line between the mouth and the external meatus of the ear, representing the most likely location of the mobile phone (the source of exposure). Alternative analyses based on various indicators of mobile phone use as the outcome were also carried out. The majority of cases were regular mobile phone users. A slightly higher proportion of gliomas among mobile phone users than non-users occurred within 4.6 cm from the presumed location of the mobile phone (28% vs. 14%). Modestly elevated odds ratios were observed for several indicators of mobile phone use, but without an exposure gradient. The highest odds ratios were found for contralateral and short-term use. Our results, though limited by the small sample size, demonstrate that detailed information on tumor location allows evaluation of the risk related to the most heavily exposed part of the brain, representing direct evaluation of the possible local carcinogenic effects of the radiofrequency fields. However, field strength varies between users and over time also within a given anatomic site, due to the output power of the phone. Collaborative analysis of a larger sample is planned., ((c) 2009 Wiley-Liss, Inc.)

Purpose: The aim of this study was to characterize the magnetic resonance imaging (MRI) findings in chronic solvent encephalopathy (CSE) patients and to study whether the findings are associated with solvent exposure indices., Methods: The brain MRI scans of 71 CSE patients were independently re-evaluated and rated by two experienced neuroradiologists. All the work tasks were analyzed and the chemical composition of lifetime exposure was categorized., Results: The MRI scans of 27/71 CSE patients (38%) were classified as abnormal. Brain atrophy in any brain area was found in 17/71 CSE patients (24%). Abnormal white matter hyperintensities (WMH) were found in 20/71 CSE patients (28%). Cerebral and cerebellar brain atrophy was associated with the duration of exposure in years, and vermian atrophy was associated with alcohol consumption. Periventricular and brainstem WMH were related to age., Conclusions: Slight brain atrophy is associated with CSE and there is a correlation between brain atrophy and the duration of exposure in years. However, all the MRI findings in CSE are non-specific and thus MRI is useful mainly in the differential diagnosis of CSE.

Background: White matter lesions (WMLs) are frequent in elderly people, and have been associated with impaired activities of daily living (ADL) and cognitive decline. We sought to examine the role of WMLs and their extent, in regard to basic ADL, instrumental ADL (IADL), and cognitive functions, in a large well-defined cohort examined 3 months after an ischemic stroke., Methods: The study group included 395 of 486 consecutive patients aged 55 to 85 years who, 3 months after an ischemic stroke, completed a neuropsychological test battery and magnetic resonance imaging, and structured medical, neurological, and laboratory evaluations; assessment included an interview with a knowledgeable informant., Results: The patients with the most severe WMLs (n = 213) were older, in comparison with those with moderate (n = 71) or mild/no (n = 111) WMLs. These patients also more often had Diagnostic and Statistical Manual of Mental Disorders, Third Edition dementia; had a lower Mini Mental Status score; were more often women; more often had impaired immediate and delayed memory performance, executive dysfunction, and impaired basic ADL and IADL functions; and had more infarcts and cortical or central atrophy in magnetic resonance imaging. However, there were no significant differences among the 3 groups in stroke severity measured on the Scandinavian Stroke Scale, in stroke-related depression as measured by the Beck Depression Inventory, or in stroke type. According to multiple logistic regression analysis, higher age (odds ratio 1.067, 95% confidence interval 1.036-1.01) and impaired IADL (odds ratio 0.852, 95% confidence interval 0.778-0.931) significantly correlated with severe WMLs., Conclusions: Although the degree of WMLs was not associated with stroke severity, it was associated with global cognitive function, impaired memory functions, executive dysfunction, sex, and impaired basic ADL. Age and IADL functions were independent correlates of severe WMLs.

The anatomic location of a glioma influences prognosis and treatment options. The aim of our study was to describe the distribution of gliomas in different anatomic areas of the brain. A representative population-based sample of 331 adults with glioma was used for preliminary analyses. The anatomic locations for 89 patients from a single center were analyzed in more detail from radiologic imaging and recorded on a three-dimensional 1 x 1 x 1-cm grid. The age-standardized incidence rate of gliomas was 4.7 per 100,000 person-years. The most frequent subtypes were glioblastoma (47%) and grade II-III astrocytoma (23%), followed by oligodendroglioma and mixed glioma. The gliomas were located in the frontal lobe in 40% of the cases, temporal in 29%, parietal in 14%, and occipital lobe in 3%, with 14% in the deeper structures. The difference in distribution between lobes remained after adjustment for their tissue volume: the tumor:volume ratio was 4.5 for frontal, 4.8 for temporal, and 2.3 for parietal relative to the occipital lobe. The area with the densest occurrence was the anterior subcortical brain. Statistically significant spatial clustering was found in the three-dimensional analysis. No differences in location were found among glioblastoma, diffuse astrocytoma, and oligodendroglioma. Our results demonstrate considerable heterogeneity in the anatomic distribution of gliomas within the brain.

Objective: It has been suggested that executive dysfunction could be the core defect in patients with geriatric or vascular depression, and that this depression-dysexecutive syndrome (DES) might be related to frontal-subcortical circuit dysfunction. The authors tested this hypothesis in 158 poststroke patients, of whom 21 had both depression and executive dysfunction., Methods: In this cross-sectional cohort study, a neurological, psychiatric, and neuropsychological examination was carried out 3 months after ischemic stroke, and brain infarcts, white-matter changes, and brain atrophy were recorded by MRI., Results: The 21 patients with DES had significantly more brain infarcts affecting their frontal-subcortical circuit structures than the 137 patients without DES, or the 41 patients with depression but without executive dysfunction. Patients with DES also had more severe depressive symptoms and worse psychosocial functioning, and they coped less well in complex activities of daily living., Conclusions: DES is a valid concept and may define a subgroup of poststroke patients with frontal-subcortical pathology and with distinct prognosis and treatment options.

Background and Purpose: Vascular cognitive impairment and vascular dementia are now seen to extend much beyond the traditional multi-infarct dementia.A more homogeneous subtype is the subcortical ischemic vascular disease (SIVD). We applied magnetic resonance imaging (MRI) criteria based on research criteria for SIVD in a large cohort of patients with ischemic stroke. We compared clinical features of patients with SIVD and patients with other stroke type., Subject and Methods: The study group comprised 337 of 486 consecutive patients aged 55 to 85 years who 3 months after ischemic stroke completed a comprehensive neuropsychological test battery and MRI, including structured medical, neurologic, and laboratory evaluations; clinical mental status examination; interview of a knowledgeable informant; detailed history of risk factors; and evaluation of stroke type, localization, and syndrome., Results: Patients with SIVD (n = 86) more often had a history of progressive cognitive decline (22.8% vs. 6.9%, P = 0.0002), walking disorder before stroke (27.9% vs. 2.0%, P = 0.02), and urinary difficulties (12.8% vs. 5.6%, P = 0.028) in comparison with patients with other stroke type (n = 251). Of the study population, 107 (31.8%) had DSM-III dementia. The patients with SIVD more often had DSM-III dementia (40.7% vs. 28.7%, P = 0.04), had less severe stroke as measured by Scandinavian Stroke Scale (56.6 vs. 55.1, P = 0.03), were more dependent in activities of daily living (ADL) functions as measured by FAQ scale (8.9 vs. 5.4, P = 0.001), were more dependent in instrumental activities of daily living (IADL) functions as measured by the Lawton scale (5.5 vs. 6.3, P = 0.01), and were more depressed as measured by the Beck Depression Inventory (11.8 vs. 8.4, P = 0.0003) poststroke than the patients without SIVD. The main cognitive domain that differentiated the patients with SIVD from those without was executive dysfunction (51.2% vs. 38.7%, P = 0.04). According to multiple regression model, apractic-atactic gait disorder (odds ratio 2.82, 95% confidence interval 1.21-6.53), ADL functions (odds ratio 1.04, 95% confidence interval 1.01-1.08), and the Beck Depression Inventory (odds ratio 1.05, 95% confidence interval 1.02-1.09) related to SIVD., Conclusions: The most significant clinical features of MRI-defined SIVD were found to be apractic-atactic gait, impaired ADL functions, and depression.

Background: Depression affects up to 40% of patients with ischemic stroke. The relationship between site and size of brain infarcts and poststroke depression is still not well characterized. Further possible contribution and interaction of white matter lesions and brain atrophy has not been studied previously. We conducted a magnetic resonance image-based study of the radiologic correlates of depression in a large, well-defined series of patients with ischemic stroke., Methods: Modified DSM-III-R and DSM-IV criteria were used to diagnose depressive disorders during a comprehensive psychiatric evaluation in 275 of 486 consecutive patients aged 55 to 85 years 3 to 4 months after ischemic stroke. A standardized magnetic resonance imaging protocol detailed side, site, type, and extent of brain infarcts and extent of white matter lesions and brain atrophy., Results: Depressive disorders were diagnosed in 109 patients (40%). Patients with depression had a higher number and larger volume of infarcts affecting the prefrontosubcortical circuits, especially the caudate, pallidum, and genu of internal capsule, with left-sided predominance. Extent of white matter lesions and atrophy did not differ in patients with and without depression. Independent correlates of poststroke depression in a logistic regression model were mean frequency of infarcts in the genu of internal capsule on the left side (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.0-10.1), mean frequency of infarcts in the pallidum of any side (OR, 1.6; 95% CI, 1.1-2.3), and mean volume of infarcts in the right occipital lobe (OR, 0.98; 95% CI, 0.96-0.99)., Conclusion: Lesions affecting the prefrontosubcortical circuits, especially on the left side, are correlates of depression after ischemic stroke.

Background: Cerebrovascular disease is a major factor related to cognitive impairment. However, behavioral correlates of ischemic brain lesions are insufficiently characterized., Objective: To examine magnetic resonance imaging correlates of dementia in a large, well-defined series of patients with ischemic stroke., Methods: Detailed medical, neurological, and neuropsychological examinations were conducted 3 months after ischemic stroke for 337 of 486 consecutive patients aged 55 to 85 years. Infarcts (type, site, side, number, and volume), extent of white matter lesions (WMLs), and degree of atrophy were categorized according to magnetic resonance images of the head. The definition for dementia of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) was used., Results: Dementia was diagnosed in 107 (31.8%) of the patients and stroke-related dementia in 87 (25.8%). Volumes, numbers, distinct sites of infarcts, extent of WMLs, and degree of atrophy were different for the demented and nondemented subjects. Particularly, volumes of infarcts in any (right- or left-sided) superior middle cerebral artery territory (27.3 vs 13.7 cm(3), P =. 002) and left thalamocortical connection (14.8 vs 4.0 cm(3), P =. 002) differentiated the 2 groups. Logistic regression analysis showed that the correlates of any dementia included the combination of infarct features (volume of infarcts in any superior middle cerebral artery: odds ratio [OR], 1.11; frequency of left-sided infarcts: OR, 1.21), extent of WMLs (OR, 1.3), medial temporal lobe atrophy (OR, 2.1), and host factors (education; OR, 0.91). In the patients with stroke-related dementia, the main correlate was volume of infarcts in the left anterior corona radiata (OR, 1.68)., Conclusion: Correlates of poststroke dementia do not include merely 1 feature but a combination of infarct features, extent of WMLs, medial temporal lobe atrophy, and host features.

Impairments in executive functions have been related to aging and frontal lobe lesions. Aging also causes slowing of mental processing. We examined whether ischemic stroke in the frontal brain area results in dysexecutive syndrome, or whether the frontal stroke causes increased slowing of mental processing. Neurological, radiological and neuropsychological examinations were carried out 3 months post-stroke on 250 ischemic stroke patients (55-85 years) and on 39 healthy control subjects. Of the patients, 62 had frontal and 188 had nonfrontal lesions. The neuropsychological examination comprised several cognitive domains, including tests considered to measure executive functions. The frontal group was slower than the nonfrontal group in tasks measuring speed of mental processing which were time-limited (Trail Making A, Stroop dots and fluency). They were also inferior in the Digit Span backwards task. There were no differences between the groups in other cognitive domains, nor in some tests which are considered to be measures of executive functions (e.g. WCST). Impairments in executive functions were evident in both the frontal and the nonfrontal groups compared with the controls, but no dysexecutive syndrome specifically related to frontal lesions was found. Frontal stroke related mainly to the slowing of mental processing., (Copyright 1999 Lippincott Williams & Wilkins)

Since the recognition of white matter changes on CT (leukoaraiosis), rating scales for the location and severity of white matter changes have been developed, mainly for research purposes, to investigate factors such as the relation with cognition, risk factors, and pathology. The main purpose of rating scales is to provide scores that can be used in statistical analyses. The development of the NINDS-AIREN criteria for vascular dementia have introduced a new application for these rating scales in investigating and delineating the amount of white matter changes on CT/MRI sufficient to fulfill the criteria. Furthermore, in Alzheimer's disease, recognition of white matter changes may serve to delineate homogeneous groups and help to identify patients with different symptomatology. We reviewed the existing rating scales for CT and MRI and judged their properties and reliability. The ideal rating scale does not yet exist, but different rating scales may serve different purposes, for which some recommendations are made.

The pharmacokinetics of dihydroergotamine (DHE) was studied in healthy volunteers (n = 6) and in neurological patients (n = 12). After a single 1.0 mg intravenous injection (n = 5) DHE quickly disappeared (T 1/2 beta = 32.9 min, Vdss = 0.33 liter/kg, Cltot = 1055.7 ml/min). In saliva (dose 1.0 mg, n =6) and cerebrospinal fluid (dose 0.5 mg, n =12) there were no measurable amounts of DHE after a single i.v. dose. The 32-h cumulative urinary excretion was 0.02-0.04% of the 1.0 mg intravenous dose. In one subject renal (0.18 ml/min) and extrarenal (692.9 ml/min) clearance of DHE was calculated. According to our results DHe is probably eliminated mainly by hepatic metabolism. The pharmacokinetic properties of DHE indicate a fast clinical response without a cumulative action.

There were no significant differeneces in the radioimmunologically determined plasma concentrations of methylergometrine, nor in its 32-hour cumulative urinary excretion after a sinlge 0.250-mg p.o. dose of Methergin (Sandoz) or Myomergin (Leiras). Peak plasma concentrations were obtained as early as 0.5 hours after the drug administration. Approximately 3% of the 0.250-mg p.o. dose was excreted in the urine during a period of 32 hours. In two subjects, after a single 0.20-mg i.v. injection, the beta phase half-life in the plasma was 1.9 hours. From the ratio of the area under the plasma curve after p.o. and i.v. administration in these two subjects, it was estimated that 64% and 63% of the p.o. dose reached the systemic circulation. No cumulation in the plasma was observed after repeated p.o. doses of 0.125 mg of methylergometrine given thrice daily to the two subjects.

After single 0.5-mg nad 1.0-mg i.v. injections, dihydroergotamine, as measured by a radioimmunoassay, disappeared quickly from the plasma of beagles, with a mean alpha-phase half-life of 1.32--1.91 min. This explains its effect of rapidly lowering the temperature of the ear of the dog. Its short beta-phase half-life (mean, 40.79--70.13 min), a moderately low volume of ditribution at beta-phase (mean 1.50--3.46 L/kg) and a rather high plasma clearance value (mean, 311.67--587.88 ml/min) indicate a rapid elimination of the drug from the organism. The 24-hr urinary excretion of dihydroergotamine was 2.7% of the 0.5-mg i.v. dose and 2.3% to 3.1% of the 1.0-mg i.v. dose. A measure of the amount of a 7.5-mg p.o. dose of the drug reaching the systemic circulation was obtained from the ratio of the area under the plasma curve after p.o. administration to that after i.v. administration, corrected for the different amounts given by the two routes. Only 1.2--1.4% of the 7.5-mg p.o. dose of dihydroergotamine reached the systemic circulation. There were no significant differences in the plasma levels of dihydroergotamine after a single dose of the two preparations tested, Vasogin (Leiras) and Orstanorm (Sandoz), given either by the oral or intravenous route.

Pharmacokinetic studies carried out on methylergometrine (methylergonovine) by a radioimmunoassay are reviewed. After intravenous injection the half-life of the distribution phase was only 1-3 min, explaining the fast and strong oxytocic response in puerperal mothers. The fast tissue uptake was also obtained in the rabbit uterus in situ with a steep dose-response curve. The rate of gastrointestinal absorption appeared to be slower in patients during puerperium (Tmax 3 h) in comparison with healthy male volunteers (Tmax 0.5 h). The bioavailability after administration was about 60%. After intramuscular injection the rate of absorption was rapid (Tmax 0.5 h). The short half-life of the elimination phase (about 0.5-2 h), low apparent volume of distribution (about that of extracellular water of the body), and the relatively high total plasma clearance value (about 120-240 ml/min) were direct evidence of the rapid elimination of the drug from the body. After repeated oral administrations no accumulation was found. Only about 3% of the single oral dose was excreted into urine, indicating hepatic metabolism and elimination. Although methylergometrine had a good penetration into breast milk in dogs, in postpartum women the mild concentrations were hardly measurable and clinically nonsignificant. Apparently there is no correlation between the plasma level and clinical effect of methylergometrine.

A new spectorophotofluorometric method for the determination of sulpiride (S) in the human plasma and urine is described. The plasma concentrations (0--24 hours) and renal excretions (0--48 hours) of sulpiride were measured after Dogmatil forte (Schürholtz), or Sulpiril (Leiras) tablets both containing 200 mg of sulpiride, after two Sulpiril capsules (Leiras) containing 50 mg of sulpiride in each capsule, and after 20 ml Dogmatil saft (Schürholtz) and 20 ml Sulpiril mixt. (Leiras) both containing 5 mg/ml of sulpiride. There were no significant differences in the sulpiride concentrations in plasma or cumulative urinary excretion of sulpiride after Dogmatil forte (200 mg S) or Sulpiril tablet (200 mg S). Two Sulpiril capsules (100 mg S) produced significantly lower plasma concentrations of sulpiride at 3 hours than a Sulpiril tablet (200 mg S) and these were also lower at 4 and 6 hours than with either a Dogmatil forte (200 mg S) or a Sulpiril tablet (200 mg S). Two Sulpiril capsules (100 mg S) gave significantly higher plasma sulpiride concentrations from 1 to 6 hours than 20 ml Sulpiril mixt. (100 mg S) and from 2 to 6 hours higher than 20 ml Dogmatil saft (100 mg S). The plasma half-life of sulpiride measured after two Sulpiril capsules, 20 ml Dogmatil saft and 20 ml Sulpiril mixt., was 9.4 hours, 9.5 hours, and 10.2 hours, respectively. The renal excretion of sulpiride after two Sulpiril capsules (100 mg S) was significantly lower than after a Sulpiril tablet (200 mg S) from 8 to 48 hours, and also significantly lower than after a Dogmatil forte tablet (200 mg S) from 24 to 48 hours. Two Sulpiril capsules (100 mg S) gave significantly higher sulpiride urine concentrations from 8 to 24 hours than 20 ml Sulpiril mixt. (100 mg S) and from 24 to 48 hours than 20 ml Dogmatil saft (100 mg S). There was no significantly differences in this respect between either a Dogmatil forte tablet (200 mg S) and a Sulpiril tablet (200 mg S) or between Dogmatil saft (100 mg S) and Sulpiril mixt. (100 mg S). Comparied with a Dogmatil forte tablet, the bioavailability, calculated by the AUC24 for a Sulpiril tablet was 159%, for a Sulpiril capsule 118%, for Dogmatil saft 77%, and for Sulpiril mixt. 89%. The same values calculated from the sulpiride urine concentrations were 118%, 114%, 71%, and 67%, respectively. There were no significant differences in the blood pressure or heart rate of the volunteers during the experiment. 2 volunteers reported a sedative effect after a Dogmatil forte tablet.

Pharmacokinetics of conventional 80 mg tablets and two types of sustained-release (SR) tablets containing 120 and 200 mg of verapamil were compared cross-over in 12 healthy volunteers. Serum concentrations of verapamil and norverapamil were analyzed both after a single oral dose and at steady state after t.i.d. administration of conventional tablets and b.i.d. administration of SR tablets. After 120 mg SR tablets serum concentrations of verapamil usually remained below 100 ng/ml for 5 days. This inadequate bioavailability was caused by very slow absorption. The relative bioavailability of verapamil in 200 mg SR tablets was 93-96% as compared to the conventional tablets. After 200 mg X 2 and 80 mg X 3, the peak serum levels were about 300 and 190 ng/ml, respectively and the trough levels 123-153 and 52-56 ng/ml, respectively. The verapamil/norverapamil ratio varied from 0.69 to 0.84 after a single dose and from 0.8 to 0.93 at steady-state. By the 4th days of treatment, the accumulation ratios ranged between 1.75-2.07 and 1.30-1.75 for verapamil and norverapamil, respectively. For each preparation studied, the apparent Cltot of verapamil was significantly reduced at steady-state. These results show that 200 mg SR verapamil tablets fulfill the basic requirements of retard preparations allowing for twice or even once daily administration.

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.

The bioavailability and effect on the systolic and diastolic blood pressure, heart rate, salivary flow, skin temperature, and subjective sedation of three brands of clonidine were studied in nine healthy volunteers after a single 300-micrograms oral dose. In the gas chromatographically determined plasma concentrations there was no significant difference, nor was there any difference in the clinical effects studied. Highly significant correlations between the plasma concentrations and drug effects were found.

In order to prevent hypotension, 1.0 mg of dihydroergotamine (Vasogin) was injected intramuscularly to 10 patients 5 minutes before spinal anaesthesia. The peak plasma concentrations were measured by a radioimmunoassay as early as at 30 minutes after drug administration, indicating a fast intramuscular absorption. According to the plasma levels the drug has to be given 15-30 minutes before spinal anaesthia.

Single oral doses of captopril (50 mg) were given in a randomized cross-over study to 10 healthy volunteers after fasting, after a standardized breakfast (440 kcal; 1804 kJ) or with 50 ml of an antacid suspension. Blood and urine samples were analyzed by gas chromatography. The peak captopril concentrations attained were 701 +/- 81 ng/ml (mean +/- s.e.m.) after fasting, 351 +/- 56 ng/ml with an antacid (p less than 0.05) and 140 +/- 14 ng/ml after a meal (p less than 0.01). The peak concentrations were reached in 0.5, 0.9 and 1.5 h (p less than 0.01), and the areas under the blood concentration-time curves were 782 +/- 86, 456 +/- 60 (p less than 0.05) and 344 +/- 47 ng X h/ml (p less than 0.01), respectively. The relative bioavailability of captopril was 0.66 and 0.48 with antacid and after food, respectively. The deleterious effect of food - but not that of antacid - was reflected as a delayed hypotensive activity of captopril.

The usefulness of labetalol, a combined alpha and beta adrenoceptor antagonist, as a moderate hypotensive agent during combination anaesthesia in otological operations was studied. These preliminary results show that an intravenous dose of 2.0 mg/kg of body weight of labetalol causes a moderate decrease in blood pressure without a concomitant increase in heart rate or excessive hypotension. The half-life of the elimination phase of labetalol in plasma varied between 3.9 and 6.3 hours. A direct relationship between the intravenous dose of the drug (0.5, 1.0 and 2.0 mg/kg i.v.) and the increase in the AUC value was observed. No correlation was found between the decrease in either the systolic or diastolic blood pressure and the plasma level of labetalol. This new type of antagonist may possess advantages over other current hypotensive drugs, i.e lack of tachycardia and excessive hypotension.

The concentrations of papaverine in the plasma of healthy volunteers were determined by a GLC-method both after single and repeated oral doses of plain and sustained-release drug formulation. In both experiments the AUC-value after the sustained-release drug form was significantly lower than after the plain papaverine and no maintenance of plasma levels for 12 hours after the sustained-release drug form was observed. Our work demonstrates that the systemic availability or papaverine can be markedly affected by product formulation.

Salbutamol increased significantly the bronchodilating effect of proxyphylline both in experimental animals and in asthmatic patients. In guinea pigs (modified Konzett-Rössler method) the reduction in response to metacholine caused by increasing doses of proxyphylline and salbutamol significantly exceeded that of either drug alone. In a double-blind, randomized cross-over study conducted on 3 consecutive days, asthmatic patients received 500 mg proxyphylline orally three times daily. On the 2nd or 3rd day a significantly greater improvement in the peak expiratory flow was found after the combination of proxyphylline and salbutamol (3 mg p.o.) in comparison with proxyphylline and placebo. Salbutamol had no significant effect on the plasma concentrations of proxyphylline, which varied between 14 and 22 microgram/ml. The combination of oral proxyphylline and salbutamol is clinically useful in increasing drug response without increased adverse effects.

The pharmacokinetics of labetalol, a combined alpha- and beta-receptor blocking agent, were studied in eight healthy volunteers. After intravenous injections (n = 4) of 1.5 mg/kg, the drug was rapidly distributed (mean T 1/2 = 4.9 min) and quite rapidly eliminated (mean T 1/2 = 4.9 hrs). The mean total plasma clearance value was 24.80 ml/min/kg. The values for Vdc (mean 1.1 l/kg) and Vdss (mean 9.41 l/kg) indicate extensive extravascular distribution of labetalol. The systemic availability was about 18%. There was a significant correlation between the calculated drug concentrations in the hypothetical compartment 2 and the percentage decreases in blood pressure after the intravenous injection. After a single 200 mg oral dose (solution, non-coated and coated tablets), the tablet formulation had no significant effect on the gastrointestinal absorption. After repeated oral doses of 200 mg twice daily (n = 4), no accumulation in plasma was observed.

The absorption and fate of vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) was studied using both unlabelled compound (rabbits, rats and dogs) and tritium-labelled compound (rats). Although vadocaine was orally absorbed in dogs, no oral absorption was found in the rabbits. The elimination of the intravenously given compound was very fast (t1/2 only about 0.6 h in the rabbits). Most of the drug was metabolized both in rats and dogs. In rats, less than 0.2% of the compound was found intact in 24-h urine. In dogs, the 24-h recovery was 1-5% of the dose. After intravenous injection to rats, 43% of the radioactivity given as tritium-labelled vadocaine was recovered in urine and 19% in faeces. After oral dosing, 37% was recovered in urine and 31% in faeces. Hence, the total 7-day recovery of the radioactivity given as tritium-labelled vadocaine was 62-68% of the dose.

The concentrations of erythromycin in the serum were comparable after a single 500 mg oral dose of two brands of erythromycin stearate (Resibion and Erythrocin) in six healthy fasting volunteers. There was no significant difference in their pharmacokinetics. Over a period of 24 hours, 4 and 5% of the 500 mg dose of each preparations was excreted in the urine. Analysis of serum erythromycin concentration data were performed according to a one-compartment open model. The short half-life in the serum (1.43-1.78 hours), small portion of the dose excreted in the urine (4-5%), and the low renal clearance value (0.43-0.51 ml/min/kg) indicate that the majority of erythromycin is extensively cleared by extrarenal mechanisms. In addition, serum concentrations of erythromycin were measured during continuous treatment (250 mg base every 6th hour) with erythromycin stearate (Resibion) or enteric-coated erythromycin base (Etromycin) in ten healthy volunteers, in both fasting and non-fasting conditions. Again in the fasting state the serum levels were comparable and those from both the stearate and base were markedly reduced by food.

In a double-blind study, 40 mg of papaverine (Group I) or the same amount of placebo (1.0 ml of physiological saline, Group II)was injected intravenously in 19 patients to study the effect of papaverine on the contractility of the gallbladder in connection with routine oral cholecystography. In both groups a standard contraction meal (200 ml of cream) caused a significant contraction of the gallbladder (at 30 minutes). Thereafter, intravenously administered papaverine significantly inhibited further contraction caused by the fatty meal, but no significant dilatation was observed. This difference between the two groups lasted throughout the whole study period to 60 minutes after the drug administration. This time period mainly consisted of the distributional alpha-phase of the drug concentrations determined by gas chromatography in the serum. Because no dilation effect on the gallbladder was found, the clinical spasmolytic response to papaverine during an acute attack of pain in a patient with gallstones seems to be questionable.

The pharmacokinetics of disopyramide and its metabolite mono-N-dealkyl-disopyramide (MND) were studied after a single oral and intramuscular dose and at steady state in healthy volunteers, after an intravenous dose in post-surgery patients, and after a single oral dose in two patients with renal insufficiency. After an oral dose in healthy volunteers the plasma elimination half-life of total disopyramide was 8.65 +/- 1.37 h, and that of the non protein-bound disopyramide, 4.74 +/- 1.20 h. The protein binding of disopyramide varied from 0.58 to nearly 1.0, and was concentration dependent. All subjects had detectable amounts of MND in plasma. Its elimination half-life was 12.9 +/- 6.43 h. The ratio of MND to disopyramide was 0.23 +/- 0.09 in plasma and 0.46 +/- 0.11 in urine. There was a close correlation (r = 0.868) between the renal clearances of free disopyramide and creatinine. The renal clearances of disopyramide (both free and total), MND, and creatinine varied with time; this resembled variation in the urine flow. The kinetics of one dose at steady state did not differ markedly from that of a single dose. The elimination half-lives of total disopyramide varied from 4.4 to 17.1 in post-surgery patients, and those of the renal patients were 10.6 and 8.7 h.

Methylergometrine concentrations in the maternal plasma and breast milk were determined by a radioimmunoassay during continuous treatment with 0.125 mg of methylergometrine 3 times daily. On the fifth postpartum day at 8:00 a.m. the patients (n=8) took 2 tablets of Myomergin (0.250 mg of methylergometrine) orally, and the levels in the plasma and milk were determined at 1 and 8 hr after the drug administration. Measurable amounts of the drug were found only in 5 out of 16 milk samples. It was concluded that this oxytocic drug does not appear in the breast milk in quantities sufficient to affect the infant. No cumulation in the plasma or in the breast milk was found.

There were no significant differences between the two brands of methylergometrine (methylergonovine), Methergin and Myomergin, in the radioimmunologically measured serum concentrations nor in the AUC after an oral 0.250 mg dose determined on the third or sixth postpartum day during a continuous treatment with methylergometrine 0.125 mg t.i.d., nor were there significant differences in the clinical response to this oxytocic drug. Peak serum concentrations were obtained at 3 hours (Methergin 6.3 nmol/1 and Myomergin 6.0 nmol/1), indicating a delayed gastrointestinal absorption in postpartum females in comparison with healthy male volunteers [6]. Spontaneous complaints of side-effects were rare and mild.