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Tasks concerning environmental medicine are a significant aspect of the expert work done by the medical review board of the social health insurance fund. Thus far there are no commonly accepted theories and/or criteria with regard to the cause of environmental incompatibilities, nor are there generally accepted criteria/standards for clinical diagnostic procedures and therapy. Problems arise from the fact that the field of environmental medicine not only offers scientifically accepted and verified diagnostic and therapeutic methods, but also numerous unconventional procedures without verified validity. The decision of the scientific expert has to be based on the legal principles of social legislation and jurisdiction. His/her opinion must be competent, objective and independent. Further research is urgently needed to improve the scientific data pool. With it, well-grounded methods and standards can be offered.

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OBJECTIVE: This was a randomised, open, three-way crossover study in 12 healthy male volunteers to determine the effect of a single oral dose of cimetidine on the pharmacokinetics of a single oral dose of the angiotensin II receptor antagonist valsartan and vice versa. The volunteers received either valsartan alone (160 mg), or cimetidine alone (800 mg), or valsartan 1 h after cimetidine. The study was designed primarily to detect a possible influence of cimetidine on the rate and extent of absorption of valsartan. METHODS: Plasma concentrations of valsartan and cimetidine, measured by means of high-performance liquid chromatography, were used to calculate pharmacokinetic parameters. The rate of absorption of valsartan and the fraction of the dose absorbed and systemically available after oral administration were calculated using data from an i.v. study with valsartan in healthy young volunteers. RESULTS: The pharmacokinetics of cimetidine area under curve (AUC0-48 h), maximum concentration (Cmax), time to reach Cmax(tmax) and apparent terminal plasma half-life (t1/2) was not changed by co-administration of valsartan. For valsartan, the AUC0-48 h increased by 7% and the Cmax by 51% (ratio of geometric means) with co-administration of cimetidine. The higher value for Cmax was attributed to the initial increase in the rate of absorption of valsartan: ka was increased 2.7-fold and another indicator for the rate of absorption, Cmax/tmax, 2.2-fold. This effect was ascribed to inhibition of acid secretion by cimetidine, which leads to a higher gastric pH, thereby increasing the solubility of valsartan; the t1/2 of valsartan was not changed. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of the possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inhibit formation of the inactive metabolite of valsartan. Cimetidine-related changes in the rate of elimination of valsartan were not anticipated, since the clearance from plasma occurs mainly by biliary excretion of unchanged valsartan; metabolism and renal excretion are only minor contributors. Therefore, even in the clinically relevant situation with multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in Cmax, are not to be expected. This increase in Cmax appears to be of no clinical significance. Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects.

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OBJECTIVE: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66-92 y) and 12 healthy volunteers (20-35 y). METHODS: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). RESULTS: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 mumol*h.l-1, clearance was reduced (5.0 vs. 11.8 l.h-1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P < 0.0001). CONCLUSION: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.

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The present study compared the extent and duration of MAO inhibition by the selective and reversible MAO-A inhibitor brofaromine with the selective and irreversible MAO-A inhibitor clorgyline using amine pressor tests and excretion of urinary amine metabolites (MHPG, tryptamine). The pharmacological characterization of clorgyline as an irreversible and brofaromine as a reversible MAO-A inhibitor in clinically effective doses was confirmed in humans.

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CGP 28,014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28,014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28,014 reduced plasma and striatal concentrations of 3-O-methyldopa (30MD) in a dose-dependent manner. Acute and subchronic administration of CGP 28,014 alone or in combination with the peripherally acting decarboxylase inhibitor benserazide decreased plasma 30MD as an index of COMT inhibition by about 50%. There seems to be a close relationship between the time-course of plasma concentrations of CGP 28,014 and the extent of COMT inhibition assessed by the 30MD/DOPA ratio in plasma.

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The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (-) oxaprotiline CGP 12,103 A (levoprotiline) and the S (+) oxaprotiline CGP 12,104 A, have been used as tools for a methodological Phase I study. Only the S (+) enantiomer CGP 12,104 A inhibits noradrenaline uptake. Intravenous amine pressor tests and ex vivo measurement of alpha 2-adrenoceptor binding to intact human platelets were compared with respect to their reliability in indicating CGP 12,104 A-induced amine uptake inhibition and possibly associated alpha 2-receptor down-regulation in healthy subjects. alpha 2-Adrenoceptor binding on intact human platelets did not distinguish between CGP 12,104 and CGP 12,103 A. However, amine pressor tests reflected the amine uptake inhibiting effect of CGP 12,104 A as a 5-fold decrease in tyramine pressor sensitivity and a 5-fold increase in noradrenaline pressor sensitivity.

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Traditional monoamine oxidase inhibitors (MAOIs) have long been associated with tyramine-related hypertension--the cheese effect. Despite their undoubted clinical efficacy, this problem has restricted their use. New, selective, and reversible MAO-A inhibitors--which act only on the A isoenzyme--appear not to have this effect. Our investigations of these drugs, exemplified by brofaromine, have shown a reduced and more rapidly reversed tyramine pressor sensitivity. Moreover, we were unable to detect any clinically significant food interaction, following ingestion of a quantity of cheese containing sufficient tyramine to increase systolic blood pressure by at least 30 mm Hg. These results confirm the improved safety of brofaromine, and other drugs in this class, when compared with classic MAOIs.

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The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.

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1. Human calcitonin was administered into the distal colon and by intravenous infusion in eight healthy subjects in an open, fixed sequence, cross-over bioavailability study. 2. Intravenously infused human calcitonin elicited a standard pharmacokinetic profile in eight healthy subjects with a biphasic elimination with half-lives of 10.2 +/- 0.7 min and 37.8 +/- 2.5 min. 3. Colonoscopically administered human calcitonin was absorbed across the distal colonic mucosa in low amounts with a bioavailability of 0.00-0.22%. 4. Absorption from the distal colon was impeded by the presence of faecal material in three of the eight subjects. 5. We conclude that human calcitonin crosses the gastrointestinal epithelium of man. This may demonstrate the feasibility of an oral form for clinical use.

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The pressor effect of intravenous tyramine (TYR) and noradrenaline (NA) has been evaluated, respectively, in 157 tests in 19 healthy unmedicated subjects, and in 202 tests in 24 similar subjects, all of whom took part in greater than or equal to 3 test sessions. The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for TYR, and from 3.5 to 17 micrograms.min-1 for NA. Coefficients of variation ranged from 3 to 47% and from 6 to 38% for TYR and NA, respectively, in the intra-subject comparison. The average inter-subject variation in the TYR PD30 was 22% for 8 females and 30% for 11 males; the corresponding variation in the NA PD30 was 27% (8 females) and 26% (16 males). While the average PD30 for NA was similar for males (10.8 micrograms/min) and females (10.9 micrograms/min), a sex-related difference was found for the PD30 of i.v. TYR: 4.4 mg for 11 males and 3.8 mg for 8 females. Additional results from volunteers who took part in fewer than 3 pressor test sessions supported this observation; PD30 of TYR 4.6 mg in 34 males vs 3.5 mg in 21 females. The large intra- and inter-subject variations in the i.v. TYR and NA pressor test results, and the sex difference in the systolic blood pressure response to i.v. TYR, should be considered in assessing the number and gender of subjects required in studies intended to show "significant" differences in the blood pressure response in amine pressor tests.

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MAO-B activity was compared in healthy volunteers following oral treatment with clinically effective doses of the selective MAO-A inhibitors brofaromine (100 mg q.d. for 14 days), moclobemide (150 mg t.i.d. for 14 days) and clorgyline (5 mg t.i.d. for 10 days). Brofaromine and clorgyline did not alter platelet MAO activity. Following moclobemide treatment, MAO-B activity was reduced by 32% (p less than 0.05). It recovered during the 5 subsequent days after discontinuation of treatment. These results confirm earlier findings. The explanation for this finding may be that metabolites of moclobemide are active inhibitors of MAO-B.

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CGP 28014 A is a specific inhibitor of catechol-O-methyl transferase (COMT). The effect on COMT was assessed with the levodopa test in 5 unmedicated subjects and after pretreatment with 200-600 mg CGP 28014 p.o. Plasma concentrations of DOPA, 3-O-methyldopa (3OMD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were measured. CGP 28014 A decreased 3OMD not dose-related by 67% (p less than 0.05). This, and an increase of DOPAC shows COMT inhibition by this compound in humans.

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The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty-five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase-B (MAO-B) when administered in doses of 20 mg/day and higher.

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The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.

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Healthy ambulatory subjects were treated p.o. for 2 to 4 weeks with 6 different MAO inhibitors (MAOI). MAOI drugs were given to (n) subjects. Brofaromine (Brof): 100-150 mg/d (39); moclobemide (Mocl): 450 mg/d (8); clorgyline (Clor): 5, 10, 15 mg/d (5); selegiline (Sel): 5, 20 mg/d (7); phenelzine (Phen): 30, 45, 60 mg/d (6); tranylcypromine (TCP): 20 mg/d (12). Pressor responsiveness to oral tyramine (TYR) was assessed before, during, and after treatment. In unmedicated subjects (Cont), doses of TYR to raise systolic blood pressure by at least 30 mm Hg (PD30), ranged between 200 and 800 mg. During treatment with MAOIs, the PD30 decreased. The median effective doses (ED 50) of TYR were: Cont (n = 55): 437 mg; Sel, 20 mg/d: 96 mg; Mocl 450 mg/d: 63 mg; Brof: 100-150 mg/d: 44 mg; Phen, 60 mg/d: 33 mg; Clor, 10 mg/d: 43 mg; CP: 8 mg. Pressor responsiveness to oral TYR normalized within 3 d (Mocl), 8 d (Brof), and 30 d (TCP). After Phen, in 2 subjects the potentiation persisted for 2 and 4 weeks, in 4 volunteers for 8 and more weeks. After Clor, only one of 4 subjects reached 83% of his early pressor sensitivity within 15 weeks. The results suggest that the two reversible MAO-A inhibitors Mocl and Brof may lessen the liability to TYR-related hypertensive reactions.

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In a placebo-controlled, randomized, double-blind cross-over study in 12 healthy volunteers the effect of acute alcohol intake during treatment with transdermally administered scopolamine (TTS-scopolamine) was investigated. One group of six subjects reached maximal blood alcohol concentrations (BAC) of 80 mg/dL and another group of six subjects a BAC of 130 mg/dL. There was no significant potentiation of alcohol effects on critical flicker fusion frequency by TTS-scopolamine. Sensorimotor function (choice reaction task) was also not significantly more influence by the combination. There was no effect of scopolamine on the elimination of alcohol. The urinary excretion of scopolamine was not influenced by oral intake of alcohol. TTS-scopolamine caused only minor side effects in a few volunteers, such as dry mouth (2 of 12) and blurred vision (1 of 12).

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The pressor effect of orally administered tyramine (TYR) has been evaluated in 124 tests of 49 healthy unmedicated volunteers, in 99 tests of 29 subjects treated with the reversible selective monoamine oxidase (MAO) A inhibitor brofaromine (BROF), and in 73 tests of 12 subjects treated with tranylcypromine (TCP). In unmedicated subjects, pressor doses of TYR to raise systolic blood pressure (BP) by 30 mm Hg (PD30) ranged between 200 and 800 mg of TYR. There was no correlation of PD30 with sex, age, or weight. In repeated tests, the intraindividual coefficient of variation of the PD30 (+/- SD) was 10 +/- 9%. During treatment for 8 to 16 days with the two MAO inhibitors (MAOIs) BROF and TCP, seven-fold and 56-fold increases of TYR pressor sensitivity were estimated. A significant correlation was found between the individual PD30 before and during MAO inhibition with BROF. Cheese with a pressor content equal to the PD30 of TYR raised the systolic BP in only three of 10 volunteers during BROF inconsistently by not more than 20 mm. Therefore, the probability of "cheese reactions" during treatment with this reversible MAOI seems to be small. For complete normalization of oral pressor responsiveness, delays of 8 and 30 days after the last doses of BROF and TCP, respectively, are needed. The total incidence of systolic BP elevations by more than 60 mm Hg was 13% in a total of 296 oral tests given to 49 subjects. This incidence of easily controllable hypertensive reactions is outweighed by the importance of the test as predictor of clinical risks for drugs with TYR potentiating effects.

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