Plasma concentration of α-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester

Summary The plasma concentrations of free -methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following -methyldopa (1 g) orally. Five of these patients subsequently received -methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of -methyldopa intravenously. After oral administration a large amount of total plasma -methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated -methyldopa in plasma (ratio at 4 hours ranged from 3.73 – 0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous -methyldopa than -methyldopate. The plasma concentration of -methyldopa (free and esterified) 60 minutes after i.v. -methyldopate was 1.7±0.3 µg/ml wile at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 µg/ml. Although small amounts of sulphate conjugate were detected after i.v. -methyldopate, insignificant quantities of conjugate were found after i.v. -methyldopa. The average fall in mean arterial pressure was 27 mm Hg following i.v. -methyldopa but only 2.7 mm Hg following -methyldopate. These results suggest that sulphate conjugation of -methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of -methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free -methyldopa have been demonstrated.     

Influence of the decarboxylase inhibitor benserazide on the antihypertensive effect and metabolism of alpha-methyldopa in patients with essential hypertension

Summary In a single-blind study, the dopa-decarboxylase inhibitor benserazide (375 mg/day for 3 days and 750 mg/day for further 3 days) and a placebo were given orally in combination with individually effective doses of alpha-methyldopa (mean 1.5 g/day) to 3 hospitalized patients with essential hypertension. Alpha-methyldopa (-MD) alone lowered blood pressure from 165/107 to 136/93 mm Hg (P<0.05). Benserazide did not alter the hypotensive effect of -MD, although the decarboxylation of -MD was markedly reduced, as shown by the urinary excretion of alpha-methyldopamine (-MDA). During administration of -MD alone, the ratio -MD/-MDA in urine of the 3 patients was 8:1, 7:1 and 22:1, respectively. When benserazide 375 mg/day was added the ratio rose to 31:1, 31:1 and 35:1; the ratio was 37:1, 18:1 and 46:1 at the higher dose of inhibitor. In a double-blind crossover study the effect on blood pressure of 3 weeks of treatment with -MD (mean 1.75 mg/day), benserazide (375 mg/day), placebo and their combinations were compared in 5 hypertensive subjects. Again, benserazide did not influence the antihypertensive action of -MD. To study whether benserazide entered the CNS, a single oral dose of¹⁴C-benserazide of 125 mg was given to 2 patients who were to undergo diagnostic lumbar puncture. Two hours after intake of the labelled drug, when radioactivity in blood had reached a maximum, the concentration of radioactivity in spinal fluid was less than 1% of the plasma level. Thus, the antihypertensive action of -MD was not influenced by oral doses of the decarboxylase inhibitor benserazide. The results suggest that benserazide in doses up to 750 mg/day does not affect central decarboxylation of -MD and that this antihypertensive agent lowers blood pressure by a central action.The study was supported by the Deutsche Forschungsgemeinschaft. Part of the results has been presented at the Spring Meeting 1976 of the Deutsche Pharmakologische Gesellschaft (Planz et al. 1976)     

Pharmacokinetic behaviour of 4‴-methyldigoxin in man

Summary In 10 patients the time course of specific activity in plasma, and the excretion rates in urine and feces after oral and intravenous administration of 12-³H-4-methyldigoxin were studied. The determined biological half life of radioactivity in plasma averaged 43 h and corresponds with the renal excretion velocity (50 h). 32.5 ± 5.0 and 31.5 ± 6.3% of the dose were found in feces and 59.7 ± 1.3 and 52.9 ± 1.8% were excreted in urine within 7 days after intravenous and oral administration, respectively. These results together with the observed plasma concentrations suggest a rapid and almost complete absorption of 4-methyldigoxin.     

Über den nachweis und die bedeutung von α-methylnoradrenalin im harn von hypertonikern bei verabreichung von α-methyldopa

Zusammenfassung An 13 Hypertonikern wurde die Harnausscheidung von -Methyldopa, -Methyldopamin und Katecholammen während einer Dauerbehandlung oder nach einer Einzeldosis von -Methyldopa untersucht. Die im Harn enthaltenen Substanzen werden durch Ionenaustausch- und Papierchromatographie voneinander getrennt und fluorometrisch oder biologisch bestimmt. — Von alien Patienten wurde außer freiem und konjugiertem -Methyldopa und -Methyldopamin auch -Methylnoradrenalin ausgeschieden. Gleichzeitig nahm die Ausscheidung von Noradrenalin gegenüber der Vor-und Nachperiode bei fast allen Patienten ab. Es kann ausgeschlossen werden, daß die bei der Behandlung durch die Nieren ausgeschiedenen Mengen von -Methyldopa, -Methyldopamin oder -Methylnoradrenalin die renale Ausscheidung von Noradrenalin herabsetzten. Die während der Behandlung ausgeschiedene Menge von Noradrenalin, Adrenalin und -Methylnoradrenalin zusammengenommen unterschied sich nicht von der Katecholamin-Ausscheidung vor und nach der Behandlung. — Das biosynthetisch vom Menschen gebildete -Methylnoradrenalin verhielt sich nach dem Ergebnis chemischer und pharmakologischer Tests wie Corbadrin, welches die Erythro-Konfiguration aufweist; -Methylnoradrenalin ließ sich eindeutig von dem Diastereomeren von Corbadrin differenzieren, welches die Threo-Konfiguration besitzt. Im Harn der Patienten konnte -Methyladrenalin nicht nachgewiesen werden. Gegen eine Beteiligung von -Methyladrenalin, welches nach Tierversuchen durch Erregung von adrenergen -Receptoren blutdrucksenkend wirkt, an der hypotensiven Wirkung von -Methyldopa spricht ferner, daß die Blutdruckabnahme nach -Methyldopa durch Propranolol nicht aufgehoben, sondern eher sogar verstärkt wurde. — Die systolische Blutdrucksenkung war sowohl der Abnahme der renalen Ausscheidung von Noradrenalin als auch dem Prozentsatz von -Methylnoradrenalin an der gesamten Katecholamin-Ausscheidung significant korreliert; auch im Zeitverlauf ergab sich bei drei Patienten nach einer Einzeldosis von -Methyldopa eine Korrelation zwischen hypotensivem Effekt einerseits und Abnahme der Noradrenalin- bzw. Zunahme der -Methylnoradrenalin-Ausscheidung andererseits. — Die Ergebnisse machen es wahrscheinlich, daß der früher in Tierversuchen nach Verabreichung von -Methyldopa nachgewiesene teilweise Ersatz des sympathischen Überträgerstoffs Noradrenalin durch -Methylnoradrenalin auch unter therapeutischer Dosierung am Menschen stattfindet. Die Korrelationen von hypotensiven Effekten und Veränderungen im Aminstoffwechsel lassen den SchluB zu, daß -Methyldopa den Blutdruek von Hypertonikern durch Freisetzung von -Methylnoradrenalin als falscher Überträgersubstanz und entsprechende Verminderung der Noradrenalin-Freisetzung aus sympathischen Nervenfasern herabsetzt.

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Detection and significance of -Methylnoradrenaline in the urine of hypertensive patients after administration of -Methyldopa

Summary In 13 hypertensive patients the urinary excretion of -methyldopa, -methyldopamine und catechol amines was analyzed either during continuous administration or after a single dose of -methyldopa. The compounds contained in the urine samples were separated by ion exchange and paper chromatography and determined fluorimetrically and biologically. — All patients excreted both free and conjugated -methyldopa, -methyldopamine, and small amounts of -methylnoradrenaline. Compared with the pre- and postdrug period, in nearly all patients the noradrenaline excretion was decreased while -methyldopa was administered. The experimental data obtained exclude the possibility that the noradrenaline excretion was diminished by the simultaneous excretion of -methylnoradrenaline or of excessive amounts of -methyldopa and -methyldopamine. The combined quantities of noradrenaline, adrenaline and -methylnoradrenaline excreted daily during administration of -methyldopa did not differ significantly from the amount of noradrenaline and adrenaline excreted daily before drug treatment was started and after it was discontinued. —Evidence was obtained that -methylnoradrenaline isolated from urine of patients given -methyldopa behaved chemically and biologically in a way similar to (–)-corbadrine (erythro-configuration) but differed markedly from the diastereomer of corbadrine (threo-configuration). Hence, biosynthesis of -methylnoradrenaline leads to the levorotatory erythro-isomer. — In animal experiments carried out previously -methyladrenaline was found as another metabolite of -methyldopa which decreased blood pressure by activation of adrenergic -receptors. The patients given -methyldopa did not excrete -methyladrenaline. The method employed was sensitive enough to detect amounts of -methyladrenaline less than 3 per cent of the -methylnoradrenaline present. Furthermore, involvement of a -adrenergic component in the response of the blood pressure to -methyldopa in hypertensive patients was made unlikely by the observation that propranolol did not antagonize but rather enhanced the hypotensive effect of -methyldopa. — There was a significant correlation between the fall of systolic blood pressure and both the decrease in urinary excretion of noradrenaline and the increase in the percentage of -methylnoradrenaline of the total catecholamine output. Likewise, the time course of the depressor response to a single dose of -methyldopa closely corresponded to the decrease in noradrenaline and the increase in -methylnoradrenaline excretion. Conversely, the return of the blood pressure to the initial level was reflected by an increase in noradrenaline and a decrease in -methylnoradrenaline excretion. — In animal experiments it was previously found that administration of -methyldopa caused a partial displacement of noradrenaline by -methylnoradrenaline which subsequently was released by sympathetic nerve stimulation. The present findings demonstrate that -methylnoradrenaline is formed in man as well. It is concluded that -methyldopa lowers the blood pressure of hypertensive patients by the release of -methylnoradrenaline as a false neurotransmitter and the concomitant decrease in noradrenaline liberation from sympathetic nerve fibres.

     

Use of the Peptide Carrier System to Improve the Intestinal Absorption of L-α-Methyldopa: Carrier Kinetics,Intestinal Permeabilities,and In Vitro Hydrolysis of Dipeptidyl Derivatives of L-α-Methyldopa

Intestinal permeabilities of five dipeptidyl derivatives of L--methyldopa (I) were studied by an in situ intestinal perfusion method. The dipeptides displayed a significant increase in their permeabilities compared to L--methyldopa. The increases ranged from 4 to 20 times. These results suggest that the peptide transport system is less structurally specific than the amino acid transport systems and can be used as an absorption pathway for peptide analogues. The kinetic advantage demonstrated by the dipeptide, L--methyldopa-L-phenylalanine, over the amino acid analogue, L--methyldopa, suggests that the peptide carrier would be a possible route for improving the intestinal absorption of pharmacologically active amino acid analogues. Furthermore, the preliminary results of in vitro hydrolysis studies of selected dipeptidyl derivatives indicate that the peptide carrier system could be used as a base for a prodrug strategy.     

Methyldopa produces central inhibition of parasympathetic activity in the cat

Summary -Methyldopa (10–100 mg/kg i.v.) produced a dose-dependent pupillary dilation in anaesthetized cats which was antagonized by subsequent administration of yohimbine hydrochloride (0.5 mg/kg i.v.). The peak effects were observed approximately 2–3h after injection. This -methyldopa-induced mydriasis was present only when the parasympathetic innervation to the iris was intact. Prior treatment with yohimbine (0.5 mg/kg i.v.) 30 min before -methyldopa also antagonized the mydriatic effect, whereas pretreatment with phenoxybenzamine (2.5 mg/kg i.v.) did not. In contrast, phenoxybenzamine, but not yohimbine, effectively antagonized the pupillary dilation produced by adrenaline (0.3–10.0 g/kg i.v.). These results suggest that -methyldopa produces mydriasis in the cat by means of CNS inhibition of tonic outflow from the oculomotor nucleus and that an -adrenergic inhibitory mechanism may be involved. This conclusion is supported further by experiments in which direct measurements of ciliary nerve activity were made.     

The influence of SK & F 64139, a phenylethanolamine-N-methyltransferase inhibitor,on centrally mediated cardiovascular effects of α-methyldopa and clonidine

Summary The inhibitor of phenylethanolamine-N-methyl transferase (PNMT), SK & F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline), when given i.v. (5 mg/kg), did not prevent the decrease of blood pressure induced in conscious spontaneously hypertensive rats (SHR) by -methyldopa (50 mg/kg i.v.). However, i.c.v. administration of SK & F 64139 (5 mg/kg) to conscious SHR reduced both the -methyldopa-and the clonidine-induced hypotension. Bradycardia in response to clonidine was also prevented by i.c.v. SK & F 64139.When the antihypertensive effect of -methyldopa or clonidine was fully established, i.c.v. administration of SK & F 64139 returned blood pressure within a few minutes to the initial value. Similarly, the bradycardia after clonidine was promptly reversed by i.c.v. SK & F 64139.In pithed rats the pressor responses to both methoxamine and clonidine were antagonized by SK & F 64139 suggesting blockade of vascular ₁- and ₂-adrenoceptors by the PNMT inhibitor.Blockade of central -adrenoceptors by SK & F 64139 appears to adequately explain the inhibition of the antihypertensive effects of -methyldopa and clonidine. The present results do not support the claim (Gerkens et al. 1980) that inhibition of the central formation of -methyladrenaline is the mechanism underlying the antagonism of -methyldopa-induced hypotension by SK & F 64139.     

A method of monitoring drugs for adverse reactions I. α-methyldopa and haemolytic anaemia

Summary Existing methods of detecting adverse drug reactions are reviewed and an information system whereby the total number of patients exposed to a drug and the total number of patients developing an adverse reaction can be ascertained is described. Its potential as a monitoring system was tested by investigating, in 204 patients identified as receiving -methyldopa, the known association of haemolytic anaemia with that drug. — Patients remaining on -methyldopa were repeatedly screened and in this series one patient had developed haemolytic anaemia and 10 patients had antibodies to -methyldopa as evidenced by a positive direct antiglobulin test. Follow-up effectively determined the frequency of haemolytic anaemia which appeared to be a relatively small hazard and should not prejudice the use of the drug. This study has highlighted the difficulties in the adequate assessment of hypertension prior to commencing treatment and has shown that drug monitoring for adverse reactions may have an important role in the establishment of criteria for the more effective use of drugs.     

Disposition of quercetin in man after single oral and intravenous doses

Summary The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8±1.2 min for the phase and 2.4±0.2 h for the phase (predominant half life), respectively. Protein binding was >98%. The apparent volume of distribution was small at 0.34±0.03 l/kg. Of the intravenous dose 7.4±1.2% was excreted in urine as a conjugated metabolite, and 0.65±0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53±5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.Supported by grant Gu 86/3 from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Germany (FRG).     

Possible subdivision of postsynaptic α-adrenoceptors mediating pressor responses in the pithed rat

Summary Additional evidence has been obtained indicating a possible subclassification of postsynaptic -adrenoceptors into ₁ and ₂-subtypes. The pressor responses to the -adrenoceptor agonists L-phenylephrine and guanfacine were quantified after i.v. administration to pithed rats. The -sympatholytic drug yohimbine (1 mg/kg) displaced both dose-response curves to the right, but the effect was greatest for guanfacine. After prazosin (0.1 mg/kg) a 53-fold shift to the right was noticed for the dose-response characteristic of L-phenylephrine. Prazosin antagonized the effect of only the higher doses of guanfacine. The findings indicate that L-phenylephrine and prazosin preferentially interact with ₁-adrenoceptors as agonist and antagonist, respectively. Yohimbine proved less selective than prazosin, but preferentially blocks postjunctional ₂-adrenoceptors in the vascular wall. The results obtained with guanfacine may be interpreted to indicate that this drug acts on ₂-adrenoceptors at lower doses and additionally stimulates ₁-adrenoceptors at higher ones. Preliminary findings with corynanthine and rauwolscine support this interpretation.     

DOPA decarboxylase inhibition does not influence the diuretic and natriuretic response to exogenous α-atrial natriuretic peptide in man

Summary The role of dopamine synthesis in the renal actions of human -atrial natriuretic peptide (ANP) was investigated in six dehydrated volunteers using the DOPA decarboxylase inhibitor carbidopa.Each subject received oral placebo or carbidopa (100 mg) followed by an infusion of ANP 10 pmol · kg^–1 · min^–1 for 1 h. The responses to placebo alone and to carbidopa alone were investigated on separate occasions. ANP produced a similar increase in plasma immunoreactive ANP whether placebo or carbidopa pretreatment had been given. Urinary dopamine excretion was increased by ANP. Carbidopa pretreatment substantially attenuated this increase without affecting the natriuretic or water-diuretic response to ANP. Carbidopa also failed to alter the change in filtration fraction produced by ANP.The results suggest that increased synthesis of intrarenal dopamine is not required for the renal effects of ANP in man.     

Pharmacokinetic investigations in man of two acetyl derivatives of 16α-gitoxin

Summary ³H-16-acetyl-16-gitoxin or³H-pentacetyl-16-gitoxin were injected iv or administered po to 15 volunteers and 3 patients. The elimination half-life and excretion in urine within 4 days were estimated as a percentage of the administered radioactivity, and metabolic studies on the fate of the administered glycosides were performed. In volunteers the following results were obtained:³H-16-acetyl-16-gitoxin 1 mg iv.: 50±11 h, 28.3±4.1%;³H-16-acetyl-16-gitoxin 1mg po: 48±8 h, 25.4±2.8%;³H-penta-acetyl-16-gitoxin 2 mg po: 51±12 h, 20.7±3.2%, respectively. In 3 patients with a cannulated bile duct 9.9% (mean) of the administered³H-16-acetyl-16-gitoxin was excreted. By comparison of the radioactivity excreted in urine following the 2 routes of 16-acetate administration, the percentage absorption was calculated to be 88.5%. In serum and urine 16-acetyl-16-gitoxin and 16-gitoxin were found as possible metabolites of both glycosides, in the ratio of 75–85: 15–25, and both metabolites were also found in bile. Within 16 h after penta-acetate administration, two additional metabolites (bis-acetylderivatives of 16-gitoxin) were detected in serum and urine within 16 h after administration of pentaacetate.     

Comparison of the antagonistic activity of tamsulosin and doxazosin at vascular α1-adrenoceptors in humans

₁-Adrenoceptor blockers such as prazosin and doxazosin are used to treat hypertension as well as benign prostatic hyperplasia (BPH), whereas the new _l-adrenoceptor blocker tamsulosin is used only for BPH and does not reduce blood pressure at the doses used to relax prostatic smooth muscle. In contrast to prazosin, tamsulosin has a higher affinity for prostatic than vascular ₁-adrenoceptors in vitro. The functional correlate of this observation in humans is the subject of this study. The ₁-adrenoceptor blockade by oral tamsulosin (0.2 mg), doxazosin (1 mg) or placebo on finger tip vascular and dorsal hand venous ₁-adrenoceptors stimulated by cold treatment (immersion in ice water) and the _l-adrenoceptor agonist phenylephrine, was thus studied in a 3-way crossover study in eight, healthy, male adults. Finger tip vasoconstriction after cold stimulation was assessed by laser Doppler flowmetry. A linear variable differential transformer was used to assess the drug effect on phenylephrine-induced venoconstriction. All study parameters were assessed at around 2 and 3.5 h after oral intake of doxazosin and tamsulosin respectively. The drug plasma levels were not significantly different. No significant differences were found for blood pressure or heart rate in the three treatments in supine and erect position. The reduction in finger tip blood flow after cold stimulation was significantly smaller after doxazosin treatment (P<0.01) than after tamsulosin or placebo, whereas there was no significant difference between tamsulosin and placebo treatments. The infusion rate of phenylephrine producing a half-maximum venoconstriction was significantly larger after doxazosin than after tamsulosin (P<0.05) or placebo (P<0.01), whereas there was again no significant difference between tamsulosin and placebo treatments. The data suggest that, at doses producing equal plasma levels after single oral doses in human subjects, the blocking activity at vascular ₁-adrenoceptors is lower for tamsulosin than for doxazosin.     

On the role of α-methyldopamine in the antihypertensive effect of α-methyldopa

Summary In renal hypertensive rats the cerebral concentration of -methyldopa, -methyldopamine, -methylnoradrenaline, dopamine and noradrenaline as well as the blood-pressure were determined simultaneously. The antihypertensive effect followed a time course identical to that of the increase in the cerebral concentration of -methyldopamine and of the decrease in the concentration of dopamine, whereas lowering of blood pressure on the one hand, and changes in the levels of -methylnoradrenaline and noradrenaline, on the other, were not related to each other. Dose-response relationships showed the same correlations and lack of correlations, respectively.These results suggest that non--hydroxylated catecholamines play a major role in mediating the antihypertensive effect of -methyldopa or, alternatively, that only the newly biosynthesized -methyl-noradrenaline is effective in lowering blood pressure.A preliminary communication has been presented at the Spring Meeting 1973 of the German Pharmacological Society at Mainz (Waldmeier et al., 1973).     

Protein Aggregates Seem to Play a Key Role Among the Parameters Influencing the Antigenicity of Interferon Alpha (IFN-α) in Normal and Transgenic Mice

Purpose. During long-term treatment of various malignant or viral diseases with IFN- up to 20% of patients develop anti-IFN- antibodies for as yet unknown reasons. Methods. To address this issue, a mouse model using Balb/C mice was established and the relevance of several potentially anti-IFN- antibodies inducing factors was studied. Results. The model revealed that both a higher frequency of injections and a higher dosage of IFN- were more immunogenic and that the route of administration affected the antibody response to IFN-. The intrinsic immunostimulatory activity of IFN- itself also enhanced the immune response. IFN- protein aggregates (IFN--IFN- and human serum albumin (HSA)-IFN- aggregates), which were recently identified in all marketed IFN- products, were significantly more immunogenic than IFN- monomers. These aggregates broke the tolerance against human IFN- monomers in human IFN- transgenic mice. Conclusions. Based on these animal studies it is proposed that the immune response to IFN- in humans is most probably elicited by a combination of several factors among which IFN- protein aggregates seem to play a key role.     

Über die Wirkung von α-Methyl-Dopa auf den Brenzcatechinamingehalt von Meerschweinchenorganen

Zusammenfassung 1. Versuche über die Wirkung von -Methyl-Dopa auf den Brenzcatechinamingehalt von Meerschweinchenorganen haben ergeben, daß Noradrenalin im Herzen, sowie Dopamin und Noradrenalin im Gehirn durch äquimolare Mengen von -Methyl-Noradrenalin bzw. -Methyl-Dopamin ersetzt werden.2. Die Adrenalinverarmung der Nebennieren nach Vorbehandlung mit -Methyl-Dopa wird demgegenüber nur zu einem geringen Teil durch die methylierten Brenzcatechinamine -Methyl-Noradrenalin und -Methyl-Dopamin ausgeglichen. Ein weiteres Brenzcatechinamin konnte nicht nachgewiesen werden, so daß -Methyl-Adrenalin wahrscheinlich nicht gebildet wird.3. Im Meerschweinchenherzen gespeichertes -Methyl-Noradrenalin wird durch Reserpin in vivo schlechter freigesetzt als Noradrenalin.4. Das in isolierten Herzgranula (Sediment 100 000·g) gespeicherte -Methyl-Noradrenalin wird durch Segontin bei der Inkubation in vitro ebenfall schlechter freigesetzt als Noradrenalin aus normalen Herzgranula.5. Der Mechanismus der -Methyl-Dopa-Wirkung wird diskutiert.6. Es wird eine fluorimetrische Methode zur Bestimmung von -Methyl-Noradrenalin angegeben.

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Summary 1. The catecholamine content of guinea pig organs after administration of -methyldopa has been determined. The results show that the loss of noradrenaline from heart and that of noradrenaline and dopamine from brain is compensated by a stoichiometric uptake of -methylnoradrenaline and -methyldopamine respectively.2. On the contrary the loss of adrenaline from the suprarenal medulla induced by pretreatment with -methyldopa is not completely restored by the -methylated amines, -methyldopamine and -methylnoradrenaline. -methyladrenaline could not be detected even by paperchromatography.3. The release of the stored -methylnoradrenaline from guinea pig heart by reserpine is very small in comparison with that of noradrenaline.4. Furthermore only small amounts of the stored -methyl-noradrenaline are released from isolated granules of the guinea pig heart after incubation in vitro with segontin. Whereas the same amount of segontin depleted completely the noradrenaline content of the granules isolated from normal hearts.5. The mechanism of action of -methyldopa is discussed.6. A method for the fluorimetric determination of -methylnoradrenaline is described. It is at first separated from -methyldopamine, dopamine and histamine by column chromatography, condensed with o-phthaldialdehyd and the obtained fluorescense is measured by using an Aminco-Bowman spectrophotofluorimeter.

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Mit 6 Textabbildungen

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Herrn Dr. H. Blaschko zum 65. Geburtstag gewidmet.

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Über einen Teil der Ergebnisse wurde auf der Frühjahrstagung der Deutschen Pharmakologischen Ges. in Mainz, April 1964, berichtet. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 247, 297 (1964).

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Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Cardiovascular effects of alpha-adrenergic drugs: Differences between clonidine and guanabenz

Summary Guanabenz induced a pressor effect in pithed rats through postsynaptic ₂-adrenoceptors whereas clonidine activated both vascular ₁ and ₂-adrenoceptors. Previous treatment with prazosin, and ₁-antagonist, or depletion of the noradrenergic stores by reserpine produced supersensitivity to the pressor response to clondine only, probably through postsynaptic ₁-adrenoceptors.The hypotension and bradycardia developed in normotensive rats after intravenous guanabenz administration were abolished by prazosin, whereas the central effects of clonidine were antagonized by both prazosin and yohimbine.Selective destruction of central noradrenergic neurons by [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP 4) or reserpine plus blockade of catecholamine synthesis by -methyl-p-tyrosine abolished the hypotension and bradycardia produced by guanabenz but merely reduced the bradycardia from clonidine.The present results suggest that, in rats, guanabenz is a selective stimulant of central -autoadrenoceptors antagonized by prazosin whereas at a vascular level guanabenz preferentially activates -adrenoceptors antagonized by yohimbine. The differences observed between the mechanisms by which guanabenz and clonidine produce their central cardiovascular responses might be attributed to their acting on different nuclei.     

Elucidation of the structure and receptor binding studies of the major primary,metabolite of dihydroergotamine in man

Summary The plasma concentrations and urinary excretion of dihydroergotamine and its metabolites have been measured after a single oral administration of 3 mg tritium-labelled drug to 6 male volunteers. The plasma level of non-volatile radioactivity declined biphasically with - and -phase half-lives of 2.1 h and 32.3 h, respectively. The peak plasma concentration was reached within 3.2h. Urinary excretion of total non-volatile radioactivity was low, amounting to 1.0% of the dose. The parent drug and four metabolites could be quantitated in urine and plasma samples. Metabolite 4 (8-hydroxy-dihydroergotamine) was isolated from incubates of rat and monkey liver microsomal preparations. In human liver microsomal incubates, metabolite 4 was shown to be the primary metabolite of dihydroergotamine. In receptor binding studies performed with mammalian brain preparations, metabolite 4 had IC₅₀-values at 6 monoaminergic binding sites similar to those of dihydroergotamine. Thus, it appears that the active principle consists at least of dihydroergotamine and its 8-hydroxy derivative. As the concentration of metabolite 4 exceeded 5–7 times that of dihydroergotamine in urine and plasma, the bioavailability of dihydroergotamine should be reevaluated, taking into account the plasma concentrations of the parent drug and of its acitve metabolite, 8-hydroxydihydroergotamine.     

Synthesis and pharmacological study of some alkylamini esters and amides of α,α-diarylaliphatic acids

Conclusions Sixteen alkylamino esters and amides of ,-diphenyl--ethoxyacetic acid and ,-diphenylpropionic acid have been synthesized and investigated pharmacologically. All the compounds prepared possess spasmolytic and cholinolytic properties. Derivatives of ,-diphenyl--ethoxyacetic acid are also characterized by the presence of analgesic and anti-cough action. Loading the alcoholic or acid part of the molecule, or replacement of the ester bond by an amide bond, leads to weakening of activity.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 1, pp. 9–14, January, 1970.     

Plasma protein binding of ritodrine at parturition and in nonpregnant women

Summary The binding of ritodrine HCl in whole plasma from healthy nonpregnant women, parturients and matched umbilical venous plasma and in solutions of HSA and ₁-AGP has been studied by equilibrium dialysis. Binding to plasma from nonpregnant subjects and HSA was independent of ritodrine concentration over a wide range.The free fraction in plasma was high and significantly different between groups of nonpregnant (=0.64), parturient (=0.68) and matched umbilical venous plasma (=0.75). It would seem that variability in transplacental transfer of ritodrine, as a result of plasma binding fluctuations, will be minor.