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SummaryModuretic® has been used for long-term treatment in 47 hypertensive patients, at the daily dose of 1 tablet (50 mg hydrochlorothiazide and 5 mg amiloride) for at least 3 months in all cases, and for more than 1 year in 30 cases. Blood pressure was recorded at monthly or bimonthly intervals following an open trial schedule. After 1, 3, 6 and 12 months of treatment, serum electrolytes, urea, creatinine and uric acid were determinated. The hypotensive effect of Moduretic® was comparable to that obtained with other diuretics, like chlorthalidone 50 or 100 mg per day. No significant variations were observed concerning natraemia and calcaemia. The mean value of kalaemia remained normal in the course of 12 months. As compared with the low values observed in the patients previously treated with chlorthalidone there was a significant and sustained increase of kalaemia. Moderate increases of blood urea, creatinine and uric acid were observed but were of the same magnitude as those noted in the patients previ...

In the presence of both oxidizable substrate and phosphate, low concentrations of sporidesmin produced rapid swelling of mitochondria isolated from guinea-pig liver. There is no requirement for alkali metal ions. Uncoupling agents or respiratory inhibitors inhibited the swelling. Mitochondria that had been swollen in the presence of sporidesmin could be contracted by addition of ATP, magnesium ions and bovine serum albumin. The rate of swelling was dependent on the concentration of both sporidesmin and mitochondrial protein and half-maximum effect was observed at 140 nmoles of sporidesmin per mg of protein. A lag period occurred before the maximal effect of sporidesmin and this period was also dependent on the concentration of both sporidesmin and mitochondrial protein. Sporidesmin decreased the respiratory control index of mitochondria by increasing the rate of state 4 respiration and decreasing that of state 3. As sporidesmin had no effect on the respiration of mitochondrial preparations that had either been treated with Triton X-100 or been subject to sonication, the toxin does not directly inhibit the respiratory chain. It is suggested that sporidesmin produces the effects described above by altering the permeability of the mitochondrial membrane.

The effects of the acute and chronic administration of Org GB 94 on the concentrations of brain monoamines, their precursor amino acids and some of their metabolites have been investigated in rats. Sedation, with slight hypothermia, lasted for approximately 2 h following the acute administration of the drug. This effect was less marked following chronic administration.

SUMMARY 1. The actions and interactions of compounds with phosphodiesterase-in-hibiting activity and of sympathomimetic amines have been studied on contractions of skeletal muscles in chloralose-anaesthetized cats treated with bethanidine and in which the adrenals were excluded from the circulation. 2. Compounds with phosphodiesterase-inhibiting activity, ICI 63,197, ICI 58,301, papaverine, theophylline, and dipyridamole, potentiated isoprenaline in its depressant effect on tension and fusion of incomplete tetanic contractions of the slow-contracting soleus muscle, the order of potency being as listed. ICI 63,197 and theophylline also potentiated adrenaline and salbutamol in depressing contractions. 3. ICI 63,197 potentiated isoprenaline in its enhancing effect on tension and degree of fusion of incomplete tetanic contractions of the fast-contracting tibialis anterior and flexor digitorum longus muscles. 4. The results are compatible with the hypothesis that the effects of sympathomimetic amines on muscle contractility are mediated by cyclic adenosine-3',5'-monophosphate, although this nucleotide and its dibutyryl analogue, injected intra-arterially, were themselves without any consistent effect. 5. High doses of ICI 63,197, ICI 58,301, papaverine and dipyridamole, themselves produced isoprenaline-like effects on the soleus muscle. These effects were partially antagonized by (±)-propranolol, (+)-propranolol, or sotalol. The (+)-isomer of propranolol was only about ten times less potent than racemic propranolol in this respect. This antagonistic action of propranolol and sotalol appeared to be independent of β-adrenoceptor blockade.

Participation of α-adreniceptors in the effects of 5-HT and tryptamine on the isolated rat stomach fundus preparation was investigated. The effects of recognized anti-5-HT agents were also investigated to determine whether or not the same type of receptors was involved in the response of the rat fundus to 5-HT and tryptamine. Methylsergide was shown to be a very active, slowly reversible inhibitor of the 5-HT-induced contrations. The degree of inhibition was dependent on the time of pre-incubation and reached its maximum after approximately 2 hr. The α-adrenolytic agent piperoxan appeared to be a competitive antagonist of 5-HT. Piperoxan was able to prevent or reduce the anti-5-HT activity of mianserin, cyproheptadine and methysergide, indicating a common site of all action. All antagonists affected the 5-HT contractions more than those induced by tryptamine. It is concluded, that the effect of 5-HT on the isolated rat stomach fundus is the result of an interaction of 5-HT with one type of receptor. This receptor probably is the classical D-tryptamine receptor. The response to tryptamine is the result of an interaction by tryptamine with two different types of receptors. One type of receptors is identical to the receptor mediating the response to 5-HT, whilst the other type of receptor is more resistant to inhibition by emthylsergide, piperoxan, cyproheptadine or mianserin, and might be identical with the PRT-receptor, described earlier as being resistant to inhibition by phenoxybenzamine.

The effects of amiloride on flow rate, osmolarity, Na + , K + and Cl − concentrations were studied in the submandibular glands of dogs. The drug was injected in a retrograde fashion into the duct system of the gland, which was subsequently stimulated to secrete with pilocarpine. In concentrations of 10 −4 and 10 −3 M, amiloride increased the Na + concentration but did not significantly alter the K + concentration of saliva. A slight decrease in Cl − concentration was observed at high flow rates after 10 −4 M amiloride, but otherwise the drug did not significantly affect the Cl − concentration of stimulated salivary secretion. The diuretic has a measurable mucosal (luminal) effect on Na + transport in dog submandibular gland, which is similar to that reported in amphibian epithelia. Its lack of effect on K + excretion differs from findings reported in other epithelial structures, where it has a marked K + -sparing effect. The drug increased the salivary osmolarity in a fashion similar to Na + , a finding that suggests a dissociation between Na + and water transport in salivary duct epithelium.

Basic and acidic fractions of the distillate of peated malt were analysed by mass spectrometry combined with gas chromatography. Six pyrazines, two pyrroles, 14 fatty acids, 2-furoic acid, phenylacetic acid, benzoic acid, and cinnamic acid were identified. The major components in basic fraction were 2, 5-dimethylpyrazine and 2-methyl-5-acetylpyrazine. The basic components identified in nonpeated malt were qualitatively similar to those of peated malt. Palmitic, stearic, and oleic acids were predominant in acidic fraction obtained from ether extract of peated malt. Benzoic acid, cinnamic acid, phenylacetic acid, and furoic acid were isolated as minor components.

Naturally occurring hydroxamic acids and hydroxamates are reviewed and classified according to the chemistry of the hydroxamic acid functions. The identity of the Fe(m) trihydroxamate albomycin o2 with antibiotic Ro 5-2667 is established. TABLE OF CONTENTS 1. Monohydroxamic acids 1.1. Linear hydroxamic acids 1.1.1. Primary hydroxamic acids 1.1.2. Secondary hydroxamic acids 1.2. Cyclic hydroxamic acids 1.2.1. Pyrazine-type skeleton

The preliminary results of an open comparative study of the oral antidiabetic glipizide and tolbutamide have shown that in all patients, except for 1 [2] of 16 glipizide cases and ¦2 [1] of 12 tolbutamide cases, an adequate control of the diabetes could be achieved. There were no side effects besides clinical signs of hypoglycaemia in 4 patients on Glipizide.

Twelve newly diagnosed and eleven previously unsuccessfully treated diabetics were included in a strictly controlled cross-over trial comparing the efficacy of glipizide with that of a placebo or the previous orally administered antidiabetic drug. All newly diagnosed diabetics responded to glipizide and in eleven of them (91%), the control of the glycaemia was “excellent” or “good”. In the cases with severe diabetes, glipizide achieved on an average a better control of the glycaemia due to meals than that produced by the previous therapy. — Neither hypoglycaemia nor side-effects have been observed. We therefore conclude that glipizide is an effective and safe high potency oral sulphonylurea.

1H-Imidazo(4,5-b)pyrazin (I) wird durch Behandlung mit 30%igem Wasserstoffperoxid in Eisessig in ein Gemisch aus dem 1H-Imidazo(4,5-b)pyrazin- 4(7)-oxid (II) und′ dem Di-N-oxid (III) ubergefuhrt.

(1) Short term studies in five subjects show that amiloride is a potassiumsparing natriuretic agent alone and with thiazide diuretic and ethacrynic acid even when the dose is 5 mg. (2) There was no loss of potassium-sparing effect in four patients receiving the drug continuously for a period of fifteen months or more. (3) Hyperkalaemia did not occur but this is a potential hazard and so regular estimation of the serum potassium is necessary, though this does not give accurate information of the total body potassium. Also, potassium supplements should not be used with amiloride. (4) No serious side effects or toxic reactions were found in this study or by other workers. (5) Amiloride is unlikely to prevent diuretic-induced hyperuricaemia.

Studies have been made on the inhibition of sodium transport, as measured by the short circiut current, by amiloride on toad colon. The dose-response curves have been treated theoretically assuming that sodium gains access to the transport mechanism by three different types of channel which differ in their sensitivity to amiloride. The results are compared to those for other epithelia.

A study has been made of the effect of some diuretics on the electrogenic component of the sodium pump in non-myelinated fibres of the desheated rabbit vagus nerve. It was found that mercurials inhibit this sodium pump; however, it seems unlikely that this action can account for their diuretic action. Ehtacrynic acid and amiloride increased the sodium permeability of the nerve fibre membrane; the importance of this permeability change with respect to the diuretic action is discussed. Chlorothiazide and triamterene appeared to be ineffective on the nerve fibre membrane.

Rats treated thrice daily with maximally natriuretic doses of amiloride or of frusemide showed a markedly diminished natriuretic response (adapted) by the third day and complete adaptation to hydrochlorothiazide by the fifth day of treatment. Normal rats supplied with 0.7 % NaCI as drinking fluid and adrenalectomized rats maintained by either a high salt intake or by injections of doca could not adapt to the natriuretic effects of hydrochlorothiazide. There was no adaptation to the effects of these diuretics on K+ excretion. Treatment of rats for eight successive days with amiloride, frusemide or hydrochlorothiazide caused significant elevation of the juxtaglomerular index and hyperactivity in the zona glomerulosa of the adrenal. Treatment for eight days with spironolactone did not produce these changes. The in vitro production of aldosterone was significantly increased in glands taken from animals pretreated for eight days with hydrochlorothiazide: spironolactone did not influence this synthesis. Plasma concentrations of corticosterone were unaffected by eight days of exposure to hydrochlorothiazide, were raised by this exposure to frusemide and were lowered by amiloride. It is considered that the reninangiotensin-aldosterone system plays a rôle in adaptation, over days, to the natriuretic effects of sulphonamide and probably other natriuretic diuretics, in the rat.