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PubMed1978

The influence of increasing albumin concentrations on the determination of the binding of sulfamethoxy-pyridazine to human and bovine serum albumin.

The binding of sulfamethoxypyridazine to human and bovine serum albumin was determined at eight constant molar drug/albumin ratios for seven different albumin concentrations ranging from 0.1% to 1.5%. The serum albumin concentration affects the determination of the albumin binding of the drug in two different ways. 1. The relative affinity of the albumins for the drug increases with increasing albumin concentrations, while the numbers of binding sites remain constant. 2. The association constants taken from Scatchard plots decrease with increasing albumin concentrations. It is concluded that a direct comparison of binding constants obtained with different albumin concentrations, as widely done, can lead to misinterpretations and should be avoided.

Animals↗
PubMed1977

Cephalosporins. I. Cephaloglycin analogs with six-membered heterocycles in the C-3 side chain.

Cephaloglycin analogs with six-membered heterocycles in the C-3 side chain have been prepared by nucleophilic substitution of 7-aminocephalosporanic acid with appropriate azine thiols followed by 7-N-acylation with phenylglycine by the mixed anhydride method. Seventeen thiols of non-substituted or substituted pyridines, pyridazines, pyrimidines, pyrazines and triazines were used as the S-nucleophiles. In general, pyridazine thiols gave cephalosporins processing good antimicrobial activity against both gram-positive and gram-negative bacteria. Among them 6-hydroxypyridazine-3-thiol gave the most active compound of this series, BB-S 118 (1f), which was significantly more active than cephalexin and cephaloglycin in vitro against gram-positive and gram negative bacteria.

Animals↗
PubMed1976

Synthesis and properties of mesoionic pyrimido[1,2-b-a1pyridazine-2,4-diones and mesoionic pyridazino[2,3-a-a1-s-trizine-2,4-diones: mesoionic analogs structurally related to fervenulin.

Derivatives of two new and unusual classes of heterocycles, possessing structural similarities to the broad spectrum antibiotic fervenulin, were synthesized and examined for in vitro antimicrobial activity. Only three of 17 mesoionic pyrimido[1,2-b]pyridazine-2,4-diones exhibited evidence of antimicrobial activity while seven of eight mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones were active against one or more microorganisms. Susceptibility toward attack by nucleophiles of both mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones and fervenulin was observed.

Animals↗
PubMed1979

Inhibition by digoxin and SC4453 of (Na+ + K+)-ATPase prepared from human heart, guinea-pig heart and guinea-pig brain.

SC4453 is a digoxin analogue with a pyridazine instead of a lactone ring on C17 beta. SC4453 was compared with digoxin with respect to inhibition of (Na+ + K+)-ATPase prepared from human heart, guinea-pig heart and guinea-pig brain. SC4453 was slightly less potent than digoxin but showed a similar sensitivity to K+. As for cardenolides, species differences in sensitivity to SC4453 were accounted for by differences in the rate of dissociation from the receptors. These observations confirm that the human heart is one of the tissues most sensitive to cardiac glycosides.

Animals↗
PubMed1976

Systemic and coronary haemodynamic effects of the new hypotensive drug L 6150.

The acute systemic and coronary haemodynamic effects of a new hypotensive drug L 6150 (3-hydrazino-6-[N,N-bis(2-hydroxyethyl)amino]pyridazine) have been studied in six patients with renal or essential hypertension. The drug, administered intravenously at a dose of 2-9 mg, caused a marked hypotension and increase of cardiac output in five cases. Though left ventricular work was reduced or unchanged after the drug, myocardial blood flow increased markedly, coronary resistance decreased and coronary A-V oxygen difference decreased by about 50% indicating coronary vasodilation. When compared with the available data on the effects of hydrazinophthalazine, L 6150 appeared to have qualitatively similar effects, but a somewhat greater direct coronary vasodilator effect.

Aged↗
PubMed1979

Long-term study of oxdralazine in hypertensive patients.

56 moderate and severe hypertensive patients entered an open long-term trial aimed at evaluating the efficacy and tolerability of a combined treatment consisting of 3-hydrazino-6-[N,N-bis-(2-hydroxyethyl)amino]pyridazine (oxdralazine, L 6150), propranolol and chlorthalidone. The mean basal blood pressure was 186.9/111.8 mmHg: after one month of treatment, the mean value was 149.7/95.5 mmHg (p less than 0.01). The heart rate was practically unaffected by treatment, the mean value changing from 75.4 b.p.m. (basal) to 73.3 b.p.m. (one month). The significant reduction in the blood pressure observed at the end of the first month remained unchanged in the following months of therapy, and only minor variations occurred. The combined treatment was well tolerated. Five patients were withdrawn from the trial during the first month; three of them because of side-effects and two of them for personal reasons.

Antihypertensive Agents↗
PubMed1979

[Bicyclic 3-hydrazinopyridazines with antihypertensive action (author's transl)].

The synthesis of a series of 3-hydrazinopyridazines is described. Several of these compounds exhibited high antihypertensive activity in the rat. The most potent member of the series is l-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido-[4,3-c]pyridazine, compound 28 [1], which is now under clinical trial [2] under the clinical code number BQ 22-708 (endrazaline, Miretilan). It was possible to discover certain structure-activity relationships.

Animals↗
PubMedDate not supplied

[Effects of the organophosphorus insecticide Ofunack on the metabolism of cells cultured in vitro].

The effects of "ofunack (0,0-diethyl-0-(3-oxo-2-phenyl-2H-pyridazine-6-y1) phosphorothionate on the metabolism of IB-RS-2 cell line were studied. "Ofunack" stimulates cell growth and protein synthesis till 24 hours after its addition to the maintenance medium. Otherwise after this time "ofunack" induces an inhibition both on cell growth and on protein synthesis. This insecticide also inhibits the synthesis of RNA and DNA.

Animals↗
PubMed1977

Cephalosporins. II. 7-(O-Aminomethyl-phnylacetamido) cephalosporanic acids with six membered heterocycles in the C-3 side chain.

7-(o-Aminomethylphenylacetamido)cephalosporanic acids with six-membered heterocycles in the C-3 side chain were prepared by nucleophillic substitution of 7-ACA at the C-3 acetoxy group followed by N-acylation of the 7-amino group. The 7-side chain acid, o-aminomethylphenylacetic acid (5), was prepared by two new convenient routes, which involved Schmidt reaction of indanone (2) followed by cleavage of the lactam ring or reduction of o-cyanophenylacetic acid (10) starting from o-nitrotoluene. The antibacterial activity of the cephalosporins in this series depends on the heterocycle in the C-3 side chain. In general pyridazines gave cephalosporin derivatives possessing better activity than those with a pyridine or pyrimidine ring. The most active member of the new cephalosporins was 7-(o-aminomethylphenylacetamido)-3-(6-hydroxypyridazin-3-ylthilmethyl)-3-cephem-4-carboxylic acid (BB-S 150) (1g) which has in vitro antibacterial activity superior to cephalothin and cefazolin against both gram-negative and gram-positive organisms. The in vitro activity of BB-S 150 determined in mice was superior to cephalothin and comparable to cefazolin.

Animals↗
PubMed1977

Cephalosporins. III. 7-(O-Aminomethylphenylacetamido)cephalosporanic acids with bicyclic heteroaromatics in the C-3 side chain.

Bicyclic heteroaromatic thiols with a bridge-head nitrogen atom were used for nucleophilic substitution of 7-ACA at the C-3 acetoxy function followed by N-acylation of the 7-amino group with o-aminomethylphenylacetic acid to afford a series of new cephalosporins (24) with potent antibacterial activity against gram-positive and gram-negative organisms. The most active member of this series was 7-(o-aminomethylphenylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acid (BB-S 226) (24e) with antibacterial activity superior activity superior to cephalothin and cefazolin.

Bacteria↗
PubMed1975

Chloroquine-resistant malaria in Burma.

Two field trials to detect chloroquine-resistant malaria were conducted according to WHO recommendations in a malaria free area near Rangoon. Peripheral blood smears were examined for asexual forms of P. falciparum on day one through to day seven, on day 14, 21, and 28 after a standard dose of 1500 mg. of chloroquine base. Haskins test to detect chloroquine in urine was done on all cases and plasma chloroquine levels were measured in some. Out of 105 patients tested RI resistance was detected in 66, RII in 19 and RIII in three. Subsequent trials with other anti-malarial drugs indicated that the chloroquine-resistant P. falciparum were also resistant to one day therapy with pyrimethamine 50 mg. or sulphamethoxypyridazine 1 G given singly; and resistant to one day therapy with combinations of pyrimethamine 50 mg. plus sulphamethoxy pyridazine 1 G, pyrimethamine 13 mg. plus dapsone 100 mg., and trimethoprim 320 mg. plus sulphamethoxazole 1600 mg. All those tested were sensitive to quinine sulphate, 0-6 G given three times a day for 10 days, and were also sensitive to one day therapy with combinations of trimethoprim 500 mg. plus sulphalene 1 G, and pyrimethamine 50 mg. plus sulphamethoxine 1 G. Pyrimethamine 12-5 mg. plus dapsone 100 mg. in weekly doses was shown to be an effective chemoprophylaxis. Quinine was tested on 38 subjects while other drug schedule were tested on six to eight subjects.

Chloroquine↗
PubMed1976

Different inhibitory effects of 2,4-dinitrophenol, iodoacetate, and probenecid on renal excretion of p-aminohippurate, cyclopenthiazide, and sulfamethoxypyridazine in rats.

The present study was undertaken to determine whether the renal excretion of drugs can be modified by inhibition of the carrier system for organic acids in vivo. The renal excretion of p-aminohippurate is not influenced by 2,4-dinitrophenol but is reduced by iodoacetate and probenecid. The renal excretion of cyclopenthiazide is decreased by all inhibitors. Rats excrete only a very small portion of the administered dose of sulfamethoxypyridazine. Renal sulfamethoxypyridazine excretion is 3 times higher when the tubular reabsorption is blocked by simultaneous administration of NaHCO3. However, even then only a small portion of the injected dose is excreted. Renal sulfamethoxypyridazine excretion is only reduced by probenecid. This finding can be explained by the reduction of the urine volume. It can be concluded that p-aminohippurate and cyclopenthiazide are renally excreted by tubular secretion, whereas sulfamethoxy-pyridazine is excreted by glomerular filtration.

Aminohippuric Acids↗