The acute LD50 for 3-O-demethylfortimicin A disulfate (ODMF) in mice and rats were 419 and 778 mg activity/kg (dosages are expressed in terms of antibiotic activity (potency), rather than on a weight basis) for single-dose im administration and, 90 and 96 mg activity/kg for single-dose iv administration, respectively. No drug-related gross or microscopic lesions were found in rabbits given single iv infusions of ODMF at dosages of 10 to 400 mg activity/kg. Minimal to mild muscle irritation was seen in rabbits given im concentrations of 3.8 or 7.5% ODMF at dosages of 48 or 93 mg ODMF activity/kg. In 1-month iv studies in dogs treated with ODMF at dosages of 0.4, 1, 4, or 8 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 1, 3, 6, or 12 mg activity/kg/day, treated animals remained essentially free of adverse effects. In 1-month im studies in dogs treated with ODMF at dosages of 1, 4, 8, or 16 mg activity/kg/day, no renal lesions occurred after an ODMF dosage of 1 mg activity/kg/day. Concurrent im studies in rats treated with ODMF at dosages of 6, 12, 24, or 48 mg activity/kg/day showed that ODMF dosages of 6 and 12 mg activity/kg/day did not produce renal lesions. In 6-month chronic im studies in dogs with ODMF dosages of 0.5, 1, or 4 mg activity/kg/day or gentamicin sulfate (GS) dosages of 2 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 0.5, 2, or 6 mg activity/kg/day or GS dosages of 3 mg activity/kg/day, less severe local irritation and nephrotoxicity occurred after treatments with ODMF than with GS. In both rats and dogs treated by either the iv or the im route of administration, higher concentrations of ODMF and GS were found in the kidneys than in the sera. Mean serum and tissue concentrations of GS were higher than those of ODMF. Local tissue irritation and nephrotoxicity were lower with ODMF than with GS on a milligram activity per kilogram basis.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDerivatives of 4,5,-dihydro-1,3,-dimethyl-1H-pyrazolo[3,4-b][1,4]benzoxazepine with antiinflammatory activityLeo R. Swett, Robert G. Stein, and Eugene T. KimuraCite this: J. Med. Chem. 1972, 15, 1, 42–45Publication Date (Print):January 1, 1972Publication History Published online1 May 2002Published inissue 1 January 1972https://pubs.acs.org/doi/10.1021/jm00271a012https://doi.org/10.1021/jm00271a012research-articleACS PublicationsRequest reuse permissionsArticle Views113Altmetric-Citations10LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

AbstractAus den Salicylaten (I) und dem Dimethyl‐nitro‐chlor‐imidazol (II) entstehen die Kondensate (III), die über Raney‐Nickel reduziert und anschließend zu (IV) cyclisiert werden.

Acute oral toxicity studies were carried out with 16 solvents in newborn rats, in 14-day olds, in young adult and in older adult rats to find the approximate doses inducing the first observable signs of toxic action. These doses were divided by 1000 or 10,000 to arbitrarily select “permissible” solvent residue limits. Eight of the solvents tested (acetone, acetonitrile, benzene, chloroform, cyclohexane, diethyl ether, dimethyl formamide, ethyl alcohol, hexane, isopropyl alcohol, isopropyl ether, methyl alcohol, methylene chloride, methyl ethyl ketone, tetrahydrofuran, and toluene) were significantly more toxic in 14-day-old rats than in young adult rats. Cyclohexane and methyl alcohol were significantly more toxic in older adult than in young adult rats. Newborn rats were uniformly and exceedingly sensitive to these solvents. Special evaluation was given to ethyl alcohol, methyl alcohol, benzene, and chloroform because of currently available documentation for these solvents with respect to their potential for toxicity.

Benzyl alcohol was injected into mice, rats, dogs, and monkeys and compared with ethyl alcohol to delineate its limits of tolerance. Intravenously, 1 ml/kg of 0.9% benzyl alcohol did not affect, in anesthetized and unanesthetized dogs and anesthetized monkeys, the blood pressure, heart rate, respiration, ECG or hematalogic parameters. The lethal iv dose of 0.9% benzyl alcohol in anesthetized, normovolemic dogs was 88–113 ml/kg (0.83–1.06 g/kg). Intracarotid and intrarenal injections of 0.9% benzyl alcohol did not cause any significant effects on ECG, blood pressure, heart rate, respiration or EEG of anesthetized dogs. Rapid iv injections of 0.9% benzyl alcohol were nonlethal in mice at 50 ml/kg (0.48 g/kg). Both 0.9% benzyl and ethyl alcohol could be given, iv, to rats, slowly, with no fatalities at 40 ml/kg. After rapid injection, the LD50 for 0.9% benzyl was 33.4 ml/kg while 37.5 ml/kg of the ethyl alcohol was nonlethal. Volumes of 22.5 ml/kg or less of 0.9% benzyl alcohol were nonlethal in rats. There is a calculated safety factor of 38 following a rapid injection of a 30-ml vial dose of 0.9% benzyl alcohol to a 50-kg adult. Intraarterially, 0.9% benzyl and ethyl alcohol were tolerated by rats at 44.5 ml/kg. Benzyl alcohol (94%) was 23 times more toxic in rats, iv, than ethyl alcohol (95%). Again, the calculated LD50 in mice for benzyl alcohol (94%) was less than 0.5 ml/kg (0.48 g/kg), and that for ethyl alcohol (95%) was 1.9 ml/kg (1.46 g/kg).

SummaryUbiquin (oligo-3-(N-methylmorpholinium)-l,2-propylene oxide chloride) is a stable, water soluble, active heparin antagonist producing prompt neutralization when administered in a 1:1 ratio to rats and dogs. Initial studies indicate that it is devoid of any effect on coagulation per se; nor are there any obvious side effects manifested during the process of neutralization. The acute toxicity is less than that of other compounds in use: toluidine blue, protamine and hexadimethrine.

A relatively large dose of ABBOTT-16612 was tolerated by most species when the compound was given as a single oral dose to mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, swine, rhesus monkeys, African green monkeys, chimpanzees, and quail.

1. Previously reported light scattering molecular weights of hexadimethrine bromide are in error due to the presence of fluorescent material. The true molecular weights are much lower and may in fact be nearly identical for all commercial samples. 2. Fractionation by gel filtration followed by pharmacological and toxicological studies indicate that a polymer of 4 monomer units would be the preferred one for clinical use.

SummaryThe above findings represent studies on the effect of hexadimethrine bromide on intravenous toxicity in mice, on in vitro mast cell disruption, and on antiheparin potency. Polymers of average molecular weight as well as dialysates of several such polymers were used in these studies. Results showed (a) that there is a definite trend for the toxicity of hexadimethrine to increase concomitantly with an increase in average polymer size, (b) that both intravenous toxicity and effects on mast cells are interrelated through the average molecular size of the samples used, and (c) that dialysis can fractionate the average molecular weight polymers into their components of varying toxicity without appreciable loss of antiheparin potency.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and Analgesic Activity of a New Bridged Heterocyclic SystemH. E. Zaugg, R. W. DeNet, and E. T. KimuraCite this: J. Med. Chem. 1962, 5, 3, 430–440Publication Date (Print):May 1, 1962Publication History Published online1 May 2002Published inissue 1 May 1962https://doi.org/10.1021/jm01238a003RIGHTS & PERMISSIONSArticle Views71Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (600 KB) Get e-Alerts

Animals partially depleted of their histamine and serotonin by pretreatment with 48/80 were rendered less sensitive to the toxic effects of hexadimethrine. Conversely, pretreatment of mice with imidazole increased the toxic effects of a subsequent injection of hexadimethrine. These results, coupled to our previous findings (1,2) suggest that some of the responses to hexadimethrine in certain laboratory animals may be mediated via histamine, serotonin and heparin release. It is probable that there are other factors which may be concerned in the over-all toxicologic and pharmacologic picture of this antiheparin agent.