Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells

The narrow "therapeutic window" of anti-tumour therapy may be the result of drug metabolism leading to the activation or detoxification of antitumour agents. The aim of this work is to examine (i) whether the diminished toxicity of a potent antitumour drug, C-1748, 9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine, compared with its 4-demethyl analogue, C-857, results from the differences between the metabolic pathways for the two compounds and (ii) the impact of reducing and/or hypoxic conditions on studied metabolism. We investigated the metabolites of C-1748 and C-857 formed in rat and human liver microsomes, with human P450 reductase (POR) and in HepG2 cells under normoxia and hypoxia. The elimination rate of C-1748 from POR knockout mice (HRN) was also evaluated. Three products, 1-amino-9-hydroxyethylaminoacridine, 1-aminoacridinone and a compound with an additional 6-membered ring, were identified for C-1748 and C-857 in all studied metabolic systems. The new metabolite was found in HepG2 cells. We showed that metabolic rate and the reactivity of metabolites of C-1748 were considerably lower than those of C-857, in all investigated metabolic models. Compared with metabolism under normoxia, cellular metabolism under hypoxia led to higher levels of 1-aminoacridine and aza-acridine derivatives of both compounds and of the 6-membered ring metabolite of C-1748. In conclusion, the crucial role of hypoxic conditions and the direct involvement of POR in the metabolism of both compounds were demonstrated. Compared with C-857, the low reactivity of C-1748 and the stability of its metabolites are postulated to contribute significantly to the diminished toxicity of this compound observed in animals.     

Screening for antagonistic agents to the lethal toxicity of neocarzinostatin. II. Effects of various drugs in inhibiting the toxicity of neocarzinostatin in vivo

In clinical chemotherapy with neocarzinostatin (NCS) against cancers, side effects such as leukopenia, anorexia, vomiting and nausea were mainly observed when parenteral administration was used. To prevent these adverse side effects without changing the anticancer activity of the drug, we attempted to apply the two-route-infusion chemotherapy using NCS and antidotes for the NCS treatment devised by Baba. This report presents the results of our study on effects of some antidotes on the acute toxicity of NCS in mice and also on the antitumor activity of NCS against Sarcoma-180 in mice (ICR-JCL strain) when used with tiopronin. The results are summarized as follows. 1. LD50 values of NCS administered via intravenous route increased 2.3- to 3.2-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered subcutaneously together with NCS, 1.3- to 1.4-fold when 50 or 100 mg/kg of sodium thioglycolate was used. When antidotes were given prior to the administration of NCS, 1.8- to 5.4-fold increase in LD50 values of NCS resulted with 300, 500 or 1,000 mg/kg of tiopronin administered 1 hour prior to NCS, 2.3-fold increase resulted with 2,000 mg/kg reduced glutathione, 1.2-fold increase with 100 mg/kg of sodium thioglycolate and 1.9-fold increase with 1,000 mg/kg of L-cysteine monohydrochloride monohydrate. Furthermore, 4.8- to 13.1-fold increase in LD50 of NCS occurred when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered 15 minutes prior to NCS. When these antidotes were administered 1 hour after the administration of NCS, however, no changes in the LD50 value occurred. 2. The LD50 value of NCS given intraperitoneally increased 1.6- to 5.8-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered intravenously at the same time as NCS, 1.4- to 1.6-fold when tiopronin was given 1 hour prior to NCS, intraperitoneally and 1.3- to 1.7-fold when it was given 1 hour after NCS. 3. It was recognized that the acute toxicity of NCS was the most effectively reduced by tiopronin, but only slightly by glutathione, sodium thioglycolate or L-cysteine monohydrochloride monohydrate. The action of tiopronin was the most effective when it was given subcutaneously 15 minutes prior to NCS administered intravenously. 4. The combination chemotherapy on Sarcoma-180 in mice using NCS intraperitoneally and tiopronin intravenously was markedly effective when these agents were given simultaneously.     

国产注射用阿莫西林钠舒巴坦钠的急性毒性研究

目的 研究国产注射用阿莫西林钠舒巴坦钠(AMSB)对小鼠的急性毒性。方法 分别用AMSB2500mg／kg、5000mg／kg静脉注射给药和5000mg/kg腹腔注射给药对小鼠进行急性毒性试验,并与进口同种产品阿莫西林钠舒巴坦钠(TFM,商品名泰霸猛)、注射用阿莫西林钠(AM)、注射用舒巴坦钠(SB)进行了急性毒性比较。结果 国产AMSB、进口TFM、AM、SB静脉注射和腹腔注射给药对小鼠的LD50均大于5000mg／kg。结论 国产AMSB毒性很低,且与进口TFM毒性相同。     

Effect of Toxogonin and P2S on the Toxicity of Carbamates and Organophosphorus Compounds

Abstract Toxogonin (80 mg/kg intraperitoneally) given 15 min. prior to the administration of organophosphorus insecticides dimethoate, malathion, parathion and azinphos-methyl, organophosphorus warfare agents soman and tabun, or carbamates physostigmine, pyridostigmine and aldicarb, reduced the toxicity in mice of these agents by increasing their LD50 dose 1.5-3 fold. The toxicity of the carbamate insecticide carbaryl, however, was significantly increased by toxogonin. Similar results were obtained for P2S (150 mg/kg intraperitoneally) with respect to the toxicity of dimethoate, soman and pyridostigmine, whereas no effect could be detected on the toxicity of tabun. Only a slight reduction in the toxicity of physostigmine was observed. The acetylcholinesterase activity in erythrocytes, cerebrum and diaphragm of surviving mice 20 hours after organophosphate intoxication was similar both in toxogonin and P2S treated animals and untreated animals.     

Toxicological and pharmacological effects of D-arginine

D-Arginine is extensively used in studies on L-arginine/nitric oxide pathway as an inactive form of L-arginine, even in man. In addition, it has previously been reported that this D-amino acid appears to have pharmacological activity. The present work aimed at evaluating the toxicity and pharmacology of D-arginine administered by the intraperitoneally route in albino male mice. Toxicity of D-arginine, alone as well as in the presence of propranolol and betamethasone was evaluated. D-Arginine in mice showed a light toxicity order (DL50: 2800 mg/kg). Previous injection of the beta-adrenoceptor blocker, propranolol (2 mg/kg, intraperitoneally), or betamethasone (0.5 mg/kg, intraperitoneally) produced a decrease in the toxicity of D-arginine (LD50: 3600 mg/kg, 3300 mg/kg, respectively). Also, a neuropharmacological screening of D-arginine using behavioural, neurological, autonomic, barbiturate-induced sleep time and pentylenetetrazole-induced convulsions tests were performed. D-Arginine 700 mg/kg displayed central stimulant properties, whereas a depressant profile was observed at a dose of 1400 mg/kg. In addition, D-arginine 1400 mg/kg produced a potentiation of pentobarbital sleeping time and a marked anticonvulsivant action against pentylenetetrazole.     

Interaction of d-pseudoephedrine with water soluble extracts of Platycodi Radix on acute toxicity (author's transl)

Effect of various combinations of Platycodi Radix water soluble extracts (Pla), 1-ephedrine (1-eph), d-pseudoephedrine (d-pseudo) and Ipecacuanhae Radix water soluble extracts (Ipe) on acute toxicity were examined in mice. Oral LD50 of Ipe, d-pseudo and 1-eph was 490 (415--578) mg/kg, 1550 (1360--1767) mg/kg and 1400 (1102--1778) mg/kg, respectively, while that of Pla was over 10 g. LD50 of Pla Ipe, d-pseudo and 1-eph given intraperitoneally was 1400 (1228--1596) mg/kg 235 (210--263) mg/kg, 245 (229--262) mg/kg and 300 (259--348) mg/kg, respectively. The ratio of the predicted LD50 value, which was calculated on the assumption that each component drug would be additively toxic when combined, to the observed LD50 value was used for comparison. The combination of d-pseudo with Pla gave a significantly greater LD50 value than the predicted LD50 value, while the combination of 1-eph with Pla showed a LD50 value which was not significantly different from Finney's additive model. A combination of d-pseudo with 1-eph and Ipe, and of 1-eph with Ipe showed a LD50 value which was not significantly different from that of the additive model.     

Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat.

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.     

7种化合物细胞毒性与小鼠急性毒性的相关性研究

目的：为减少实验动物的使用,利用化学物质的体外细胞毒性数据对体内急性毒性进行预测。方法：MTT比色法检测7种新化学实体对CHL细胞的毒性作用,利用RC（Registry of Cytotox-icity）预测模型对急性毒性LD50值进行预测,并使用小鼠急性毒性上下法进行验证。结果：各化合物（1～7）细胞毒性IC50值分别为0.43、0.49、0.18、0.67、3.03、1.68、1.79mg/mL;根据RC预测模型,急性毒性LD50的预测值分别为2376.4、2478.3、1574.8、2087.6、4897.3、3331.8、3300.7mg/kg。经上下法检测,4号化合物的LD50值为1634.0mg/kg,其余6种化合物的LD50值均大于2000.0mg/kg。分别以预测值和实测值为依据对化合物毒性进行分级,二者相比,仅3号和4号化合物毒性分级略有差异,其它5种化合物的毒性分级基本一致。结论：体外细胞毒性数据可用来预测体内急性毒性,减少实验动物使用。     

Single dose toxicity study on catena-(S)-[mu-[N alpha-(3-aminopropionyl) histidinato(2-)-N1,N2,O:N tau]-zinc] in mice and rats.

The toxicity of Z-103 (catena-(S)-[mu-[N alpha-(3-aminopropionyl) histidinato(2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7) was evaluated in mice and rats after single administration. LD50 values in mice were 1269 mg/kg for males and 1331 mg/kg for females by the oral route, 220 mg/kg for males and 165 mg/kg for females by the intraperitoneal route, and 758 mg/kg for males and 874 mg/kg for females by the subcutaneous route. LD50 values in rats were 8441 mg/kg for males and 7375 mg/kg for females by the oral route, 405 mg/kg for males and 422 mg/kg for females by the intraperitoneal route and more than 5000 mg/kg for both sexes by the subcutaneous route. No sex differences were observed. A decrease in locomotor activity, ventral posture, crouching, hypothermia and respiratory depression were observed in both mice and rats as the main clinical signs. In addition to these changes, induration, swelling and crust formation were observed at the subcutaneous injection site.     

Antagonism of cyanide poisoning by dihydroxyacetone

Dihydroxyacetone (DHA) effectively antagonized the lethal effect of cyanide in mice and rabbits, particularly if administered in combination with thiosulfate. Oral DHA (2 and 4 g/kg) given to mice 10 min before injection (i.p.) of cyanide increased the LD50 values of cyanide from 5.7 mg/kg to 12 and 17.6 mg/kg, respectively. DHA prevented cyanide-induced lethality most effectively, if given orally 10-15 min before injection of cyanide. A combination of pretreatment with oral DHA (4 g/kg) and post-treatment with sodium thiosulfate (1 g/kg) increased the LD50 of cyanide by a factor of 9.9. Furthermore, DHA given intravenously to rabbits 5 min after subcutaneous injection of cyanide increased the LD50 of cyanide from 6 mg/kg to more than 11 mg/kg, while thiosulfate (1 g/kg) given intravenously 5 min after cyanide injection increased the LD50 of cyanide only to 8.5 mg/kg. DHA also prevented the convulsions that occurred after cyanide intoxication.     

Acute and Environmental Toxicity Studies with Hexazinone

Acute and Environmental Studies with Hexazinone. KENNEDY, G.L, JR. (1984). Fundam. Appl. Toxicol. 4, 603–611. Theacute toxicity of hexazinone, a herbicide intended for generalnoncropland areas and selected crop uses (alfalfa and sugarcane),has been evaluated to establish proper handling guidelines andto measure its potential impact on the environment The materialis slightly to moderately toxic when given as a single oraldose; its LD50 in male rats is 1690 mg/kg, in male guinea pigs860 mg/kg, and in male dogs greater than 3400 mg/kg althoughin the dog emesis prevented accurate quantitation. When thematerial is administered intraperitoneally, the LD50 in ratsis 530 mg/kg. Repeated doses (five oral doses per week for 2weeks) of 300 mg/kg to rats produced slight weight loss in oneof two replicate experiments. In both studies, no gross or histologjcalterations were apparent Hexazinone is a moderate to severeeye irritant in the rabbit and produced only mild erythema inrabbit skin at 5278 mg/kg, a dose which did not produce lethalityor other clinical signs. Subchronic dermal exposures (10 consecutivedoses) to rabbits produced increases in serum alkaline phosphataseand glutamic-pyruvic transaminase at the highest levels tested(680 and 770 mg/kg in two separate experiments) with no effectsseen at 150 mg/kg. There were no alterations in livers fromtreated rabbits examined by light microscopy. No dermal sensitizationwas produced when concentrations of up to 50% were tested inguinea pigs. One-hour inhalation exposure of up to 7.48 mg/literdid not produce mortality in rats. In freshwater biota, thematerial had slight to low toxicity with 96-hr LC50 values beingbetween 370 and 420 mg/liter in bluegill sunfish, between 320and 420 mg/liter in rainbow trout, and 274 mg/liter in fatheadminnows. The 48-hr LC50 in Daphnia magna was 152 ppm. In marinebiota, similar low toxicity was indicated by a 48-hr EC50 of320 to 540 ppm in eastern oysters, a 96-hr LC50 of 56 to 100ppm in grass shrimp, and a 96-hr LC50 greater than 1000 ppmin fiddler crabs. Bobwhite quail were not killed by feedingof up to 10,000 ppm. When given to quail as a single oral doseby intubation, the LD50 value was 2258 mg/kg. Ducks survivedfeeding of 10,000 ppm indicating that the material has a loworder of toxicity in water fowl and upland game birds. Hexazinonehad a low order of acute toxicity when tested in mammals, freshwaterand marine biota, and birds. The material is an eye irritantand should be handled carefully. Dermal irritancy, sensitizationpotential, and systemic toxicity are low.     

Drug-drug interaction potential of antitumor acridine agent C-1748: The substrate of UDP-glucuronosyltransferases 2B7, 2B17 and the inhibitor of 1A9 and 2B7

Background

The compound 9-(2′-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), the promising antitumor agent developed in our laboratory was determined to undergo phase I metabolic pathways. The present studies aimed to know its biotransformation with phase II enzymes – UDP-glucuronosyltransferases (UGTs) and its potential to be engaged in drug-drug interactions arising from the modulation of UGT activity.

Ortho-iodosobenzoic acid: its acute toxicity and neurobehavioral effects in mice

o-Iodosobenzoic acid (IBA), in a surfactant micellar medium, is a rapid and efficient catalyst for the hydrolysis of organophosphate (OP) esters. Since little is known about the toxicity of IBA, a primary screen of neurobehavioral toxicity was evaluated in male ICR mice. IBA was administered intraperitoneally in a pH 7.4 phosphate buffer solution containing 8% dimethylformamide. The predominant overt signs of toxicity included an immediate and transient writhing reflex and/or persistent spasmodic myotwitching of the abdomen, and conspicuous suppression of orienting/exploratory behavior and emotional defecation. The dose ranges for ED50 of writhing response, suppression of rearing and spontaneous motor activity overlapped at levels of about one-tenth the acute LD50, 742 (633-856) mumol/kg, being 94.9 (74.5-122.5), 69.8 (47.9-105.4) and 71.1 (49.9-101.3) mumol/kg, respectively; the dose ranges for ED50 of abdominal myotwitching and depression of emotional defecation in a novel environment also overlapped but at levels of about one-fifth the acute LD50, being 138.4 (115.3-167.2) and 146.2 (110.7-196.3) mumol/kg, respectively. Morphine (1.25-10 mg/kg s.c.) antagonized the IBA-induced writhing response and abdominal myotwitching in a dose-dependent manner, with a PD50 of 4.2 and 4.9 mg/kg, respectively. The present report demonstrates that acute intraperitoneal administration of IBA produces an intriguing, non-specific behavioral syndrome, probably resulting from nociceptive stimulation. This implies that IBA might be irritating to the skin and mucosa.     

Comparative acute systemic toxicity of several quinoxaline 1,4-di-N-oxides in Wistar rats

The acute toxicity of six quinoxaline 1,4-di-N-oxides has been evaluated in an attempt to determine: a) the feasibility of testing systemic toxicity of these compounds in a very preliminary phase without an adequate formulation for in vivo administration, b) the LD50 range and the toxic target organ of these compounds in order to have an approximation of the structure-activity relationship. Quinoxaline 1,4-di-N-oxides have shown a great variety of biological activities with potential therapeutic application in cancer, malaria, etc. Problems of toxicity hinder the progression of these compounds to clinical phases. The compounds dissolved in DMSO at their solubility limit were administered i.v. to female Wistar rats (8 weeks, 160 g), using an infusion pump (300 microL; 20 microl/min). Animals were observed for a period of 14 days. This dose of the vehicle (1.7 ml/kg) was well tolerated by the animals. The LD50 could not be determined, but a marked hypoactivity was induced by the treatment. The same compounds were also injected intraperitoneally, suspended in 0.01% Tween 80/0.09 % saline, and the animals that did not die were observed for a period of 14 days. The LD50 could be estimated to be in a range between 30 and 120 mg/kg, except for one of the compounds. A decrease in the evolution of body weight and hypoactivity were the principal symptoms induced by the treatment. In both assays, histopathologic study of heart, liver, kidney, lung, spleen and ovaries indicated that the target organs may be heart and spleen. In conclusion, the i.v. route is not adequate for estimating the LD50 of these compounds due to solubility problems; by i.p. route, the LD50 interval is between 30 and 120 mg/kg. The data did not permit the deduction of any specific structure-activity relationship.     

Toxicological studies on pepleomycin sulfate (NK 631). I. Acute toxicity of pepleomycin in mice, rats and dogs (author's transl)]

Studies on acute toxicities of pepleomycin sulfate were carried out in both sexes of mice and rats, comparing with bleomycin, and male dogs. Pepleomycin was administered subcutaneously, intravenously and intraperitoneally in both sexes of mice and rats, and intravenously in male dogs respectively. Mice and rats, and intravenously in male dogs respectively. Mice and rats were observed respectively for 10 and 14 days after the administration. LD50 values were calculated by the method of Litchifield & Wilcoxon. LD50 values of pepleomycin were 4 approximately 6 times smaller than those of bleomycin in all routes of mice, but difference between them was not significant in all routes of rats. Additionally sex-difference of LD50 values was scacely recognized in all routes of both species. Toxicological findings observed in common to all routes of both species were ataxia, depression, tremor and epiphora, and only in all routes of mice, head-twitch, running-round and rolling were especially recognized as toxic behavior, which were not observed in bleomycin. Hepatic and renal lesions were recognized in biochemically and histopathologically in the survived rats. The dogs treated with pepleomycin 50 and 30 mg/kg had the decrease in food intake and the loss of body weight. They became moribund in 9 approximately 36 days after administration. In these dogs the lesions of liver and kidney were severely recognized in biochemical and histopathological findings. One of them which received 50 mg/kg recovered biochemically and histopathologically in 209 days after administration by the supplemental nutrition in early stage.     

The effect of nortriptyline-specific active immunization on amitriptyline toxicity and disposition in the rabbit

Rabbits were actively immunized by a conjugate of nortriptyline (NT) to study the effect of specific anti-NT antibodies on toxicity and disposition of amitriptyline (AT). Control and immunized rabbits received 115 mg/kg AT intraperitoneally (i.p.). The lethality dose (LD) profile exhibited a gentle slope; LD100 and LD0 were separated by 100 mg/kg. Mortality was significantly reduced from LD67 to LD43 (P less than 0.05). Total plasma concentrations of the toxin were increased in the immunized group compared to the control group. AUC0.5-24 h value was 5-fold higher in the immunized group than in the control group. Moreover, a smaller fraction of unbound toxin in plasma was observed in the immunized group than in the control group. These observations indicate that AT was actively sequestered by antibodies. The intensity of this phenomenon was a function of both the antibody affinity constant (10(9) M-1) and the neutralizing capacity (varying from 0.005 to 0.2 mg/kg) of the circulating antibodies in each immunized rabbit. Results clearly show that anti-NT antibodies are able to effectively sequestrate AT.     

Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models, and has been evaluated in a phase I study. In order to establish the toxicity profile of this prodrug, acute and repeat-dose toxicity studies were performed with DOXO-EMCH in CD1-mice, Sprague-Dawley rats and Beagle dogs. Although the objective of the acute toxicity studies was not the determination of LD50 values, the LD50 of DOXO-EMCH was >60 mg/kg doxorubicin equivalents in both male and female mice (the LD50 of doxorubicin in CD-1 mice is -12 mg/kg). In Sprague-Dawley rats, the LD50 was 23.4 and 45.9 mg/kg doxorubicin equivalents for males and females, respectively. For comparison, the LD50 of doxorubicin in Sprague-Dawley rats is -10.5 mg/kg. The major clinical sign noted following intravenous administration of DOXO-EMCH in mice and rats was a dose-dependent peripheral neuropathy which, in general, developed as a delayed toxicity 1-3 weeks after application. The observed neurotoxicity has been well documented for Sprague-Dawley rats treated with doxorubicin at a dose of 5 and 10 mg/kg. In Beagle dogs, LD10 was not reached for DOXO-EMCH at 4.5 mg/kg doxorubicin equivalents. A four-cycle intravenous study with DOXO-EMCH at dose levels of 4 x 2.5, 5.0 or 7.5 mg/kg doxorubicin equivalents in rats revealed approximately three-fold less side effects on the hemolymphoreticular system when compared to 4 x 2.5 mg/kg doxorubicin dose, whereas effects on the testes/oligospermia seem to be comparable between both drugs at equitoxic dose. A No Observable Adverse Effect Level (NOAEL) for DOXO-EMCH of 4 x 2.5 mg/kg doxorubicin equivalents was established in this study. This dose is equivalent to the maximum tolerated dose (MTD) of doxorubicin in rats. In a two-cycle study over a period of 6 weeks in Beagle dogs (intravenous administration of DOXO-EMCH at dose levels of 1.5, 3.0 or 4.5 mg/kg doxorubicin equivalents), dose-related systemic histamine-like reactions within the first 3 hours after injection were noted in all treated groups. Only transient and temporary effects on hematology, urinary function, as well as on histopathology in mid- and/or high-dose animals, were observed. The low dose of 2 x 1.5 mg/kg was considered to be the NOAEL in this study, which is equivalent to twice the MTD o f doxorubicin i nBeagle dogs. In summary, the toxicity studies with DOXO-EMCH in mice, rats or dogs have not identified any other special toxicity when compared to the toxicity data for doxorubicin. Preclinical tolerance of DOXO-EMCH was higher in mice, rats and dogs compared to doxorubicin. A dose of 20 mg/m2 doxorubicin equivalents was recommended as the starting dose for a phase I study with DOXO-EMCH.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-10. Toxicity of metabolites of miocamycin: acute toxicity of Mb12 in mice

We evaluated acute toxicity and estimated LD50 values of Mb12, one of the main metabolites of MOM, in male and female mice after single oral administration. Observations were continued for 1 week after treatment. The LD50 values were calculated according to Litchfield-Wilcoxon's method. It is concluded that LD50 values of Mb12 were 5,750 mg/kg (4,914.5-6,727.5 mg/kg) in male mice and 4,950 mg/kg (4,194.9-5,841.0 mg/kg) in female mice, respectively.     

Toxicological studies on a new veterinary antibiotic turimycin.

Turimycin is a fermentation product ofStreptomyces hydroscopicus (DDR W-Patent-Nr. 84 450). It is highly active in vitro against a range of mycoplasma species and gram-positive bacteria. The acute toxicity was determined in mice, rats and dogs. In mice and rats LD50 values ranged from 750 mg/kg intraperitoneally to higher than 3000 mg/kg orally. In a chronic study on dogs oral doseas of 50 nad 125 mg/kg Turimycin were given daily in capsules for 12 months. The results showed no functional or morphological differences between treated and control animals.     

Acute toxicity of bemithyl and bromithyl

The experiments on rats showed for bemithyl LD50 = 581.48 (350.17-965.57) mg/kg and for bromithyl LD50 = 1750.30 (1463.07-2093.92) mg/kg (males) and 1584.29 (1280.46-1960.22) mg/kg (females). The therapeutic ratios are 4-6 for both drugs, while the toxicity index is 10-15 for bemithyl and 20 <196> 22 for bromithyl. It was established that ergotropic effects prevail in the toxicity of bemithyl administered in the 20-80 mg/kg dose range, while trophotropic effects are dominating at doses above 100 mg/kg. Bromithyl exhibits a dose-dependent trophotropic effect in the entire dose range.