Iv LD50 Research Articles

Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes

cis-Bis(neodecanoato)(trans-(R,R)-1,2-diaminocyclohexane)platinum( II) [L-NDDP] is a liposome incorporated lipophilic cisplatin analogue that has shown promising antitumor activity against tumors resistant to cisplatin and liver metastases in mice. L-NDDP is currently under clinical evaluation. However, NDDP is an isomeric mixture of different species having various isomeric neodecanoic moities as liganded leaving groups. A series of new highly lipid-soluble cis-bis(neodecanoato)(trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) [Pt] complexes, using single isomers of neodecanoic acid, were synthesized and characterized by analytical and spectroscopic techniques (infrared and 195Pt NMR). Multilamellar vesicles (MLVs) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a molar ratio of 7:3 were used as carriers of the Pt complexes. The efficiency of incorporation of the liposomal-platinum (L-Pt) preparations was greater than 95% and stability in normal saline at 4 degrees C was greater than 95% at day 14 in each case. The iv LD50 values of all L-Pt preparations tested were in the range of 62.3 to 104 mg/kg. The % T/C obtained after a single ip injection of the optimal dose of L-Pt preparations against L1210 leukemia was in the range of 150 to 253 (160 for cisplatin). When a multiple ip injection schedule was used (on days 1, 5, and 9) the L-Pt preparations of R,R complexes (1, 7, and 9) were more active than cisplatin at the optimal dose (% T/C = 257 for each vs 220 for cisplatin). The L-Pt preparations of R,R complexes were also markedly active against L1210 leukemia resistant to cisplatin (% T/C 355, 231, and 185 respectively vs 112 for cisplatin). These studies show that the single isomers of NDDP are comparable to the original isomeric mixture in terms of toxicity and biological activity.

Characteristics of the prolonged inhibition produced by a range of pyrethroids in the rat hippocampus

Eight different synthetic pyrethroids were examined to determine their effects on the excitability of hippocampal granule cells in urethane-anesthetized rats. A paired stimulus approach was used. All eight prolonged the depression of granule cell excitability that follows stimulation of their major synaptic input, the perforant path. The magnitude of this effect depended upon the class to which the pyrethroid belonged. Type I pyrethroids (those primarily producing tremor) prolonged the depression of granule cell excitability for shorter periods than did type II pyrethroids (those primarily producing salivation and choreoathetosis) or pyrethroids producing a mixed type of intoxication. No overlap was found between groups. To determine whether the difference observed between type I and type II pyrethroids was the result of an infelicitous selection of doses, cismethrin (type I) was tested over a dose range of 1.5–24 times the conscious rat iv LD50. Even at the highest dose, the prolongation remained well below that produced by type II pyrethroids. The effect of deltamethrin was shown to be consistent with the production or potentiation of a surmountable inhibitory response. This action of deltamethrin was antagonizable by mephenesin and lidocaine, but not by picrotoxin or halothane. The type of effect, its time course, and the antagonism data suggest that type II pyrethroids enhance inhibition in the dentate gyrus. This action does not appear to be mediated by GABA A receptors.

Short‐term toxicity studies of Sanguinarine and of two alkaloid extracts ofSanguinaria CanadensisL.

The short-term toxicity of sanguinarine, a benzophenanthridine alkaloid, and of two alkaloid extracts of Sanguinaria canadensis L. are presented. The acute oral LD50 in rats of sanguinarine was calculated to be 1658 mg/kg, and of the two alkaloid extracts, 1440 and 1250 mg/kg. The acute iv LD50 in rats of sanguinarine was found to be 29 mg/kg. No toxic effects were observed in rats fed up to 150 ppm sanguinarine in the diet for 14 d and in rats treated by gavage with up to 0.6 mg/kg body weight for 30 d. The acute dermal LD50 in rabbits was found to be greater than 200 mg/kg.

Preliminary toxicity findings in dogs and rodents given the iron chelator ethylenediamine- N,N′-bis(2-hydroxyphenylacetic acid) (EDHPA)

Because of a projected pilot study with EDHPA in Cooley's anemia patients, animal studies with emphasis on reversibility of potential toxic signs were performed. Young dogs were treated iv with 6–18 mg/kg or orally with 30–240 mg/kg for 14 days followed by a 16-day recovery period. Drug-induced emesis, elevated BUN changes in kidney, spleen, and thymus weights diminished during recovery. One deceased dog exhibited nephrotoxicity consisting of tubular necrosis and deposition of the iron-EDHPA complex. The latter was observed in the excreta of survivors but kidney damage was not evident. Atrophy of the spleen and thymus in the deceased dog was consistent with less intense organ weight changes in recovered survivors. In the absence of morphologic changes after recovery, the precise effect on the immune system is unknown. The iv LD50 was 53 mg/kg for rats and mice. No rodent deaths occurred at an oral dose of 6000 mg/kg. An elevated BUN and changes in kidney, spleen, and thymus weights were confirmed in rodents given iv doses of 5–20 mg/kg or oral doses of 150–600 mg/kg for 5 days. It is cautioned that during the use of EDHPA derivatives that the functions of the renal and immune systems be monitored.

Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor

Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly ( p < 0.05) decreased and the blood urea nitrogen was slightly but significantly ( p < 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.

Enhanced sensitivity to digoxin in dystrophic mice.

We estimated the effect of digoxin on the myocardial potassium content and the action potentials of the left ventricular papillary muscles in dystrophic mice (C57BL/6JCL dy X dy). All of 10 dystrophic mice died following ip injection of digoxin at a dose of one quarter of the iv LD50 for normal mice. The myocardial digoxin concentration and the myocardial potassium content in dystrophic mice were similar to those in normal mice before and 60 min after the ip injection of digoxin. The action potential durations (APD) in dystrophic mice were significantly longer than those in normal mice. Perfusion of digoxin (2 micrograms/ml) for 30 min reduced the APD significantly and induced arrhythmias in dystrophic mice, but it did not bring about any significant change in normal mice. These data suggest that dystrophic mice have increased sensitivity to digitalis. This hypersensitivity to digitalis is not due to increased myocardial digoxin uptake or decreased myocardial potassium content.

Toxicity of Secalonic acid D.

Toxicity of secalonic acid D was examined by using lethality, growth retardation, and histopathology as indexes. The ip LD50 values of 37, 31, and 27 mg/kg were obtained for Charles River CD-1, Texas (ICR), and Sprague-Dawley (CF-1) strains of mice, respectively. The ip LD50 was 52 mg/kg in female CD-1 mice. The iv LD50 was 25 mg/kg in CD-1 male mice. Oral LD50 values of 400 mg/kg in male CD-1 mice and 25 and greater than 400 mg/kg in Sprague-Dawley day-old and weanling (21 d) rats of both sexes, respectively, were obtained. Doses of 20 mg/kg or more ip retarded growth and doses of 30 mg/kg or more ip were lethal to CD-1 mice. Oral doses required to produce such effects in day-old rats were 5 and 20 mg/kg (or higher), respectively. All ip doses of secalonic acid D caused pulmonary atelectases and foccal peritonitis in male CD-1 mice. The latter involved surfaces of abdominal viscera and produced limited subcapsular necrosis of hepatic parenchyma. Exposure to a single lethal dose iv (25 mg/kg or more) of secalonic acid D caused limited hepatic portal necrosis but no peritonitis or other associated local effects observed in CD-1 male mice after ip exposure. Cytoplasmic liposis and loss of glycogen and RNA from hepatocytes were observed in a single mouse receiving 50 mg/kg iv. Death resulting from cardiac and/or pulmonary insufficiency was suggested by atelectasis, pulmonary hemorrhages and edema, and massive atrial dilation in mice that died after lethal ip or iv doses of secalonic acid D. Five daily sublethal ip doses in CD-1 male mice resulted in dose-dependent mortality (LD50, 11.5 mg/kg) indicating cumulative effects.

Concentrations of 2-hydroxyiminomethyl- N-methylpyridinium ion in plasma and aqueous humor as indices of the toxicity of pralidoxime mesylate (P2S) for the rabbit

Plasma pralidoxime mesylate (P2S) concentrations were measured at various times up to 2 hr in female rabbits after a single injection of the im LD50 (258 mg/kg) or iv LD50 (118 mg/kg). The results indicate that plasma P2S concentrations at death are generally greater than 200 μg/ml; plasma concentrations of 90–160 μg/ml, if maintained for a few minutes, are not lethal, but if sustained, then an abrupt rise in concentration may occur with death ensuing at concentrations greater than 200 μg/ml; sustained plasma concentrations of 90 μg/ml or less are not lethal. P2S was present in measurable amounts in the aqueous humor, but always at concentrations lower than in plasma. In a separate study to define the relationship between plasma and aqueous humor P2S concentrations, rabbits were sacrificed after receiving 50% the im LD50 (129 mg/kg). At 5 min, P2S was detected in aqueous humor in concentrations 5–15% that in plasma. Peak aqueous humor concentrations were measured at 1 hr, at which time the plasma concentrations had decreased to similar values. Thereafter, plasma and aqueous humor concentrations declined at similar rates. Rabbits having im P2S injections of 40 mg/kg showed increases in intraocular tension, significant at 1 hr after injection and persisting for a further 4 hr.

Reproductive, acute and subacute toxicity studies with nefopam in laboratory animals

Nefopam hydrochloride, a compound with non-narcotic analgesic activity, was evaluated for its acute and subacute toxicity in mice, rats, and dogs. Potential teratogenic effects in mice and rabbits and its effect on general reproduction and postnatal development in rats were also studied. The LD50 by various routes of administration showed that in all three species oral LD50 values (80–178 mg/kg) were greater than im LD50 values (30–57 mg/kg) which were higher than iv LD50 values (20–45 mg/kg). A comparative oral acute toxicity study did indicate a strain difference in rats. Repeated daily administration of nefopam hydrochloride to rats and dogs at doses up to 10 mg/kg/day parenterally and 80 mg/kg/day orally revealed no toxic effects except for mild tissue irritation at injection sites and slight weight loss in some dogs receiving the high dose. Reproduction studies did not reveal any effects on fertility, lactation, or pup development and viability.

The effects of dibenz[ b,f][1,4]oxazepine (CR) upon rat and rabbit embryonic development

Pregnant rats and rabbits were exposed to CR aerosols at concentrations of approximately 2, 20 and 200 mg/m 3 for 5–7 min on days 6–15 and 6–18 of pregnancy, respectively. In addition rats and rabbits were dosed intragastrically with CR solutions on alternate days throughout the period of organogenesis at dosages ranging from 0.2 to 100 mg/kg, and rabbits were injected iv on 3 consecutive days with 0.33 of the acute iv LD50. No teratogenic response which could be attributed to CR was noted in any case, and only in the iv studies were embryolethal effects observed. These effects may have been due to precipitation of CR from saturated solution upon injection.

Inhalation, parenteral and oral LD50 values of Δ 9-tetrahydrocannabinol in Fischer rats

In order to resolve the differences in reported LD50 values for Δ 9-tetrahydrocannabinol ( Δ 9-THC) obtained with various vehicles and rat strains, the oral LD50 values of Δ 9-THC in a natural vegetable oil vehicle and in an aqueous emulsion were determined in the same rat strain. In addition an iv LD50 value obtained with the emulsion formulation was compared with an inhalation LD50. The natural vegetable oil was pure sesame oil and the aqueous emulsion used orally was comprised of 13% sesame oil, 1% polysorbate 80 and isotonic saline. A similar emulsion (7% sesame oil and 0.5% polysorbate 80) was used to establish the iv and ip LD50 values. The young adult Fischer rat was used in all experiments and the polysorbate 80 concentration in emulsion formulations was maintained below toxic levels for the rodent. Marihuana cuttings were impregnated with Δ 9-THC and formed into cigarettes which were smoked under controlled conditions of puff volume and duration in an automatic smoking machine to obtain an inhalation LD50. It was demonstrated that behavioral and physiological responses to Δ 9-THC occurred sooner with the oral emulsion formulation than with the vegetable oil. The intragastric LD50 with the emulsion was 800 mg/kg and with the sesame oil formulation, 1270 mg/kg. The iv LD50 was 36–40 mg/kg, similar to the inhalation dose when the latter was corrected for Δ 9-THC losses in the rodent nasal passages. The results from this study affirmed that the LD50 values obtained were reliable and that the vehicle did not contribute to the toxicity.

The parenteral toxicity of clindamycin 2-phosphate in laboratory animals

The ip and iv LD50 values of 1145 and 855 mg/kg of clindamycin 2-phosphate in the Swiss white mouse were approximately 3 times higher than those of clindamycin hydrochloride. The lesion produced by single injection of 50 or 100 mg/ml of clindamycin 2-phosphate in the loin muscles of the New Zealand White rabbit was graded as slight. The 24-hr serum creatine phosphokinase value was 1500 IU/liter which was less than one-half that of the parent antibiotic. Body weight gains and food conversion ratios in groups of 10 Sprague-Dawley rats injected sc with 120 mg/kg for 6 days were comparable to those of the control group; 90 mg/kg was tolerated in these terms nearly as well for 30 days as no treatment or doses of 30 and 60 mg/kg. From 22 to 33 injections (each equivalent to 30, 60 or 90 mg/kg) were made bilaterally in the posterior thigh muscles of groups of 3 beagle dogs. The terminal elevations of serum glutamic-oxaloacetic transaminase varied from 54 to 400 Reitman-Frankel units. The characteristic pathologic change resulting from the superimposed injections was dose-related progressive scarring of the muscle bundles. Intravenous administration of 60 and 120 mg/kg daily in divided doses in 2 groups of 4 dogs each for 30 days produced no detectable irritation in the peripheral veins or drug-related hemolysis. Tests for drug-induced hemolysis and changes in erythrocyte fragility by in vitro methods were negative. In dogs treated iv with 120 mg/kg for 1 week, as light increase in neutral lipid droplets was present in hepatocytes from 3 hr to 3 days when examined by electron microscopy. This transient change was not observed in dogs injected im with 90 mg/kg for the same period.

The oral and dermal toxicity of hexachlorophene in rats

The single oral LD50 of hexachlorophene in adult male Sherman strain rats was 66 mg/kg, in females 56 mg/kg; in famale weanling rats the single oral LD50 was 120 mg/kg. The acute dermal toxicity was low. The iv LD50 in adult male rats was 7.5 mg/kg. Rats fed 500 ppm of hexachlorophene for 98 days developed leg weakness in 12–19 days. At sacrifice, after 98 days' exposure, status spongiosus was present throughout the white matter of the brain. Rats fed 100 ppm of hexachlorophene for 98 days did not develop leg weakness, but in 50% of the brains focal areas of status spongiosus were observed in the white matter. Rats fed 20 and 100 ppm of hexachlorophene for 258 days did not develop leg weakness. The brains of rats fed 20 ppm were normal, while the brains of some rats fed 100 ppm showed focal vacuolization of the white matter. One hundred parts per million reduced the survival of pups in the F 1 generation. This was statistically significant in the F 1b generation. The F 2 generation litters tended to be smaller. Reproduction was normal in rats fed 20 ppm or given hexachlorophene by oral intubation at doses as high as 10 mg/kg/day during day 7 to day 15 of pregnancy. Dermal application of 12 mg/kg/day of hexachlorophene for 30 days produced no microscopic changes in the brain and produced only erythema and desquamation of the treated skin. Doses of 24 and 48 mg/kg/day produced ulceration of the treated skin and status spongiosus of the entire white matter of the brain in some rats.

Comparative toxicity and distribution of endrin and dieldrin after intravenous administration in mice

Acute iv LD50 values and median survival times (ST50) of endrin and dieldrin were determined in male mice. The duration of components of the seizures induced by an LD90 of endrin (5 mg/kg) or dieldrin (15 mg/kg) were timed. Brain, liver, fat, blood and bile were analyzed by gas chromatography at intervals corresponding to the appearance of seizure components. In addition, brain tissue was analyzed 5 min after equimolar doses and 15 min after equitoxic doses (dose producing ataxia in 90% of the population). The seizure patterns produced by either insecticide were similar, except for the shorter duration of seizure components induced by dieldrin. The LD50 of dieldrin was five times that of endrin, and its ST50 was less at equilethal doses. At equimolar doses, however, the ST50 of dieldrin was greater than that of endrin. The concentrations of the insecticides in the brain reached equilibrium before the appearance of the seizure components. Ratios of brain concentration to dose were the same for both compounds after equipotent, equilethal or equimolar doses. No insecticide was detected in the bile. Thus, the rate and extent of distribution into whole brain and other tissues cannot account for differences in LD50 between endrin and dieldrin, but may explain differences in ST50 values obtained from equilethal doses. The results suggest the presence of time dependent events in the mechanism of action of the cyclodienes.

Absorption, distribution and excretion of luteoskyrin with special reference to the selective action on the liver

Pharmacokinetic experiments with 3H-luteoskyrin disclosed the following findings on absorption, distribution and excretion of the compound: (1) Luteoskyrin (luteo), when administered sc or po, rapidly concentrates in the liver, reaching maximum concentration about 1 day after administration. Although similar uptake curves are shown by other organs, the maximum luteo value for the liver is singularly high. The trend toward selective concentration in the liver explains the specific hepatotoxicity of luteo. (2) Most luteo administered iv quickly disappears from the blood, and a considerable amount enters the liver. The effective concentration in the liver for hepatotoxicity is low but within definite limits and is nearly the same after sc and po administration. (3) The luteo uptake varies with different organs and tissues, and the amount entering the liver shows a wide difference depending on the route of administration. This accounts for the differences seen between the iv LD50 and those values obtained after sc and po administration. (4) A slow uptake of luteo by the liver and a time lag for development of liver damage were observed; this accounts for the slow onset of toxicity of luteo. (5) Elimination of luteo gradually takes place through the liver, gastrointestinal tract and kidney, and the residual luteo is detectable in the blood, feces and urine for many days.