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Biomedical subjects

E H Herman

Publications and source records attributed to E H Herman.

At least 55 records · Page 3Linked to original sources
PubMed1985

Comparison of the effectiveness of (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles.

This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.

Acetylcysteine↗
PubMed1985

Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters.

Comparisons were made of the protective activity of ICRF-187 and a series of related bis-dioxopiperazine analogues against acute daunorubicin toxicity in Syrian golden hamsters. A single dose of daunorubicin (25 mg/kg) caused a marked decrease in body weight and was lethal to 84% of the animals within 1 to 4 weeks. Pretreatment with ICRF-187, the d-isomer of ICRF-159, ameliorated the lethal effects of daunorubicin. Over 70% of the animals given 50 to 200 mg of ICRF-187 before daunorubicin were alive at 8 weeks. Similar results were obtained with ICRF-186, the 1-isomer of ICRF-159, indicating that the protective activity is not stereospecific. Eighteen other analogues were also evaluated for protective activity; only bimolane, a central chain desmethyl analogue of ICRF-187 with N-morpholinomethyl substituents in each dioxopiperazine ring, was as effective as ICRF-187 in reducing the mortality of daunorubicin. The role of the N-morpholinomethyl groups in the biological activity of bimolane needs further study since ICRF-154, a similar compound without these substituents, exerted only minimal protective activity. Protection against daunorubicin lethality was minimal or absent when hamsters were pretreated with various doses of ICRF analogues in which slight changes had been made in dioxopiperazine rings (ICRF-158, ICRF-198) or in the central chain (ICRF-161, ICRF-192, ICRF-193, ICRF-197, ICRF-198, and ICRF-202). Similarly, animals pretreated with a number of conformationally constrained cyclopropane analogues of bis-dioxopiperazine compounds before receiving daunorubicin died at the same rates as those given only daunorubicin. These results confirm the effectiveness of ICRF-187 against daunorubicin toxicity and indicate that very little alteration can occur in the basic structure of ICRF-187 without loss of this protective activity.

Animals↗
PubMed1985

Poikilocytosis in dogs with chronic doxorubicin toxicosis.

Peripheral blood smears made during 2 studies of chemical antidotes for doxorubicin (DRB) cardiotoxicity in dogs were examined to determine the incidence of poikilocytosis. The 1st study had significantly (P less than 0.05) increased numbers of poikilocytes in 3 groups of 5 dogs, each treated with DRB alone, DRB plus thyroxine (0.5 mg/day), and DRB plus thyroxine (2.0 mg/day), respectively, compared with 1 group of 5 dogs treated with thyroxine alone (2.0 mg/day). In addition, the DRB-treated dogs had regenerative anemia characterized by an increased reticulocyte index. The 2nd study had a significant (P less than 0.05) increase in poikilocytes in 4 groups of 6 dogs, each treated with DRB alone, DRB plus +/- -1,2-bis(3-5-dioxopiperazinyl-1-yl; ICRF-187), DRB plus N-acetylcysteine (NAC), and drb plus ICRF-187 plus NAC, respectively, compared with 4 groups of 3 dogs, each treated with ICRF-187 plus saline solution (SS), NAC plus SS, ICRF-187 plus NAC plus SS, and SS alone, respectively. In both studies, the poikilocytes were identified as echinocytes, spiculated erythrocytes, and schizocytes. Administration of thyroxine and ICRF-187 did not prevent the occurrence of poikilocytosis in DRB-treated dogs. Administration of NAC with DRB resulted in a mild decrease in the extent of poikilocytosis compared with that observed in dogs given DRB alone. The hematologic changes observed in both studies were not accompanied by adverse clinical signs referable to the DRB-induced alterations in erythrocytes.

Acetylcysteine↗
PubMed1984

Cardiac morphologic alterations in acute minoxidil cardiotoxicity in miniature swine.

Minoxidil, a vasodilating antihypertensive drug, was given orally at 10 mg/kg daily for 2 days to twelve 25- to 35-kg miniature pigs. Twelve control pigs were also studied. Minoxidil-treated pigs had tachycardia and hypotension and were killed 24 hr after the second dose. Gross examination showed diffuse hemorrhage in left atrial epicardium in all pigs, and also in ventricular epicardium (2 of 12 pigs) and endocardium (3 of 12 pigs). Pale areas of necrosis were observed on incision of the left ventricular papillary muscles in 3 pigs. Light and electron microscopic studies showed acute vascular damage with hemorrhage in the left atrial epicardium. Affected arterioles had endothelial cell swelling and transmural and perivascular accumulations of leukocytes, edema fluid, fibrin clumps, and erythrocytes. The swollen endothelial cells had large, irregularly shaped nuclei with abundant euchromatin; mitotic figures were frequent. The cytoplasm contained numerous polysomes and cisterns of rough endoplasmic reticulum. Fibroblasts adjacent to damaged vessels had edematous cytoplasm and increased amounts of rough endoplasmic reticulum. In the affected left ventricular papillary muscles, necrotic myocytes showed contraction bands, mitochondrial matrical densities, lipid accumulation, initial lysis of I bands, and pyknotic nuclei. The lesions were judged to result from two mechanisms: (1) hemorrhagic lesions from drug-induced vascular injury centered on epicardial and subepicardial arterioles and (2) papillary muscle necrosis from ischemic injury from hypoperfusion during minoxidil-induced tachycardia and hypotension.

Animals↗
PubMed1983

Examination of the protective effect of ICRF-187 and dimethyl sulfoxide against acetaminophen-induced hepatotoxicity in Syrian golden hamsters.

The protective activity of 1,2-bis(3,5-dioxopiperazin-l-yl)propane (ICRF-187) and dimethyl sulfoxide (DMSO) was tested against acetaminophen-induced hepatotoxicity. Male Syrian golden hamsters injected intraperitoneally between 18:00 h and 20:00 h for 2 consecutive days with acetaminophen (N-acetyl-p-aminophenol) (300 mg/kg) displayed signs of hepatotoxicity as evidenced by increases in enzyme activity and cellular damage. Forty-eight hours after the second acetaminophen dose, the activities of serum glutamic-pyruvic transaminase and alkaline phosphatase were increased compared with levels found in hamsters given only saline. In addition, hepatocellular necrosis was evident in acetaminophen-treated animals. ICRF-187 (300 mg/kg) given 1 h before acetaminophen attenuated the increases in enzyme activities, and both DMSO (7.3 g/kg) and ICRF-187 reduced the incidence and severity of acetaminophen-induced hepatocellular injury. Both ICRF-187 and DMSO are capable of altering free radical-mediated toxicity in other experimental systems. Whether these compounds reduce acetaminophen-induced liver toxicity by a similar mechanism remains to be determined.

Acetaminophen↗
PubMed1983

Influence of vitamin E and ICRF-187 on chronic doxorubicin cardiotoxicity in miniature swine.

Studies were made of the potential of vitamin E and ICRF-187 to protect against the cardiotoxicity resulting from chronic administration of doxorubicin. Miniature swine (19 to 40 kg) received six injections of doxorubicin (1.6 mg/kg) at 3-week intervals (total dose, 9.6 mg/kg), either alone or concurrently with vitamin E (5000 IU/day for 4 days and 1000 units/day for the next 17 days). In a second study, miniature swine received six injections of doxorubicin (2.4 mg/kg) at 3-week intervals (total dose 14.4 mg/kg), either alone or 30 minutes after 12.5 mg of ICRF-187/kg (intraperitoneally). All animals were sacrificed 3 weeks after the last injection. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were scored on a scale of 0 to 4+. Such lesions were noted in eight of nine pigs given 9.6 mg/kg of doxorubicin alone and in all pigs receiving doxorubicin and vitamin E; however, the severity of the lesions was decreased in the latter animals (average score 1.0, compared with 1.8 in those receiving doxorubicin alone). All swine receiving 14.4 mg/kg of doxorubicin alone developed myocardial lesions (average score, 2.7); these lesions were severe (3+) in four of the animals. In contrast, cardiac lesions were absent in two and minimal (average score, 0.7) in five of the seven animals given 14.4 mg/kg of doxorubicin in combination with ICRF-187.

Animals↗
PubMed1983

Reduction by ICRF-187 of acute daunorubicin toxicity in Syrian golden hamsters.

Administration of a single dose of daunorubicin (25 mg/kg) to Syrian golden hamsters caused a marked decrease in food consumption and body weight and death within 1 to 3 weeks. The severity of acute daunorubicin toxicity was reduced by pretreatment with ICRF-187 at doses of 12.5 mg/kg or greater. Although most animals pretreated with 12.5 to 50 mg ICRF-187/kg were alive after 5 weeks, body weight was below control levels. Animals pretreated with 100 mg ICRF-187/kg were the only group able to regain initial weight loss and increase body weight above the preinjection control level. Different degrees of protection were observed when the 100 mg/kg dose of ICRF-187 was given at various times before and after daunorubicin. Significant numbers of animals (45%) survived when ICRF-187 was given 48 h before daunorubicin. Optimal survival was observed when 100 mg ICRF-187/kg was given from 3 h before to 3 h after daunorubicin. The protective effect of ICRF-187 was lost when it was administered more than 6 h after daunorubicin. The lethal effects of high doses of daunorubicin may be due to profound gastrointestinal toxicity. Alterations in the heart, liver, or kidneys did not appear to be of sufficient magnitude to be responsible for the lethality in the hamsters. In contrast, marked histopathological changes were found throughout the entire length of the gastrointestinal tract from the colon to the tongue. ICRF-187 appears capable of altering daunorubicin toxicity on this tissue.

Animals↗
PubMed1983

Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation.

Antitumor drugs such as doxorubicin have been encapsulated into liposomes as a means of enhancing activity and reducing toxicity. The present study was initiated to determine whether chronically administered liposome-encapsulated doxorubicin would be less toxic than the free drug. Doxorubicin was prepared in positively charged cardiolipin liposomes, and 1.75 mg/kg was given i.v. to each of five beagles. A second group received the free drug at 1.75 mg/kg. Additional animals received i.v. injections of either doxorubicin-free liposomes or 0.9% NaCl solution. All substances were given at 3-week intervals, and the experiment ended 1 week after the seventh injection (total dose, 12.25 mg/kg). A temporary reduction in food consumption was noted during the first few days after the administration of either form of doxorubicin. The effect was more severe in the dogs given free doxorubicin, and body weight decreased significantly only in this group of animals. Three dogs given free doxorubicin died or were killed before the end of the study because they were in poor condition. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all five dogs given free doxorubicin. The severity of the lesions ranged from 2 to 4 (average, 3.4). In contrast, no abnormalities were found in any of the hearts from dogs given the liposomal doxorubicin. The most obvious general toxic effect caused by administration of free doxorubicin was alopecia, which was entirely prevented when doxorubicin was encapsulated into liposomes. At the dosage regimen utilized, liposomal doxorubicin and free doxorubicin exerted comparable degrees of bone marrow suppression. Thus, liposomal encapsulation of doxorubicin decreased cardiac and other toxic effects elicited by free doxorubicin. Whether this advantage can be translated into effective antineoplastic activity will need further evaluation.

Amines↗
PubMed1983

Reversal of propranolol and verapamil toxicity by calcium.

Because of the increasing use of propranolol and verapamil in combination, a study of their interaction was conducted. In rabbits, propranolol given IV at 1 mg/kg followed by an IV infusion of verapamil at 0.1 mg/kg/min for 15 min caused profound hypotension, bradycardia, A-V block, and death in less than 1 h in each of 30 animals. In rabbits treated with propranolol and verapamil as above, calcium chloride (300 mg/kg) given IV immediately after verapamil infusion restored blood pressure and cardiac conduction to normal but the heart rate remained slow; all 12 animals survived. In miniature swine under sodium pentobarbital anesthesia, propranolol (0.5 mg/kg) and verapamil (0.5 mg/kg) IV produced the same physiological changes and death within 15 min in each of eight animals. Calcium chloride given at 150 mg/kg to miniature swine after propranolol and verapamil injections prevented death of each of the five animals; blood pressure and the electrocardiogram were restored to normal, although bradycardia persisted. In mice, the IP LD50 value of propranolol HCl, which is 80 +/- 2.7 mg/kg, was decreased to 10 mg/kg when the drug was given in combination with verapamil HCl at an IP dose of 3 mg/kg, which is less than 1/10 of its LD50. Deaths occurred within minutes and were preceded by convulsions. Pretreatment of mice with calcium chloride (600 mg/kg, IV) prevented death due to the combination of propranolol and verapamil. The data indicate that verapamil enhances the toxicity of propranolol and that calcium can antagonize this effect.

Animals↗
PubMed1982

Anthracycline-induced histamine release from rat mast cells.

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.

Aclarubicin↗
PubMed1982

Tolbutamide enhancement of ouabain cardiotoxicity in rabbits.

The amount of ouabain necessary to produce ventricular fibrillation (VF) was significantly decreased by 2-hour pretreatment with 50, 100 or 200 mg/kg tolbutamide in anesthetized rabbits. The two higher doses also decreased the dose of ouabain needed to produce ventricular ectopic (VE) beats. Only the 200 mg/kg dose decreased blood glucose. In unanesthetized rabbits, 30-min pretreatment with tolbutamide (200 mg/kg i.v.) significantly decreased the doses of ouabain that produced VE beats and VF. A similar effect was noted when the same dose (200 mg/kg) was given subcutaneously 30 min, 2 or 4 h before ouabain. In these experiments blood glucose decreased after 1 h. Pretreatment for 30 min with subcutaneous administration of 50, 100 or 200 mg/kg tolbutamide significantly reduced the doses of ouabain needed to produce VE beats and VF. Blood glucose was unaltered by any tolbutamide dose after 30 min. Insulin (1 unit) decreased blood glucose but did not alter the amount of ouabain that produced VE beats and VF. The mechanism for enhancement of ouabain cardiotoxicity by tolbutamide appears to be independent of alterations in blood glucose and may be related to some direct myocardial effect.

Anesthesia↗
PubMed1981

Divergent effects of propranolol and furosemide pretreatment on acute cardiomyopathy induced by minoxidil in beagle dogs.

Previous studies have shown that oral administration of minoxidil on 2 consecutive days produces an increase in heart rate and myocardial necrosis in Beagle dogs. Propranolol treatment (1.0 or 3.0 mg/kg every 8 h) did not abolish tachycardia and did not alter the incidence or severity of minoxidil-induced necrosis. In the present studies, pretreatment with either furosenmide (10 mg/kg) or hydrochlorothiazide (250 mg/kg) reduced serum potassium levels. However, only furosemide (for 11 days) reduced significantly the incidence of minoxidil-induced necrosis; only 2 of 10 animals (20%) developed myocardial lesions compared to 11 of 14 (79%) in the non-treated group. The incidence and severity of lesions in hearts from animals treated with furosemide for 3 days or hydrochlorothiazide for 11 days were essentially the same as in animals given minoxidil alone. Thus, furosemide, under certain conditions, can reduce the incidence of acute ventricular lesions induced by minoxidil.

Animals↗
PubMed1981

Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits.

To determine whether ICRF-187 (NSC-169780) would alter chronic daunorubicin (NSC-82151) cardiac toxicity, male New Zealand rabbits were given 3.2 mg/kg or daunorubicin iv alone or 30 minutes after 12.5 or 25.0 mg/kg of ICRF-187 ip at 3-week intervals. Control rabbits received either saline iv or ICRF-187 (12.5 or 25.0 mg/kg) ip on the same schedule. Three weeks after the fifth injection, the animals were sacrificed. The frequency and extent of cellular alterations were graded on a scale of 0 to 4. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all 12 rabbits given daunorubicin alone. The severity ranged from 1 to 3 (average 1.8). In contrast, no abnormalities were noted in one of five (12.5 mg/kg) and three of seven (25.0 mg/kg) ICRF-treated rabbits. The remaining eight hearts from both pretreatment groups displayed animal alterations ranging from 0.5 to 1.0 (average 0.9). Thus, concurrent administration of the antineoplastic agent ICRF-187 may offer a means of reducing chronic daunorubicin cardiac toxicity.

Animals↗