Injection Of Nitrogen Mustard Research Articles

Acute hypovolemia after weaning from isolated limb perfusion

A FTER THE description by Klopp in 1950 of the negative effect on tumor growth of an injection of nitrogen mustard into a tumor-supplying artery, I the techtuque of isolated organ perfuslon has been developed by Creech et al. 2 This involves the use of an extracorporeal circuit, incorporating a blood pump and an oxygenator to deliver high doses of chemotherapeutic drugs to neoplasms, especially malignant melanomas in the extremities without the occurrence of systemic toxic reactions. It enables the use of, for instance, hyperthermla, different types of chemotherapeutic agents, and high or low oxygen tensions, which have all been claimed to have useful benefits. 3-5 The increasing incidence of malignant melanomas in the United Kingdom population makes this procedure a vital part of available treatment until a better alternative is found because the results remain encouraging. 6 The anesthetic management of this procedure has not been much discussed. Presented is a potentially life-threatening complication and a review of the hazards of isolated lamb perfusion

Clastogenic effects of transplacental exposure of mouse embryos to nitrogen mustard or cyclophosphamide.

Embryos from day 12 pregnant Swiss mice given intraperitoneal injections of nitrogen mustard (HN2) or cyclophosphamide (CP) were evaluated for chromosomal aberrations. Both agents induced dose-dependent increases in the frequency of cells with aberrations observed in embryos from females treated 6 hr before sacrifice. The highest frequencies of cells with aberrations were observed when females were injected 15 or 18 hr before sacrifice on day 12. A teratogenic dose of HN2 (1.0 mg/kg) induced significantly higher frequencies of damaged cells than a teratogenic dose of CP (20 mg/kg). Cytogenetic analysis of rodent embryos from pregnant females exposed to xenobiotic agents may be an effective screening test for evaluation of genetic effects induced by transplacental exposure.

Bioelectric phenomena in the ototoxicity of nitrogen mustard.

The effects of nitrogen mustard on the electrical potentials of the inner ear were studied, and the results were correlated with the histopathologic findings which have been reported in nitrogen mustard ototoxicity. The endocochlear DC potential (EP) decreased rapidly after an injection of nitrogen mustard (NM). The amplitude of the cochlear microphonics potential (CM) diminished rapidly, and no substantial recoveries were observed. No significant changes in the magnitude of the negative potential of organ of Corti (NPOC) were observed. A large negative summating potential (SP) was recorded even when the amplitude of the CM had diminished.

Effects of single and combined chemotherapeutic agents on hemopoietic stem cells in mice.

Bone marrow cell responses to injections of nitrogen mustard, oncovin, procarbazine, hydrocortisone, and a regimen of all four drugs (MOPH) were evaluated in CRF1 and C57B1/6 mice by determining bone marrow cellularity and content of transplantable colony forming units (CFU) after treatment. The study was done to determine whether the combined regimen, which is widely used clinically in treatment of disseminated Hodgkin's disease, is more or less detrimental to the hemopoietic system than the same drugs used as single agents. Nitrogen mustard and procarbazine used clinically as single drugs are given in three and two times, respectively, greater doses than in the combined regimen. Hydrocortisone, given singly, was least toxic of the drugs, reducing the CFU/femur to 63% and 71% of control values. MOPH appeared slightly more toxic than hydrocortisone, resulting in 41% and 52% of the CFU/femur surviving, and was about equally as toxic as oncovin alone. Nitrogen mustard and procarbazine, administered as single drugs in high doses, were highly suppressive, resulting in only 10-19% survival of CFU/femur, whereas, reduced doses of the two drugs as used in the MOPH regimen spared 30-45% of the CFU/femur. Survival of CFU after MOPH treatment was three to four times greater than after high doses of nitrogen mustard or procarbazine alone. The component drugs of the combined regimen did not act on separate populations of stem cells to produce an additive effect but appeared to inactivate the same population of cells.

The role of granulocytes in the activation of intravascular coagulation and the precipitation of soluble fibrin by endotoxin

This study examines the role of neutrophils (PMN) in the pathogenesis of endotoxin-induced microclot formation. It is intended to clarify whether granulocytes are involved in endotoxin-induced activation of intravascular coagulation (generation of soluble fibrin) and/or in endotoxin-induced precipitation of soluble fibrin. Precipitation of soluble fibrin was achieved by injection of endotoxin into ancrod- infused rabbits with circulating soluble fibrin (first model). Activation of intravascular coagulation was elicited by two intravenous injections of endotoxin into rabbits (second model). Seventy-two and ninety-six hours after injection of nitrogen mustard, leukopenic rabbits had PMN counts between 0 and 50 cells per mul. Neutropenia did not prevent the occurrence of glomerular microclots after infusion of ancrod and injection of endotoxin (first model). Neutropenia influenced neither the decrease in mean fibrinogen concentrations nor the drop in mean platelet counts after ancrod and endotoxin administration. In contrast to the first model, neutropenia prevented the occurrence of glomerular microclots and of circulating soluble fibrin after two injections of endotoxin (second model). It did not, however, protect rabbits from the decrease in mean platelet counts after endotoxin administration. These data indicate that granulocytes are involved in endotoxin-induced activation of intravascular coagulation and the production of soluble fibrin but are not essential to endotoxin-induced precipitation of soluble fibrin.

The Role of Granulocytes in the Activation of Intravascular Coagulation and the Precipitation of Soluble Fibrin by Endotoxin

This study examines the role of neutrophils (PMN) in the pathogenesis of endotoxin-induced microclot formation. It is intended to clarify whether granulocytes are involved in endotoxin-induced activation of intravascular coagulation (generation of soluble fibrin) and/or in endotoxin-induced precipitation of soluble fibrin. Precipitation of soluble fibrin was achieved by injection of endotoxin into ancrod-infused rabbits with circulating soluble fibrin (first model). Activation of intravascular coagulation was elicited by two intravenous injections of endotoxin into rabbits (second model). Seventy-two and ninety-six hours after injection of nitrogen mustard, leukopenic rabbits had PMN counts between 0 and 50 cells per mul. Neutropenia did not prevent the occurrence of glomerular microclots after infusion of ancrod and injection of endotoxin (first model). Neutropenia influenced neither the decrease in mean fibrinogen concentrations nor the drop in mean platelet counts after ancrod and endotoxin administration. In contrast to the first model, neutropenia prevented the occurrence of glomerular microclots and of circulating soluble fibrin after two injections of endotoxin (second model). It did not, however, protect rabbits from the decrease in mean platelet counts after endotoxin administration. These data indicate that granulocytes are involved in endotoxin-induced activation of intravascular coagulation and the production of soluble fibrin but are not essential to endotoxin-induced precipitation of soluble fibrin.

Effect of nitrogen mustard on the development of the bristle organ and on the rate of transdetermination ofDrosophila melanogaster

1. Injection of nitrogen mustard (HN-3) into late third instar larvae ofDrosophila melanogaster and treatment of male foreleg disks with HN-3in vitro results in the following: formation of fewer bristles and hairs, reduction in size of leg parts, alteration of normal bristle patterns, and differentiation of bristle organs without sockets and bracts. 2. When disks, treated with HN-3, were cultivated in adult hosts for 14 days before transplantation into metamorphosing larvae, mostly complete bristle organs were formed, whereby bristles of distal leg parts usually form bracts. 3. Transdetermination is completely suppressed after HN-3-treatment, although proliferation occurs in disks treated with a concentration of 0,02 Μl HN-3 per ml Insect-Ringer. 4. Injection of HN-3 into late third instar larvae results in the induction of somatic mutations. 5. The effect of nitrogen mustard is compared with the effect of mitomycin C treatment and discussed with respect of the suppression of transdetermination.

Experience with Injection of Nitrogen Mustard into Joints of Patients with Rheumatoid Arthritis*

Experience with Injection of Nitrogen Mustard into Joints of Patients with Rheumatoid Arthritis*

Treatment of a giant cutaneous hemangioma by intraarterial injection of nitrogen mustard

Treatment of a giant cutaneous hemangioma by intraarterial injection of nitrogen mustard

The Effects of Nitrogen Mustard on the Intestinal Epithelium of the Mouse

Villus epithelial cells of mice that had received daily injections of nitrogen mustard for 4 days showed a progressive loss of ribosomes, reduction in terminal web material, and failure to absorb and transport lipid in normal amounts from the gut lumen to the lamina propria. There was also a progressive shortening of crypts and villi and occasional loss of epithelium by day 4. These results parallel to a large extent conditions existing in the intestinal epithelium in mice at 3 to 4 days posttreatment with 3 krads of X-rays.

Suppression of virus-induced corneal toxicity in rabbits by pretreatment with nitrogen mustard.

SummaryPretreatment of rabbits with 2 intravenous injections of nitrogen mustard (HN2) partially suppressed production of NDV-induced toxic corneal reactions. In most animals this treatment suppressed development of opacity and reduced markedly the extent of fusions of endothelial cells. It did not inhibit formation of endothelial rosettes. The suppressive effects in the HN2-treated animals lasted for at least 20 days, well after leucopenia had disappeared. Decreased response to injected virus is neither a result of suppression of circulating leucocytes nor of rapid inactivation of virus in aqueous humor.Treatment of rabbits with a single intravenous injection of HN2 4 days, 2 days, or immediately before virus injection caused no demonstrable suppression of virus-induced toxic reactions of rabbit corneas. Leucocytes appeared to play no essential role in production of corneal reaction.The authors wish to express their deep gratitude to Dr. C. A. Evans for advice and criticism during this investigation.

Intra-Aortic Nitrogen Mustard for the Palliation of Advanced Pelvic Cancer

A feeling of despair grips each of us when we face the problem of the management of intractable pain and pressure symptoms due to advanced incurable pelvic cancer. At this point the life expectancy may be brief, finances are depleted, and the patient's courage is nearly exhausted by the unrelenting course of his disease. In the interest of diminishing or alleviating the symptoms in the most rapid, least traumatic, and least expensive way possible, we have utilized nitrogen mustard introduced into the aorta in the manner to be described. Our experience in treating 52 patients over a seven-year period will be recounted here. The systemic use of HN2 has had widespread and beneficial application for many years. Our interest in its more localized and concentrated use by the arterial route was stimulated by the report of Klopp and associates in 1950 describing the experimental treatment of malignant tumors (17). Their experimentation followed the accidental intra-arterial administration of HN2 and the recognition of its potentiality. In animals they have shown radiomimetic tissue changes following the arterial distribution of nitrogen mustard, which could not be reproduced by intravenous doses of even lethal amounts of the drug. The rapid alleviation of symptoms in certain patients is consistent with the experimental evidence of Sugar and Kellner (21) that some cellular effect appears as early as ten minutes after injection of nitrogen mustard. The evidence of nuclear injury is seen microscopically in thirty to sixty minutes (21). Klopp states that the maximal microscopic cellular effect is demonstrable in twelve to twenty days. He observed some clinical reduction in the size of cervical and vaginal tumors approximately four days after intra-aortic injection of HN2 and a marked effect in eight days (18). The rapidity of action as compared with conventional radiation therapy provides an advantage which can well be utilized in dealing with intractable pain and pressure symptoms. Advanced malignant tumors of the head and neck, extremities, skin, and liver, as well as of the pelvis, have been treated with intra-arterial nitrogen mustard (4, 9, 13, 20). In those patients with sufficient life expectancy, if the skin tolerance dose has not been surpassed, the combined use of intra-aortic HN2 and external roentgen therapy has sound theoretical and experimental support (2, 3, 14, 16, 23). Fourteen cases receiving combined therapy are included in our group. method The intra-aortic administration of nitrogen mustard is carried out on a radiographic table in the radiology department approximately one hour after premedication with Demerol or scopolamine. General anesthesia is usually not needed.

骨髓の病態生理に関する研究

Today anatomical studies on the bone marrow, particularly on features of vascular construction are almost completely known, and no one can refute that more than a half of the bone marrow is composed of blood vessels, thus naturally the space occupied by the vessels is quite extensive. In view of this, with the use of an isotope I131 as a tracer, the author has estimated in figures the volume of blood in the bone marrow of adult rabbits as well as that of the spleen whose vascular construction is similar to that of the bone marrow at the same time measured in the same manner the volume of blood in the bone marrow and the spleen of various experimental anemic rabbits. After comparing the results of those two groups, the following data have been obtained:1) On the average, 0.5 c. c. of blood is contained in 1 g. of the bone marrow of the normal rabbit, the average of 0.44 c. c. in the spleen, and in 1 g. of muscle 0.07 c. c. of blood is containd on the average, thus it is clear that both the bone marrow and spleen are the organs rich in blood. Especially the voluminousness of the blood vessels in the bone marrow has been proven in figures from the peculiar vascular construction itself which enables an anatomical estimation.2) The amounts of blood in the bone marrow and spleen decrease accompanying the decrease in the amount of blood in the circulation by bleeding, and following the recovery of the amount of circulating blood the recovery in the spleen is faster than that in the bone marrow. This due to the fact that the spleen is more elastic of the two organs.3) As regards various experimental anemic rabbits, especially in those caused by leucocyte toxins (x-ray irradiation, injection of nitrogen mustard, or administration of benzol), the amount of blood in the bone marrow has been found to have decreased in the bone marrow whereas in the spleen it has been found to have increased. This phenomenon can be explained by the fact that in the bone marrow it is caused by disturbances of blood circulation while in the spleen by hyperemia.Again in the case of injection of phenylhydrazin which is considered to be especially toxic to erythrocytes, the amounts of blood both in the bone marrow und spleen do decrease but this is so because in this case the blood circulation is disturbed in both organs.