Vesicant activity

Nitrogen mustards are tertiary hw(2-chloroethyl)amines with vesicant activity (NDRC, 1946). AH are active alkylating agents. The nomenclature, chemical and physical properties of HNl, HN2, and HN3 are summarized in Tables 8.3 and 8.4. Due to their toxicity and various... 

Sesqui-mustard, agent Q, QN2. Solid, Mp 56°C. volatility <1 mg/m3 at 20°C. British laboratory reported vesicant activity to be five times that of mustard gas and this may have been an underestimate. 

Based on the Draft Final Standard Operating Procedure for the EDS (U.S. Army, 2001e), the mixture of sulfur mustard and phenylarsenic chlorides contained in Winterlost is likely to be treated according to the same protocol as HD alone, i.e., 90 percent MEA, 10 percent water, at 60 C for 4 hours. While MEA will break the As-Cl bonds associated with the vesicant activity of DA and PD, it is unclear whether the treatment will break the phenyl-As bonds. Further posttreatment may be needed to prepare the neutralent for disposal. Much the same situation arises with the proposed neutralization of DA and PD in the absence of HD. The Army plans to treat the agent and mnnition residues in the EDS with denatured 95 percent ethanol (or possibly acetone for DA) at ambient temperature for 1 hour. While this treatment will dissolve the organoarsenic compounds and partially hydrolyze the As-Cl bonds, it will produce a neutralent requiring signiflcant further treatment. 

The freezing point of sulfur mustard has been reduced in a number of ways to prevent the agent from solidifying in weapons in cold weather. In WWI, mustard was mixed with various solvents, e.g. carbon tetrachloride and benzene. In WWII, Britain produced it from thiodiglycol and hydrogen chloride as a 6 4 mixture with the oligomer T (Scheme 1.1), also known as O mustard. T has somewhat greater vesicant activity than sulfur mustard, is less volatile and more persistent. Other nations mixed mustard with lewisite, which also accelerated the onset of effects and increased the vapour hazard. 

A number of analogues and oligomers of sulfur mustard with similar or slightly greater vesicant activity were developed as agents of lesser importance (Scheme 1.1). The homologue Q, sesquimustard, is a solid (melting point 57 °C) and like T was mixed with sulfur mustard. 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

Toxins present a variety of both incapacitating and lethal effect. Most toxins of military significance can be broadly classified in one of two ways. Neurotoxins disrupt the nervous system and interfere with nerve impulse transmission similar to nerve agents (Chapter 1). However, all neurotoxins do not operate through the same mechanism of action or do they produce the same symptoms. Cytotoxins are poisons that destroy cells or impair cellular activities. Symptoms may resemble those of vesicants (Chapter 3) or they may resemble food poisoning or other diseases. Toxins may also produce effects that are a combination of these general categories. The consequences of intoxication from any individual toxin can vary widely with route of exposure and dose. In addition, some toxins act as biomediators and cause the body to release excessive, and therefore harmful, amounts of chemicals that are normally produced by the body. 

The blister agents are skin vesicants that evaporate very slowly, although somewhat faster than VX.7 The active ingredient in all these blister agents is bis-chloroethyl sulfide, (C1CH2CH2)2S. HD, called distilled mustard, is nominally pure mustard. H, often... 

The toxic effect of various species of rove beetles pertaining to the genus Paederus on the skin and eyes of mammals, including man, are due to the presence in their hemolymph of three vesicant amides pederin (104), pederone (105) and pseudopederin (106) (Fig. 18) [94,95], pederin being the major and most active of the three compounds. Their structure determination [96, 97] revealed rather unique substances until similar natural products with comparable biological activities were isolated from sponges of the genera Mycale [98,99], Stylinos [100] and Theonella [101-104]. 

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyl-transferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an impaired capacity to sulfate phenol (Ramakrishna et al. 1991), which may increase the amount of unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater surface area. A study in which 10-day-old rats were more sensitive to lethality following oral exposure to phenol than 5-week-old or adult rats (Deichmann and Witherup 1944) further suggests that the young may be more sensitive to phenol. (For a more detailed discussion please see Section 2.6.) Because phenol is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol. Individuals with kidney or liver diseases that impair metabolism or excretion of phenol and phenol metabolites may be more susceptible to phenol. 

Dimercaprol (BAL, British Anti-Lewisite) was developed in World War 11 as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is di-mercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects. 

A review of the literature on experiments to assess possible chronic effects, especially mutagenic activity and carcinogenicity, of the irritant and vesicant agents reveals that these effects have not been studied systematically by current standards and techniques. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

Although the benzyl nitroso compound appears to be a much less active vesicant than the methyl nitroso compound, it is, nevertheless, a wise precaution to wear heavy rubber gloves during the isolation of this product. 

Active alkylating agents have direct vesicant effects and can damage tissues at the site of injection as well as produce systemic toxicity. Toxicities are generally dose-related and occur particularly in... 

Like acid chlorides, anhydrides are activated acid derivatives, and they are often used for the same types of acylations. Anhydrides are not as reactive as acid chlorides, and they are occasionally found in nature. For example, cantharidin is a toxic ingredient of Spanish fly, which is used as a vesicant ( causing burning and blistering ) to destroy warts on the skin. 

Conte B, Maggi CA, Parlani M et al. (1991) Simultaneous recording of vesical and urethral pressure in urethane-anesthetized rats Effect of neuromuscular blocking agents on the activity of the external urethral sphincter. J Pharmacol Meth 26 161-171... 

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