Situational smoke toxicity testing: hazard assessment as the 'front end' of a smoke toxicity test.

Traditionally, the toxic potency of the smoke from a material or product is part of the assessment of the fire hazard in a given scenario. The assessment also requires a knowledge of virtually all the details of the fire environment and, until they are identified, a 'safe' or 'acceptable' level of smoke toxicity is a term without meaning. This paper suggests a method of using the knowledge of these factors to simplify smoke toxicity testing. Faster, cheaper, and better-targeted smoke toxicity tests would result if the rest of the hazard assessment were carried out first. This is accomplished by determining or specifying all the relevant fire properties except the toxic potency, identifying the other environmental conditions (such as those typical of an aircraft cabin interior) and the desired tenability limits (such as the minimum necessary escape time), and then solving the equations for the buildup of toxic conditions in terms of the single remaining unknown, the toxic potency. The result is the greatest toxic potency which would meet the requirements of the analysis. In this approach, a material or product is acceptable if its smoke is no more toxic then the computed result and unacceptable if it is not. It would not be necessary to obtain an EC50 (product concentration which will cause an effect in half the animals) or dose-response profile, only the response at whatever dose is dictated by the analysis. Two sample cases are presented to illustrate the technique.

Pyrrolo[1,4]benzodiazepine antitumor antibiotics: relationship of DNA alkylation and sequence specificity to the biological activity of natural and synthetic compounds.

The DNA alkylation and sequence specificity of a group of natural and synthetic pyrrolo-[1,4]benzodiazepines [P(1,4)Bs] were evaluated by using an exonuclease III stop assay, and the results were compared with in vitro and in vivo biological potency and antitumor activity. The P(1,4)B antibiotics are potent antitumor agents produced by various Actinomycetes, which are believed to mediate their cytotoxic effects by covalent bonding through N-2 of guanine in the minor groove of DNA. In this article we describe the results of a sensitive DNA alkylation assay using exonuclease III which permits both estimation of the extent of DNA modification as well as location of the precise guanines to which the drugs are covalently bound. Using this assay, we have evaluated a series of natural and synthetic compounds of the P(1,4)B class for their ability to bind to DNA and also determined their DNA sequence preference. The compounds included in this study are P(1,4)Bs carrying different substituents in the aromatic ring, having varying degrees of saturation in the five-membered ring, or differing in the stereochemistry at C-11a. These same compounds were evaluated for in vitro cytotoxic activity against B16 melanoma cells, for potency in vivo in B6D2F1 mice (LD50), and for antitumor activity (ILSmax) against P388 leukemia cells. A good correlation was found between extent of DNA alkylation and in vitro and in vivo potency. Furthermore, on the basis of electronic and steric considerations, it was possible to rationalize why those compounds that showed negligible biological activity were unable to bond covalently to DNA. Last, we have determined that the degree of saturation in the five-membered ring of the P(1,4)Bs has a significant effect on the DNA bonding reactivity and biological activity of this class of compounds.

The NCI Drug Information System. 4. Inventory and Shipping Modules.

The Inventory/Shipping package of the NCI Drug Information System (DIS) is designed to support all inventory and shipping operations associated with the testing by the NCI of large numbers of chemicals for anticancer activity. Two major databases, an Inventory database and a Shipping History database, contain all of the data associated with these operations. Software that supports the operations in an online interactive manner also provides for the accessing and updating of these databases as necessary. Special hardware in the form of barcode reader/printers and digital balances is also interfaced to the system to improve the efficiency of the operations.

Aridicins, novel glycopeptide antibiotics. II. Isolation and characterization.

A new antibacterial antibiotic complex, aridicin, was produced by a new genus, Kibdelosporangium aridum (SK&F-AAD-216). The individual factors, aridicins A, B and C, were isolated from the fermentation broth by an Amberlite XAD-7 resin extraction and purified by preparative reversed phase HPLC. The aridicins were found to be novel members of the glycopeptide class of antibiotics as exemplified by ristocetin and vancomycin, based on chemical and spectroscopic data, their molecular weights as determined by FAB mass spectrometry (1,786, 1,800 and 1,814), the detection of actinoidinic acid in their acid hydrolysates, and detailed TLC and HPLC comparisons with representative members of this class.

The aminoglycoside antibiotics.IV. Synthesis of aminodeoxy analogs of neamine.

An efficient synthesis of the key 3',4'-galacto epoxide intermediate 4 obtained from the known 5,6-O,O'-cyclohexylidene-N,N'-bis-(methoxycarbonyl)-4-O-[2,6-bis(methoxycarbony lamino)-alpha-D-glucopyranosyl]-2-deoxystreptamine (5) is described. Treatment of this epoxide with sodium azide, followed by reduction and acetylation, yielded the protected4'-amino-4'-deoxyneamine 18 (3',4'-diequatorial), whereas treatment with ammonia followed by acetylation yielded the protected 3'-amino-3'-deoxyneamine analog 19 with a diaxial configuration of its 3' and 4' positions. Reaction of the previously described protected 3',4'-allo epoxide 3 with sodium azide yielded separable mixtures of the protected 3'-amino-3'-deoxyneamine 14 and the protected diaxial 4'-amino-4'-deoxyneamine isomer 13, the ratios of products depending on the solvent temperature. Structural assignments for 13, 14, 18 and 19 were based on their PMR spectra. An additional 4'-amino-4'-deoxyneamine analog (24) with an axial configuration as its 4' position was also prepared by azide displacement of an approximately protected 4'-methanesulfonyl neamine intermediate 10. The five protected isomers were deblocked to yield a series of aminodeoxyneamine analogs (15, 16, 20, 21 and 25), all of which were less active in vitro than neamine against a group of Gram-positive and Gram-negative bacteria.

In vitro and in vivo laboratory studies on three hydroxyiminophenylacetyl cephalosporins with particular reference to SK&F 80303, an unusually long-acting cephalosporin.

Three cephalosporins with 7-(2-hydroxyiminophenylacetamido) side chains (SK&F 79433, 80000 and 80303), differing in their 3-substituents, exhibited similar broad-spectrum antibacterial activity in vitro against strains of Staphylococcus aureus, Streptococcus faecalis and various Gram-negative bacilli. All three were active in vivo (s.c., mouse) against S. aureus, Escherichia coli or Klebsiella pneumoniae, but they differed significantly in serum pharmacokinetic profiles. SK&F 80303 produced high and extremely prolonged serum levels and protected mice when administered up to 24 hours prior to challenge with beta-lactamase-producing S. aureus or K. pneumoniae. It was resistant to hydrolysis by beta-lactamases from S. aureus, and variably so to beta-lactamases from E. coli strains. SK&F 80303 was bacteriolytic to logarithmically growing S. aureus, E. coli, Proteus mirabilis, K. pneumoniae and Enterobacter cloacae (partially). SK&F 80303 illustrates further the effect of the 3-sulfoalkyltetrazole substituent on the pharmacokinetic properties of cephalosporins. Its combined biological properties make it a possible candidate for therapeutic and long-term prophylactic use.

SK&F 75073, new parenteral broad-spectrum cephalosporin with high and prolonged serum levels.

SK&F 75073, a new parenteral cephalosporin, was found to have broad in vitro and in vivo antibacterial activity including isolates usually resistant to cephalothin and cefazolin. This activity included indole-positive Proteus and Enterobacter species and some Serratia isolates. Proteus mirabilis strains were particularly susceptible, as were Haemophilus influenzae and Neisseria species. The activity of SK&F 75073 against gram-positive bacteria was poorer than that of the control cephalosporins. This cephalosporin is highly bound to serum proteins, and a loss in in vitro activity was observed in the presence of serum. Parenteral administration of SK&F 75073 to experimental animals (mice, dogs, squirrel monkeys) resulted in high and prolonged serum levels when compared with cefazolin and other injectable cephalosporins. This favorable serum profile was reflected in the excellent protection observed in mice infected with pathogenic bacteria.

Semisynthetic cephalosporins. Synthesis and structure-activity relationships of analogues with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones.

The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.

Semisynthetic cephalosporins. Synthesis and structure-activity relationships of 7-sulfonylacetamido-3-cephem-4-carboxylic acids.

The synthesis and in vitro and in vivo activities of a series of 7-sulfonylacetamido-3-cephem-4-carboxylic acids with acetoxymethyl or heterocyclic thiomethyl substituents at the 3 position are described. Lengthening the alkyl chain attached to the sulfonyl group increased gram-positive activity but the effect on gram-negative activity was variable. Other structural changes on the 7-acyl side chain resulted in only minor changes in vitro activity. the protective effectiveness in infected mice generally paralleled the in vitro activity, except that the butylsulfonyl derivatives were less protective than predicted by in vitro activity. replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in an overall improvement of activity both in vitro and in vivo.

Orally active 7-phenylglycyl cephalosporins. Structure-activity studies related to cefatrizine (SK&F 60771).

The synthesis of a series of related broad-spectrum 7-phenylglycyl cephalosporins with 3-heterocyclicthiomethyl substituents is described. The effects of benzene-ring hydroxylation and 3-substituent variation on the in vitro antibacterial activity, height and duration of mouse serum levels, and effectiveness in protecting against bacterial infection in the mouse are examined. Included for comparison are cephalexin, cephaloglycin and their ortho-, meta- and para-hydroxy derivatives. The biological properties examined were influenced by the position of the hydroxyl group and by the nature of the 3-substituent. The 7-(p-hydroxyphenylglycyl)-3-heterocyclicthiomethyl analogs were found to produce significantly higher serum levels on oral administration to mice than their unhydroxylated counterparts. This effect was not observed with the 7-(m-hydroxyphenylglycyl)-3-heterocyclicthiomethyl cephalosporins, nor with the p-hydroxyphenylglycyl analog of cephalexin. While m- and p-hydroxylation had little effect on in vitro activity and o-hydroxyphenylglycyl cephalosporins tested had very low antibacterial activities and were not examined further. One derivative, 7-[R-2-amino-2-(4-hydroxyphenyl)acetamido]-3-(1H-1, 2, 3-triazole-4(5)-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 60771) was found to have outstanding in vitro and in vivo activities along with oral and subcutaneous serum levels in the mouse that were significantly higher than those obtained with cephalexin. This derivative which has been given the generic name cefatrizine was selected for extensive additional biological evaluation.

Laboratory studies with cefatrizine (SK + F 60771), a new broad-spectrum orally-active cephalosporin.

Cefatrizine (SK&F 60771), a new orally-active semisynthetic cephalosporin antibiotic with broad-spectrum antibacterial activity, was compared with cephalexin and cefazolin for in vitro and in vivo antibacterial activity and pharmacokinetic behavior in laboratory animals. The average MIC values obtained with cefatrizine against gram-positive and gram-negative bacteria were superior to those obtained with cephalexin and somewhat poorer than those of cefazolin. In addition, a large percentage of the enterobacter and enterococcus isolates were found to be susceptible. Cefatrizine had a longer biological half-life and a higher peak serum level than either cefazolin or cephalexin when administered parenterally or orally to mice at 20 mg/kg. It had striking in vivo protective activity in mice infected with Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Hemophilus influenzae, Proteus morganii or Staphylococcus aureus reflecting its superior pharmacokinetic profile in this animal species. A variable pharmacokinetic response between animal species was observed when cefatrizine was administered either orally or parenterally to dogs, squirrel monkeys or rabbits.

A new parenteral cephalosporin, SK&F 59962: 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. Chemistry and structure activity relationships.

The synthesis, microbiological profile and in vivo effectiveness in laboratory animals of a series of cephalosporins having 7-acyl substituents derived from methylthioacetic acid are described. Structure-activity relationships examined include the effect of oxidation of the side-chain sulfur atom, replacement of the (side-chain) methyl hydrogens by fluorine and replacement of the 3-acetoxy substituent by thioheterocycles. One derivative, 7-trifluoromethylthioacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (SK&F 59962), was found to have outstanding antibacterial activity in vitro and in vivo.

A new parenteral cephalosporin. SK&F 59962: in vitro and in vivo antibacterial activity and serum levels in experimental animals.

SK&F 59962, a new parenteral cephalosporin was found to have a high order of in vitro and in vivo antibacterial activity against a broad-spectrum of clinical isolates. When tested in vitro against gram-negative organisms, SK&F 59962 was consistently more active than cefazolin and far superior to cephalothin. This new antibiotic had activity equal to that of cephalothin against gram-positive bacteria. Enterobacter species were found to be susceptible to SK&F 59962. In mouse infection studies using bacterial pathogens, SK&F 59962 had protective activity of the order of that of cefazolin and superior to that of cephalothin. Following parenteral administration the serum profile of SK&F 59962 in the mouse, dog and squirrel monkey was similar to that of cephalothin. SK&F 59962 and cephalothin had lower peak serum concentrations and shorter biologic half-lives than those of cefazolin.