[Analysis of beta-propiolactone by gas chromatography. I. A residue of beta-propiolactone in rabies vaccine. II. Hydrolysis of beta-propiolactone at pH 7.4].
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Comparison of the clastogenic and carcinogenic effects of intravenous beta-propiolactone and benzo(a)pyrene in rats.
Scored at 24 hours, the LD-50 of a solution of beta-propiolactone administered intravenously to young rats was 225 +/- 55 mg/kg. Twenty-four hours after a single intravenous injection (100 mg/kg = 1.4 m mole/kg) of beta-propiolactone into male and female rats of both the Long-Evans and Sprague-Dawley strains, the incidence of breaks found in the chromosomes of metaphase marrow cells was low (8.8 percent vs. 5.0 percent in controls). The s5 chromosomes were preferentially damaged. A 200 mg/kg dose increased the incidence modestly to 11.3 percent. In comparison, a single intravenous dose of benzo(a)pyrene (40 mg/kg = 0.16 m mole/kg) produced a break incidence of 19 percent. In long-term experiments multiple (five) intravenous injections (100 mg/kg each) of beta-propiolactone given in a 6 week period elicited only two neoplasms (a chloro-leukemia and a mammary fibroadenoma) among 37 animals during the following 12-13 months. In contrast, four injections of benzo(a)pyrene (40 mg/kg) produced a 14-times greater mammary tumor incidence in the Sprague-Dawley female rat than did beta-propiolactone. Marrow cell chromosome examination indicated no significant chromosomal changes due to the earlier beta-propiolactone treatment except for one animal with a consistent 43-chromosome karyotype resulting from S1 trisomy; no neoplasm was evident in that animal. Earlier treatment with benzo(a)pyrene produced a persistent and significant elevation in break incidence. Both the carcinogenic and clastogenic effects of intravenous beta-propiolactone are low in rats and are not comparable in magnitude to those produced by benzo(a)pyrene.
Animals↗
Elimination and organ distribution of intravenously administered allogeneic and xenogeneic IgG modifications. (Standard IgG, F (ab)2-fragments and beta-propiolactone treated IgG) in dogs.
Dog IgG was produced by fractionation procedures used for the production of clinically used i.v. gammaglobulins. Chemical modification of dog IgG was done by pepsin or beta-propiolactone treatment. The intravascular half-life of beta-propiolactone IgG was 8.5 +/- 2.1 days compared to 4.5 +/- 1.6 days of pepsin treated IgG. Tissue concentrations of radioactive labelled beta-propiolactone IgG were generally higher than of pepsin digested IgG. Pepsin treated Igg was degraded to a significantly higher extent (26% of the administered radioactivity was bound to fragments smaller than 6000 MW after three days) than beta-propiolactone IgG (9% fragments after the same interval, P less than 0.001). It is concluded that the short intravascular half-life of pepsin IgG cannot be explained by increased extravascular filling, but is due to rapid degradation and excretion via the kidneys. There was no obvious difference in elimination and organ distribution between standard and beta-propiolactone IgG.
Animals↗
Effect of beta-propiolactone treatment on the complement activation mediated by equine antisera.
Reduction of complement activation through an alteration of the Fc fragment of immunoglobulins by beta-propiolactone treatment was carried out in equine antisera raised against rabies virus, Bothrops venoms and diphtherial toxin. Results were evaluated by means of an anaphylactic test performed on guinea-pigs, and compared to the ones obtained with the same sera purified by saline precipitation (ammonium sulfate), followed or not by enzymatic digestion with pepsin. Protein purity levels for antibothropic serum were 184.5 mg/g and 488.5 mg/g in beta-propiolactone treated and pepsin-digested sera, respectively. The recovery of specific activity was 100% and 62.5% when using antibothropic serum treated by beta-propiolactone and pepsin digestion, respectively. The antidiphtherial and anti-rabies sera treated with beta-propiolactone and pepsin presented protein purity levels of 5,698 and 7,179 Lf/g, 16,233 and 6,784 IU/g, respectively. The recovery of specific activity for these antisera were 88.8%, 77.7%, 100% and 36.5%, respectively. beta-propiolactone treatment induced a reduction in complement activation, tested "in vivo", without significant loss of biological activity. This treatment can be used in the preparation of heterologous immunoglobulins for human use.
Animals↗
Capillary gas chromatographic determination with electron capture detector of beta-propiolactone in biological materials.
A method has been developed for the determination of beta-propiolactone by derivatizing it to the volatile N-hexyl-3-heptafluorobutanoyloxypropanamide, which can be separated and identified by a capillary CP-Sil 8 column, and detected by an electron capture detector (ECD). First, beta-propiolactone is reacted with N-hexylamine to yield N-hexyl-3-hydroxypropanamide. The fluorobutanoyl ester derivative is next prepared by using heptafluorobutyric acid anhydride in the presence of trimethylamine. The method is very sensitive, simple, and specific, and can be used to detect and quantitate residual beta-propiolactone in lyophilized biological materials. The limit of detection is 0.2 ppm beta-propiolactone in a 50 mg sample; however, because of variability at low levels, the limit of quantitation is 1 ppm. Detector response was linear for 2-500 mg beta-propiolactone. Recoveries were 98% or greater from lyophilized vaccines spiked at the 2-20 ppm level. No side products or interference peaks were observed in the derivatization reaction.
Chromatography, Gas↗
Effect of beta-propiolactone inactivation of polyoma virus on viral functions.
Polyoma virus was inactivated by treatment with beta-propiolactone. T-antigen production, polyoma-RNA synthesis, induction of host DNA synthesis (measured by incorporation of labeled thymidine into the cell culture), and in vitro transforming ability were inactivated to a similar degree by various beta-propiolactone concentrations (0.25% beta-propiolactone reduced these functions approximately 96%), whereas plaque-forming ability and the ability of the virus to replicate its DNA and to synthesize capsid antigen were inactivated by a given concentration of beta-propiolactone to a much greater degree (0.25% beta-propiolactone led to a reduction of plaque-forming ability of over 8 logs). The significance of these data and their relationship to previously published experiments are discussed.
Animals↗
The reaction of beta-propiolactone with derivatives of adenine and with DNA.
The reaction of deoxyadenosine with beta-propiolactone produces two derivatives. One is 1-(2-carboxyethyl)-2'-deoxyadenosine (CEdA) first described by Maté, et al. The proposed structure for the other is 3-(beta-D-2-deoxyribosyl)-7,8-dihydropyrimido-[2,l-i]purine-9-one (dDPP). Spectral characteristics of both compounds are presented. These include u.v. spectra of each in acidic, neutral and alkaline solutions, i.r. spectra, fluorescence spectra, and n.m.r. spectra. The extinction coefficient for CEdA is 12,900 M--1cm--1 at 258 nm and that for dDPP is 12,400 M--1cm--1 at 305 nm. The dDPP can be converted to CEdA by mild acid hydrolysis, and the CEdA can be converted to dDPP by reaction with a carbodiimide derivative. When poly A was reacted with beta-propiolactone, the yield of dDPP in the polymer was 7-9%. When double-stranded DNA was alkylated by [3H]beta-propiolactone at relatively high concentrations and then acid hydrolyzed to separate 1-(2-carboxyethyl)adenine (CEA) and 7-(2-carboxyethyl)guanine (CEG), a CEA to CEG ratio of up to 0.62 was obtained. With relatively low concentrations of [3H]beta-propiolactone, the yield of CEA was low with double-stranded DNA but was 5--6 fold greater with single-stranded DNA.
Adenine↗
IgE and IgG antibodies to beta-propiolactone and human serum albumin associated with urticarial reactions to rabies vaccine.
We examined the antibody response to a rabies vaccine doubly inactivated with 0.025% beta-propiolactone and 0.1% tri(n)butyl phosphate and stabilized with 2.5% human serum albumin. Antibodies were measured by using the following four antigen preparations: complete doubly inactivated rabies vaccine, rabies vaccine inactivated only with tri(n)butyl phosphate, beta-propiolactone and human serum albumin, and human serum albumin alone. The fluid phase of the preparation of beta-propiolactone and human serum albumin completely inhibited IgE binding to solid-phase vaccine. Of 21 subjects with urticarial reactions to a booster, 19 had IgE to doubly inactivated vaccine and to beta-propiolactone and human serum albumin. None of 27 immunized subjects without urticaria had detectable IgE. In paired pre- and postimmunization sera, IgE appeared in six of seven of the subjects with urticaria and in one of seven nonreactors. These sera did not contain a significant level of IgE to singly inactivated vaccine or to human serum albumin alone.
Antibodies, Viral↗
Inactivation of HIV in plasma derivatives by beta-propiolactone and UV irradiation.
The inactivation of HIV in human plasma and plasma derivatives by combined treatment with beta-propiolactone and UV-irradiation was investigated. beta-propiolactone inactivated greater than or equal to 3.5 log10 and UV greater than or equal to 2.8 log10 HIV in plasma and beta-propiolactone greater than or equal to 3.5 log10 in cryoprecipitate and UV irradiation greater than or equal to 4.5 log10 in factor VIII concentrate.
Drug Contamination↗
Inactivation of poliovirus with beta-propiolactone.
The recovery of poliovirus D-antigen after virus inactivation was studied for two inactivating agents (beta-propiolactone and formalin) using the three poliovirus types (Sabin types 1, 2 and 3). With beta-propiolactone (BPL), D-antigen recoveries were high (88, 88 and 60%, respectively) but were significantly less when formalin was used (22, 15 and 25%). beta-Propiolactone inactivated virus was purified, combined with Freund's adjuvant and used to hyperimmunize rabbits. High titres (50 000-200 000) of specific neutralizing antibody were obtained.
Animals↗
Principles of selective inactivation of viral genome. VI. Inactivation of the infectivity of the influenza virus by the action of beta-propiolactone.
The kinetics of inactivation of the infectivity of the influenza virus by beta-propiolactone have been studied. Rate constants have been determined for inactivation of the A/Leningrad/385 (H3N2) and B/Leningrad/489/80 influenza virus under the action of beta-propiolactone on a virus-containing allantoic fluid and on a purified viral suspension. The data obtained allow calculation of the time required for inactivation of the influenza virus infectivity to a given extent in virus-containing solutions at any initial concentration of beta-propiolactone.
Animals↗
Beta-propiolactone for the inactivation of non-A/non-B type 1 hepatitis virus capable of inducing cytoplasmic tubular ultrastructures in chimpanzees.
Non-A/Non-B type 1 hepatitis virus may be recognized because it induces characteristic tubular ultrastructures in the hepatocyte cytoplasm of chimpanzees. 3 chimps received 0.1 ml of a chimp serum containing more than 100 chimp infecting units of non-A/non-B type 1 hepatitis virus after it had been treated with beta-propiolactone with or without combined ultraviolet irradiation. All of the chimps escaped infection throughout the observation period of 23 weeks. The treatment of the serum with beta-propiolactone at the mildest condition employed (0.05%, 4 degrees C, 20 min) was still effective in inactivating the virus. The susceptibility of the chimps was ascertained by the subsequent challenge with 0.1 ml of the untreated serum which invariably induced non-A/non-B type 1 hepatitis in them. On the basis of these results, beta-propiolactone was extremely efficacious for the cold sterilization of non-A/non-B type 1 hepatitis virus.
Animals↗
Inhibition of beta-propiolactone-induced mutagenesis and neoplasia by sodium thiosulfate.
Studies have been initiated to find compounds that can trap direct-acting carcinogens within the stomach. Sodium thiosulfate (STS) is a potent nucleophile and in initial experiments was found to inhibit mutagenesis resulting from exposure of Salmonella typhimurium strain TA100 to the direct-acting carcinogens beta-propiolactone and styrene oxide. In in vitro experiments STS was shown to maintain its nucleophilicity in the acid pH range. It reacted with beta-propiolactone as rapidly at pH 2 as at pH 7.4. Thus STS has the prerequisite attributes to inhibit the carcinogenic effects of electrophiles in the stomach. Experiments were performed in which STS was administered by p.o. intubation to female A/J mice 5 min before p.o. administration of beta-propiolactone. Under these conditions, inhibition of formation of the forestomach tumors occurred. The data obtained suggest that use of nucleophiles to protect against direct-acting carcinogens is a potential strategy for chemoprevention.
Animals↗
On the mutagenicity and immunogenicity of a beta-propiolactone-treated therapeutic IgG-preparation.
During the production of Intraglobin, an i.v. tolerable IgG-immunoglobulin preparation, fraction Cohn II is treated with beta-propiolactone. Thereby the IgG-molecules are chemically modified thus preventing an increase in secondary aggregates which could give rise to adverse reactions in the patients treated with the IgG-preparation. The safety tests described here neither showed any evidence for the presence of unhydrolysed mutagenic-beta-propiolactone in the final product nor that neoantigenic determinants had been created by the reaction of beta-propiolactone with the protein molecules.
Animals↗
[Experimental studies and clinical experiences with homologous tendon grafts preserved with beta-propiolactone].
In dog experiments homologous tendon grafts preserved in beta-propiolactone have been examined by means of light-polarisation microscope and electronmicroscope. The histologic data showed that grafts preserved by beta-propiolactone were completely reorganised within 8 weeks after the transplantation similarly to autologous grafts. This process takes place with very little initial inflammatory reaction, followed by fibroblast reaction. The original collagen fibrous framework is decomposed and new tendon is formed by new collagen fibres on this frame. Cicatrisation was not encountered and graft function was excellent. Functional results in 5 patients were investigated 2 years after replacement of the flexor tendons of the hand and were found to be good in 4 cases, satisfactory in 1 case. The results of animal experiments and the excellent experience with preliminary clinical application of the method suggest that homologous tendon grafts preserved in beta-propiolactone may be used for replacement of injured human flexor tendons of the hand.
Adult↗
Validation of virus inactivation and removal for the manufacturing procedure of two immunoglobulins and a 5% serum protein solution treated with beta-propiolactone.
Intravenous immunoglobulins and serum protein solutions are manufactured from human plasma pools of healthy, screened donors. A step-by-step validation of virus removal and/or inactivation was performed for the manufacturing process, which includes cold ethanol fractionation, beta-propiolactone (beta-PL) treatment, UV irradiation, thermal inactivation and other chemical and physical purification steps. The total viral clearance factors achieved for the entire manufacturing process were by several magnitudes greater than the potential virus load of current plasma pools. Human immunodeficiency virus 1 (HIV-1) infectivity was reduced by > 13.4 log for 7S immunoglobulin, > 15.3 log for IGM enriched immunoglobulin and > 16 log for a 5% serum protein solution. In addition, high clearance rate for a broad spectrum of model viruses was demonstrated for all three blood derivatives being > 23.2 to > 27.8 log for pseudo rabies virus (PSR), > 12.3 to > 22.6 log for vesicular stomatitis virus (VSV) and 6.9-10.6 log for simian virus 40 (SV40). For the beta-propiolactone inactivation step Hepatitis C model viruses, e.g. equine arteritis virus (EAV) and bovine viral diarrhoea virus (BVDV) were also investigated.
Blood↗
Evaluation by polymerase chain reaction on the effect of beta-propiolactone and binary ethyleneimine on DNA.
Inactivating treatments for viruses such as pasteurization or alkylation by beta-propiolactone or binary ethyleneimine were tested for their capacity to modify nucleic acids. The modification of a nucleic acid was measured as the decrease in spot intensity in Southern blots after polymerase chain reaction (PCR) amplification. The inactivating treatments were applied to cellular and viral genomic material from a human lymphoblastoid cell line immortalized by Epstein Barr Virus (EBV), which produced a monoclonal antibody. Pasteurization did not modify the ability to amplify and detect cellular or viral DNA. Binary ethyleneimine strongly reduced the amount of detectable DNA and beta-propiolactone under particular conditions of incubation abolished all trace of DNA.
Alkylating Agents↗
Reactions of beta-propiolactone, beta-butyrolactone and gamma-butyrolactone with nucleic acids.
Reactivity of beta-propiolactone, beta-butyrolactone and gamma-butyrolactone with guanosine, RNA, DNA and 4-(p-nitrobenzyl)pyridine was studied. beta-Propiolactone was 50--100 times more reactive with all the nucleophiles than beta-butyrolactone whereas gamma-butyrolactone was completely inactive. The rate of alkylation by the lactones was guanosine greater than RNA = denatured DNA greater than double-stranded DNA. The type of the adducts formed were characterized by fluorescence and ultraviolet spectroscopy. Similar alkylation products were formed by the two lactones. The main sites alkylated were N-1 at adenosine, N-3 at cytidine and N-7 at guanosine. The results suggest that the carcinogenic potency of the lactones correlates with their reactivity rather than with specificity of the adducts formed.
4-Butyrolactone↗