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PubMed1980

[Problems of intravenous gammaglobulin therapy (author's transl)].

The presently available i.v. gammaglobulines (GG) can be classified into two groups. Degraded GG are produced by pepsin or plasmin digestion. Intact GG are obtained by beta-propiolactone treatment, acidification at pH or precipitation with polyethylenglycol-hydroxyethylstarch (PEG/HES). The various products have different characteristics with regard to their biological activity (certain functions of complement activation and opsonization are connected with the Fc structure) as well as their elimination (intact GG have longer intra- and extravasal half-life times). While their is no doubt about an effect of GG in animal experiments, little controlled studies have been done for most of the clinical indications. One controlled prospective study showed that in surgical high risk patients the frequency of septic complications can be reduced by prophylactic application of high doses of 7 S-GG. For the future, the development of a broad spectrum of hyperimmunoglobulines seems desirable.

Humans↗
PubMed1976

Chilling of somatic cells unnecessary for Sendai virus-induced heterokaryon formation.

Incubation of cell suspensions or monolayers at 4 degrees C for 20 min after addition of beta-propiolactone-inactivated Sendai virus did not enhance heterokaryon formation as compared to parallel cell cultures incubated at 37 degrees C immediately after the addition of Sendai virus. These findings show that the routine chilling of somatic cells in fusion experiments can be omitted.

Cell Fusion↗
PubMed2000

Cross-protection and reassortment studies with avian H2 influenza viruses.

In order to assess the degree of immune cross-protection among avian H2 influenza virus strains, mice were immunised with beta-propiolactone-inactivated virus preparations and infected intranasally with mouse-adapted variant of A/Black Duck/New Jersey/1580/78 (H2N3) strain. The experiments with 11 avian H2 strains revealed that both Eurasian and American H2 avian influenza viruses exhibit either high or moderate degree of cross-protection. The grouping of the strains in accordance with their cross-protection efficiency does not coincide with H2 phylogenetic branches. Several reassortant clones were obtained with the use of A/Pintail Duck/Primorie/695/76 (H2N3) strain and high-yield X-67 reassortant as parent viruses, among them a high-yield H2N3 reassortant. Taking into account the data on cross-protection among avian H2 strains, the high-yield H2N3 reassortant may be regarded as a prototype strain to be used for the preparation of killed vaccines in the case of a new appearance of avian H2 haemagglutinin in circulation in humans.

Animals↗
PubMed1987

The isolation and characterization of 2-carboxyethyl adducts following in vitro reaction of acrylic acid with calf thymus DNA and bioassay of acrylic acid in female Hsd:(ICR)Br mice.

Reaction of acrylic acid (AA) at pH 7.0 and 37 degrees C for 40 days with 2'-deoxyadenosine (dAdo), 2'-deoxycytidine (dCyd), 2'-deoxyguanosine (dGuo) and thymidine (dThd) resulted in the formation of 2-carboxyethyl (CE) adducts via Michael addition. The alkylated 2'-deoxynucleoside adducts isolated (percent yield after 40 days) were 1-CE-dAdo (5%), N6-CE-dAdo (11%) (via Dimroth rearrangement of 1-CE-dAdo), 3-CE-dCyd (7.5%), 7-CE-Gua (4%), 7,9-bis-CE-Gua (0.9%) (formed by reaction of AA with depurinated 7-CE-Gua during the course of the reaction) and 3-CE-dThd (0.5%). The products isolated following in vitro reaction of AA with calf thymus DNA at pH 7.0 and 37 degrees C for 40 days were (nmol/mg DNA) 1-CE-Ade (9.9), N6-CE-Ade (8.2), 7-CE-Gua (7.2) and 3-CE-Thy (1.9). Compound 3-CE-Cyt was not detected. Thus the adducts formed following in vitro reaction of AA with DNA are identical to those formed by in vitro reaction of the carcinogen beta-propiolactone (BPL) with DNA as reported in an earlier paper. Structures were assigned on the basis of identical UV spectra, Rf values on paper chromatograms and Rt values on HPLC as marker compounds prepared from reactions of BPL with 2'-deoxynucleosides and 2'-deoxynucleotides-5'-monophosphoric acids. AA was assayed for carcinogenic activity by s.c. injection (20 mumol, once a week for 52 weeks) in female Hsd: (ICR)Br mice. Two mice with sarcomas at the site of application were observed out of 30 mice. Malignancies were not observed in solvent and no-treatment controls. The bioassay results reported in this paper and elsewhere in the same strain of mice suggest that AA is a weak carcinogen in female Hsd:(ICR)Br mice.

Acrylates↗
PubMed1983

Effect of environmental carcinogens and other chemicals on murine alpha/beta interferon production.

Mouse embryo fibroblast cultures were pretreated with a variety of chemicals found in the environment. After chemical treatment, polyriboinosinic-polyribocytidylic acid was added to the cultures to induce alpha/beta interferon. Pretreatment of the cell cultures with the chemical carcinogens chloroform and beta-propiolactone severely inhibited the production of alpha/beta interferon, while pretreatment of the cell cultures with their poorly or noncarcinogenic analogs 1,1,1-trichloroethane and gamma-butyrolactone had no effect on interferon induction. Pretreatment of the cell cultures with the possible carcinogen diethylstilbestrol had no effect on alpha/beta interferon induction. Pretreatment of the cells with the poor or noncarcinogens pyrene and ascorbic acid did not effect interferon induction; in fact, treatment with ascorbic acid may have enhanced interferon production. These results augment previous findings that most potent carcinogens can inhibit the induction of alpha/beta interferon.

Animals↗
PubMed1981

A "spiral test" applied to bacterial mutagenesis assays.

A new procedure (the spiral test) has been set up and validated for the distribution of chemicals in bacterial mutagenesis assays. This method involves the use of a special instrument (spiral plater), which dispenses, along a spiral track, decreasing volumes of liquid samples, from the near centre to the periphery of a rotating agar plate. A gradient of concentration of a compound up to about 1500:1 is thus formed on a single plate. The activity of 18 mutagens of various potencies and chemical classes was checked in the Salmonella/microsome test by dispensing their solutions either on the surface of top agar (method A) or of the minimal-glucose agar medium, before the addition of molten top agar incorporating bacteria and eventually S9 mix (method B). Compared with the spot test, the gradient of concentration of a compound produced by the spiral diluter was much wider and more gradual. Even nondiffusible chemicals (e.g. benzo[a]pyrene and benz[a]anthracene) were efficiently detected in the spiral test, as well as very weak (e.g. mebanazine and trimethylphosphate) or borderline (e.g. perylene, 1,1-dimethylhydrazine and procarbazine) mutagens, which were negative in the spot test. Method B was at least as sensitive as the plate-incorporation test, such a goal being achieved in a single plate instead of in serial plates. Technical problems made method A less sensitive, but it was more efficient in detecting unstable mutagens (e.g. beta-propiolactone). Like the plate test, the spiral test appeared to be suitable for a semi-quantitative assessment of mutagenicity data, and was efficient in demonstrating both the activation of promutagens and the deactivation of some directly acting mutagens. Preliminary assays were also carried out with repair-proficient (WP2) or -deficient (TM1080: lexA-/polA-/R391, and CM871: lexA-/uvrA-/recA-) trp- strains of E. coli.

Culture Media↗
PubMed1982

Mutagenic responses of five independent genetic loci in CHO cells to a variety of mutagens. Development and characteristics of a mutagen screening system based on selection for multiple drug-resistant markers.

With the aim of developing a sensitive mutagen screening system, the responses of 15 different chemical mutagens at 5 independent genetic loci in Chinese hamster ovary (CHO) cells have been determined. The genetic markers which have been employed include resistance to thioguanine (Thgr), ouabain (OuaR), the protein synthesis inhibitor emetine (Emtr), the polyamine synthesis inhibitor methylglyoxal bisguanylhydrazone (Mbgr) and the nucleoside analog 5,6-dichlororibofuranosyl benzimidazole (DrbR). The optimal selection conditions for all of these genetic markers in CHO cells have been described. The chemicals whose response was investigated in these studies include direct-acting alkylating agents (ethyl methane-sulfonate, methyl methanesulfonate, beta-propiolactone, ethyleneimine, N-nitrosomethylurea and 4-nitroquinoline-N-oxide), DNA intercalating and cross-linking agents (ICR-170, acridine orange, ethidium bromide, mitomycin C and actinomycin D), polycyclic hydrocarbons (benzo[a]pyrene (B(a)P) and 7,12-dimethylbenz[a]anthracene (DMBA)) and aromatic amines (benzidine and beta-naphthylamine). Simultaneous examination of the response of the set of genetic markers to these chemicals revealed that although all of these chemicals caused a dose-dependent increase in the frequency of mutations at many of the above genetic loci, the magnitude of the mutagenic response at different genetic loci varied greatly depending upon the chemical. Of the genetic loci examined, no one single locus showed higher response to all of the above chemicals, instead, depending upon the chemical, specific loci were found to be more responsive than others. The polycyclic hydrocarbons and aromatic amines were weakly mutagenic in this system at several genetic loci even without any exogenous microsomal activation, although in the presence of a rat liver S9 fraction similar toxic and mutagenic effects of B(a)P and DMBA were observed at 5-20-fold lower concentrations. These results indicate that CHO cells may possess significant capacity for the metabolic activation of many procarcinogens, and also underscore the merits of measuring the mutagenic response at multiple genetic loci in mutagen screening studies.

Animals↗
PubMed1983

Quantitative comparison of carcinogenicity, mutagenicity and electrophilicity of 10 direct-acting alkylating agents and of the initial O6:7-alkylguanine ratio in DNA with carcinogenic potency in rodents.

The quantitative relationship between carcinogenicity in rodents and mutagenicity in Salmonella typhimurium was examined, by using 10 monofunctional alkylating agents, including N-nitrosamides, alkyl methanesulfonates, epoxides, beta-propiolactone and 1,3-propane sultone. The compounds were assayed for mutagenicity in two S. typhimurium strains (TA1535 and TA100) and in plate and liquid assays. The mutagenic activity of the agents was compared with their alkylating activity towards 4-(4'-nitrobenzyl)pyridine and with their half-lives (solvolysis constants) in an aqueous medium. No correlations between these variables were found, nor was mutagenic activity correlated with estimates of carcinogenicity in rodents. There was a positive relationship between carcinogenicity and the initial ratios of 7-:O6-alkylguanine formed or expected after their reaction with double-stranded DNA in vitro. The results suggest that alkylation of guanine at position O6 (or at other O atoms of DNA bases) may be a critical DNA-base modification that determines the overall carcinogenicity of these alkylating agents in rodents.

Alkylating Agents↗
PubMed1986

Comparison of two routes of chemical administration on the lung adenoma response in strain A/J mice.

This study was undertaken to determine the ability of a series of 19 compounds representing different chemical classes of carcinogens to induce lung tumors in strain A/J mice after either ip or po administration. Aflatoxin B1, dibutylnitrosamine, 1,2-dimethylhydrazine, and methylnitrosourea induced a significant increase in the lung tumor response in both sexes after ip and po administration. Azaserine was active in both sexes only after ip administration. Benzene, 1,2-dibromoethane, and epichlorohydrin, following ip administration, produced significant increases in the tumor response in at least one sex. Aflatoxin B1, azaserine, benzene, 1,2-dibromoethane, dibutylnitrosamine, and epichlorohydrin were more active when given ip than after po administration. In contrast, dimethylhydrazine and methylnitrosourea were more active (in females only) when given po. 2-Acetylaminofluorene, azobenzene, chloroform, 1,4-dioxane, FANFT (N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide), lead subacetate, methylmethanesulfonate, beta-naphthylamine, beta-propiolactone, safrole, and 2,4,6-tri-chlorophenol did not induce lung tumors in strain A/J mice. These data confirm previous observations on the importance of the route of chemical administration on the lung tumor response in strain A mice, and on the inability of the lung tumor bioassay to detect certain liver and bladder carcinogens and unstable alkylating agents.

Adenoma↗
PubMed1984

Use of a new chemically modified intravenous IgG preparation in severe primary humoral immunodeficiency: clinical efficacy and attempts to individualize dosage.

Sixteen patients with severe primary humoral immunodeficiency diseases were treated intravenously for 12 months with a beta-propiolactone stabilized preparation of IgG (Intraglobin) as part of a phase II study of safety and efficacy. In order to evaluate the metabolism of IgG in these patients and to determine whether increased doses of IgG would lead to a decrease in the rate of infections, the study was divided into two periods. All patients were infused with a standard dose of 100 mg/kg/month for 6 months and the peak and trough serum IgG concentrations were determined. The half-life of the IgG was determined in each patient after the fourth month and this value was used to calculate the dose necessary to raise the trough serum IgG concentration to a minimum of 200 mg/dl. The patients received this individualized dose in the final 6 months and the half-life determination was repeated at the conclusion of the study. Only 3 of 10 patients who received a higher dose in the second period had a substantial increase in trough serum IgG concentrations, but the failure to achieve higher concentrations was not due to a shortening of the half-life. The Intraglobin was well tolerated with no patient unable to complete the study due to side-effects. Ten percent of the infusions were associated with minor, self-limited reactions, with 16 of the 19 reactions occurring in the first 6 months. There were no life-threatening infections during the 12-month period. A total of 105 episodes of infections were recorded, but only a cumulative total of 51 days of normal school or work activity were lost by the 16 patients during the 12 months of the trial period. Most infectious episodes were due to chronic bronchitis, sinusitis, and otitis. There was no reduction in the number of infections in the second, higher dose period of the study; however, as there was little increase in serum IgG concentration, more data are required before it will be possible to determine if the incidence of chronic infections can be reduced by a further increase in the serum IgG concentration.

Adolescent↗
PubMed1982

[Evaluation of an experimental rabies vaccine by the oral and intestinal route with inactivated vaccines, concentrated or non-concentrated].

Application of beta-propiolactone inactivated rabies vaccine prepared in bovine embryo kidney cells, concentrated or non concentrated, by intestinal or oral route resulted in antibody production in rats and cats. 80-100% of vaccinated rats were protected against challenge with street rabies virus. The same vaccines (lyophilized in gelatin capsules) stimulated antibody production in more than 50% (5/8) cats which received the vaccine by the oral route.

Administration, Oral↗
PubMed1983

Sensitivity of two Chinese hamster cell lines to SCE induction by a variety of chemical mutagens.

SCE induction in Chinese hamster Don (lung) cells was compared with that in CHO (ovary) cells exposed under identical conditions to 14 known mutagens. Test protocols used for comparison were selected following a study of Don and CHO cell responses to aflatoxin B1 and benzo[a]pyrene. In the absence of added metabolizing enzymes 9-aminoacridine, 4-nitroquinoline 1-oxide, N-methyl-N-nitrosourea, dimethylcarbamoyl chloride, beta-propiolactone, daunomycin, aflatoxin B1 and 2-aminoanthracene were directly active in both cell lines; every substance positive in CHO cells was also positive in Don cells. However, the latter detected cyclophosphamide, hydrazine sulphate, benz[c]acridine, 3-methylcholanthrene and benzo[a]pyrene without addition of S9. CHO cells did not respond equivalently to these mutagens, either in the presence or absence of S9. Other differences between the cell lines depended on chemical exposure time, S9 pre-incubation or co-incubation conditions. For example, the ability of CHO cells to detect SCEs due to 2-aminoanthracene was acutely dependent on exposure time. In addition, Don cells exhibited lower background SCE values which were less variable than those of CHO cells under the same culture conditions. Although incapable of detecting 4-dimethylaminoazobenzene (butter yellow) and not as sensitive to cyclophosphamide as certain cell lines of liver origin, the pseudodiploid Don cell line possesses other desirable characteristics required for in vitro SCE assays, particularly with regard to intrinsic metabolic activation of polycyclic aromatic hydrocarbons and related substances.

Aflatoxin B1↗
PubMed1996

Comparison of p24 measurement by ELISA versus indicator cells for detecting residual HIV infectivity in vitro.

Inactivation of HIV-1 contaminated materials or biological samples is of great importance and requires the use of a reliable assay to detect residual infectivity. In this study we treated cell-free or cell-associated (monocyte-derived macrophages) HIV-1 with two chemicals known for their antiviral activities, beta-propiolactone (beta PL) and formaldehyde (FO), and tested it for the presence of residual infectivity. HIV-1 infected primary monocyte-derived macrophages (MDM) or cell-free HIV-1 were fixed with increasing concentrations of either beta PL or FO for 1 day at 4 degrees C. Then either fresh primary MDM or fresh medium was added, and the supernatant p24 levels were assayed up to 12 days after infection. All the supernatants harvested were added to indicator cells, fresh primary MDM, to assess for residual infectivity. The results show that p24 measurement is not a reliable assay for the detection of residual infectious virions after chemical fixation of HIV-infected primary MDM. In contrast, the use of indicator primary cells (MDM) is a much more sensitive and reliable assay. By performing an indicator cell assay we showed that FO efficiently inactivates cell-associated and cell-free HIV-1 at concentrations as low as 1% v/v. In contrast beta PL is more efficient in inactivating cell-free than cell-associated virus and does not inactivate cell-associated HIV-1 at concentrations as high as 1% v/v.

Cells, Cultured↗
PubMed1982

Antibody response to rubella virus proteins in different physical forms.

The immunogenicity of different antigens, containing rubella virus hemagglutinating (HA) membrane protein, was studied using live virus, beta-propiolactone-inactivated virus, detergent and lipid-free octamers and virosomes. Whole virus particles, live or inactivated, induced hemagglutination inhibition (HAI) antibodies in rabbits after one subcutaneous injection of 0.16 micrograms of HA protein. Hemagglutinin rosettes or virosomes failed to induce antibodies even at a dose of 120 micrograms. Apparently, the extraction of viral membrane hemagglutinin, for the preparation of a rubella subunit vaccine, led to destruction of the antigenicity responsible for the induction of hemagglutination inhibiting antibodies. These results are discussed in the light of earlier studies on the preparation of a rubella subunit vaccine.

Animals↗
PubMed1993

Protection of three strains of mice against lethal influenza in vivo by defective interfering virus.

This report examines the protective effects of defective interfering (DI) WSN on three strains of mice (C3H/He-mg (H-2k), C57BL/6 (H-2b) and BALB/c (H-2d)) infected with various doses of A/WSN influenza virus. All three strains were protected in terms of morbidity and mortality, to varying extents, DI WSN protected optimally against a low but lethal dose of A/WSN in C3H/He-mg mice, but also protected this and other strains against very high doses of A/WSN. Intermediate sized inocula gave little, if any, protection. In all cases protection required an active DI genome since inactivation with beta-propiolactone abrogated any sparing effect. Consolidation of the lungs was reduced by treatment with active DI virus, but at some doses of inoculum there was reduction in lung pathology without reduction of mortality. Treatment of infected mice with DI virus did not reduce the lung virus titre, but in C3H/He-mg mice resulted in recovery of infectious virus from other tissues, notably the heart, where it was not normally found. No infectivity was recovered from brain, liver or serum. Haemagglutination-inhibiting (HI) antibody could not be detected in the lungs of any of the infected mice co-inoculated with the control BPL-inactivated DI WSN but was present in considerable amounts in all three strains when these were co-inoculated with DI virus. These and previous data (Morgan and Dimmock, 1992) suggested that influenza virus was immunosuppressive and that active DI virus abrogated these suppressive effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Studies on cell-mediated immune response to rabies virus immunization in dogs.

Peripheral blood leucocytes (PBL) from unvaccinated dogs and dogs vaccinated subcutaneously with beta-propiolactone (BPL) inactivated sheep brain antirabies vaccine were exposed in vitro to rabies antigen. A direct leucocyte migration inhibition (LMI) assay in agarose was used to study the cell-mediated immune (CMI) response. The CMI response could be detected as early as 7 days postvaccination. It reached a peak by 14 days postvaccination followed by a decline. The PBL from unvaccinated control dogs were not stimulated by rabies virus antigen.

Animals↗
PubMed1996

Longitudinal study of an epitope-biased serum haemagglutination-inhibition antibody response in rabbits immunized with type A influenza virions.

This paper describes a longitudinal study of the antibody specificities generated to the haemagglutinin (HA), the major envelope glycoprotein of type A influenza virus particles, during primary and secondary antibody responses in rabbits. Two New Zealand White rabbits (no. 191, no. 192) and an English Half-Lop rabbit (no. 193) were immunized intravenously with beta-propiolactone-inactivated virus at 0, 28 and 56 days. Haemagglutination-inhibition (HI) antibody specificities were measured using neutralizing antibody double escape mutants selected with monoclonal antibodies (mabs) specific for an epitope in antigenic site A, site B and site D. In this regard the epitope reactivity to these mabs was represented as A+B-D-, A-B+D- and A-B-D+, where "+" and "-" represent the non-mutated and mutated epitopes respectively. The HI response was well developed at 7 days after primary immunization and at this time the response was equally divided between all three epitopes. Two rabbits (no. 191 and no. 193), showed a bias to the site B epitope from 14 days onwards, such that about half of the total HI activity was to this epitope and the other half was made up of HI antibody to the other two epitopes in approximately equal proportions. In the other New Zealand White rabbit (no. 192) a non-biased response extended throughout the primary response and for one week after the second immunization. Apart from this, a bias to a single epitope was clearly evident in all rabbits after the second immunization, and this constituted up to 70% of the total HI antibody response. The antibody response did not broaden and remained essentially unchanged even after a third immunizing injection. The observed bias to the site B epitope during the secondary response of HA-specific antibody is in accord with a previous cross-sectional study of nine other rabbits.

Animals↗
PubMed1995

Detection of Newcastle disease virus in poultry vaccines using the polymerase chain reaction and direct sequencing of amplified cDNA.

In order to develop an in vitro method for the control of poultry vaccines for identity and the absence of extraneous agents, reverse transcription-polymerase chain reaction (RT-PCR) was applied for the detection of Newcastle disease virus (NDV). NDV vaccines were employed for the establishment of the method, using two primer pairs spanning the cleavage site of the F0 fusion protein coding sequence. Amplification of a specific cDNA segment was possible from live and inactivated, oil-adjuvanted NDV vaccines without prior treatment. The cDNA was characterized by restriction endonuclease digestion as well as by direct nucleotide sequencing. The RT-PCR was able to detect between 5 x 10(2) EID50 (in live vaccine preparations) and 10(5) EID50 or 0.056 haemagglutinating units of NDV (in inactivated vaccine preparations). In addition, live vaccine preparations were inactivated with beta-propiolactone (beta-PL). Amplified cDNA was obtained after treatment with 0.1% beta-PL, whereas at a concentration of 1% or 10% no specific bands were visible in the agarose gel. These results demonstrate the applicability of the method for the control of poultry vaccines for identity and for the absence of extraneous agents, and additionally allow a rapid characterization of the respective NDV strain.

Animals↗