Usage of animals in the European Pharmacopoeia (EP). A comparison between the first and second edition.
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Animal Testing Alternatives↗
Biomedical subjects
W Hennessen
Publications and source records attributed to W Hennessen.
Inactivation of poliovirus.
Inactivation of Polioviruses has been studied extensively in the 1950s and 1960's. It was shown that, to a certain extent, the kinetics of inactivation depend on the viral structure with which the inactivating agents react. Polio-RNA will loose its capacity for multiplication after one hit of an appropriate agent, thus being inactivated in a first order reaction. Multiple hits on the viral protein are needed to render the virus non-proliferate, which is characterized by a second order reaction. Examples for both types of reaction are given. While the "classical" inactivating chemicals are still in use for poliovaccines, other RNA viruses have successfully been treated with other agents and experimentally yet different substances have been described. Aiming for the highest possible antigenicity, the least harmful procedure seems essential. Since the inactivation procedure includes factors other than chemicals, such as temperature, time, pH etc., they too are part of the discussion evaluating the benefits and the shortcomings of the various technologies.
Antigens, Viral↗
Replacement of animals in manufacture and control of vaccines.
The first vaccines were obtained from animals infected with the vaccine viruses. Bacterial vaccines were derived from culture media prepared from animal tissues. In some cases the principles of manufacture remained unchanged for more than a century, the methods only were refined. Animal cell culture was not introduced into vaccine production until the second half of of this century. After more than 25 years the search for non-animal substrates and their improvement still goes on. Control of vaccines lagged behind this progress. After a period of no control for the early vaccines, animal tests enabled immunologists to measure safety and potency, thus eliminating the disasters attributable to unsafe products or failures in protection. In vitro methods of control led to a better understanding of the immunology of vaccines. Replacement of animals in manufacture is now to be paralleled by their replacement in control. This will require courage from both the manufacturer and the controller.
Animals↗
The clinical uses of albumin: report of an IABS study.
Medical indications for the use of human albumin (HA) by the clinician have been described in the past. They were invariably based on the knowledge of the function of the HA molecule and its feasible role in circulation. So these indications in fact became recommendations to the clinician. In recent years various authorities were faced with the necessity to review requirements for HA, wherever they existed, or to define new requirements, where none were considered before. IABS was, therefore, asked to find out if and how the recommended indications were accepted by physicians of various disciplines. Using a questionnaire more than 800 replies were received. These answers and their evaluation permitted the statement that the clinical use of HA is not limited to the recommended one, but used for additional and newer indications with obvious success. In addition it was noted that present requirements by control authorities do not seem to cover sufficiently the needs of the patients.
Blood Banks↗
Clinical requirements for albumin: report of an IABS study.
Requirements for human serum albumin (HSA) asked for by physicians in six countries were analyzed. Compilation of data obtained by a questionnaire revealed differences of opinion that could be traced to the frequency of HSA therapy in the respective country. Where albumin was used frequently clinical and experimental evidence for the efficacy of this therapy was high too, and so was the interest in the binding capacity of HSA for a number of substances. In contrast, negative attitudes towards HSA therapy were reported predominantly from countries where the frequency of use of albumin was low. Since the request to obtain more information on the binding capacity of HSA was strongly expressed by responding physicians, this wish should be considered for future quality control preferably in the process of manufacture.
Bilirubin↗
[Side effects of whooping cough inoculation].
During 1970 to 1977 adverse reactions after pertussis vaccination were reported for 149 children, 56% male and 44% female. Their symptoms permitted to divide the vaccinees into 2 groups: one with more severe (S) and the second with other symptoms (0). No differences were observed in age and sex among the two groups. The interval between vaccination and appearance of first symptoms was longer for the 0 than for the S group. While less than one quarter of the reactions in the 0 group occurred after primovaccination, more than half of the S side effects were seen after the first vaccination. Further analysis of the S group revealed, that all but two of their symptoms (fever and encephalopathy) corresponded to the hypoglycaemic syndrome. The consequences hereof are discussed with regard to prevention and therapy.
Child↗
Report of a working group for the European Pharmacopoeia. Collaborative assay on human albumin of different origin.
A collaborative assay was conducted by 9 laboratories on 31 samples of human albumin which were in clinical use. It was the object of the study to establish test systems which would differentiate between albumins of venous or placental origin. The properties examined for this purpose were: appearance, total protein, haem, polymers, alkaline phosphatase and blood group substances. Additional tests such as for beta-thromboglobulin and citrate were included; pyrogenicity, however, was excluded because this was under study for all plasma proteins at that time. Results obtained were in satisfactory agreement both between laboratories and between samples. They, therefore, enabled the verification of a number of correlations in the test systems. The evaluation did not allow, however, the differentiation of the samples in relation to their origin. The results were, therefore, regarded as a tool to define the upper limits of acceptance for human albumins corresponding to the quality prescribed by the European Pharmacopoeia.
ABO Blood-Group System↗
BCG vaccination of neonates, infants, schoolchildren and adolescents. Part I: Dose finding studies with BCG strain 1331 Copenhagen.
A BCG vaccine prepared from strain 1331 Copenhagen was given to newborns and infants in four logarithmically decreasing doses (expressed in VU = viable units): 25 X 10(4), 11 X 10(4), 5 X 10 (4), and 2.2 X 10(4). The efficacy of the vaccine was determined through the conversion rate (tuberculin skin test) with 2 and 10 T. U. of RT 23, AND 10 AND 50 I. U. of GT (Hoechst). The results indicated that the conversion rate is a function of the dose of VU of the vaccine, as well as of the units of tuberculin used for testing.
Adolescent↗
BCG vaccination of neonates, infants, schoolchildren and adolescents. Part II: Safety of a vaccine with strain 1331 Copenhagen.
The safety of the vaccine could be assessed by three different investigations: a) During the dose finding study (part I) the vaccine showed good safety in all concentrations employed concerning reactions at the site of injection; palpable lymph node enlargement was common. There was one case of suppurative lymphadenitis amond the 262 children who were given the vaccine in the highest concentration (25 X 10(4) VU). b) Subsequent trials in the course of 21 months, when high risk persons could be vaccinated, revealed a rate of this complication in the 1:1,000 range, no case was reported among older persons. c) After the official approval of the vaccine (10 - 30 X 10(4) VU/ml) in the FRG 1 supp. lymphadenitis among 5,000 vaccinated newborns can be calculated.
Adolescent↗
Mono- and polyneuritis after tetanus vaccination (1970--1977).
Due to the similarity of symptoms, 22 cases of mono- and polyneuritis after tetanus vaccination from our own records covering the years 1970--1977, as well as 6 additional cases taken from existing literature, are being analyzed. As expected, the number of male vaccinees exceede that of female vaccinees, the former being younger than the latter and women generally received less previous tetanus vaccination than men. Three out of four cases occurred during the summer season. The interval between vaccination and the first symptoms was shorter in mononeuritis than in polyneuritis. The prognosis of most cases was benign, irrespective of age, sex and tetanus vaccination history. Cases with delayed recovery only occurred during the summer months. In cases of polyneuritis it seems that the longer the interval between vaccination and the first symptoms, the slower the recovery. It has to be emphasized that the discussed cases of neuritis have to be viewed as extremely rare complications due to tetanus vaccine.
Adult↗
Vaccine induced mumps-like diseases.
Sixteen cases of parotitis and 2 cases of diabetes mellitus after mumps vaccination have been reported since the introduction of the live attenuated mumps vaccine in the F. R. Germany in the fall of 1976. Due to the post-vaccination incubation of 7 to 10 days, support is given to the assumption that these cases are vaccine induced and not coincidental wild virus infections. The diabetes mellitus cases, however, are too few to be included in this rational.
Diabetes Mellitus↗
Adverse reactions after pertussis vaccination.
During 1970 to 1977 adverse reactions after pertussis vaccination were reported for 149 persons, 56% male and 44% female. Their symptoms permitted to divide the vaccinees into 2 groups, the first with more severe (S) and the second with other symptoms (O). No differences were observed in age and sex among the two groups. The interval between vaccination and appearance of first symptoms was longer for the O than for the S group. While less than one quarter of the reactions in the O group occurred after primovaccination, more than half of the S side effects were seen after the first vaccination. Further analysis of the S group revealed that all but two of their symptoms (fever and encephalopatht) corresponded to the hypoglycaemic syndrome. The consequences hereof are discussed with regard to prevention and therapy.
Child↗
[A purified rabies vaccine from human diploid cell cultures (author's transl)].
In order to improve the tolerance of rabies vaccine from human diploid cell cultures, the rabies virus antigen is purified in the sucrose density gradient by means of a flow ultracentrifuge. The purified virus has a specific infectiosity of 10(9) LD50 and a speicific activity of 250 units "relative activity" per 1 mg protein. The purified vaccine has been shown to be well tolerated, effective and stable.
Animals↗
[Experience in man with a purified rabies vaccine from huamn diploid cell (HDC) cultures (author's transl)].
A rabies HDC vaccine purified by density gradient centrifugation was used before and after exposure and the antigenic activity and tolerance investigated. Three injections on days 0, 7 and 21 induced neutralizing antibodies between 1:100 and 1: less than 1000 with 100% conversion rate, while one injection is sufficient for a booster. Vaccination after exposure is described; simultaneous passive immunization does not imply inhibition of the active immune response. Quantifiable local and general reactions seldom occur and serious neurological complications are not to be expected.
Antibody Formation↗
[Neurologic affections after influenza inoculation (author's transl)].
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Adolescent↗
[Investigations carried out to ascertain the dose-effect relationship of a BCG vaccine, strain 1331 Copenhagen, in neonates and young infants (author's transl)].
1405 neonates and infants were vaccinated with BCG Vaccine (strain 1331 Copenhagen) at five clinics in the Federal Republic of Germany. Doses in logarithmic increments from 22000 to 250000 VU (viable units)/0.1 ml were given by strictly intradermal injection. Carrying out the post-vaccinal tuberculin test by the MENDEL-MANTOUX technique, the dose-effect relationship could be demonstrated (Fig. 3). Conversion rates raised from 43% to 76% (Tab. 1); they are furthermore depending from the tuberculin dose and the assessment of the skin reaction. Tests with up to 50 I.U. of purified tuberculin were resulting in conversion rates over 90% for vaccination doses of 100 000 VU and more, any palpable infiltration regarding as a positive result (Fig. 4). The vaccine showed good safety in all concentrations employed concerning reactions at the site of injection. Lympnode enlargement, palable even 12 weeks postvacc., was common. In the course of the trial there was one case of suppurative lymphadenitis among the 262 children who were given the vaccine in the highest concentration (250000 VU). Subsequent trials revealed a rate of this complication in the 1:1000 range. The approval for the vaccine with 100000-300000 VU/dose has subsequently been given by the Federal Bureau for Sera and Vaccines.
BCG Vaccine↗
A purified human diploid cell rabies vaccine.
Continuous-flow isopycnic banding of rabies virus in sucrose gradient was used to purify the antigen for the preparation of a human diploid cell rabies vaccine. Prior to the addition of the stabilizer, the average specific potency of several vaccine batches was 234 antigenic values per 1.0 mg of protein. Further data regarding potency and stability of this vaccine are presented.
Antigens, Viral↗
[Prevention of influenza epidemics through vaccination. On the comment by W. Ehrengut and H. Allerdist in this journal 102 (1977), 1399].
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Disease Outbreaks↗