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Biomedical subjects

J van Noordwijk

Publications and source records attributed to J van Noordwijk.

At least 19 recordsLinked to original sources
PubMed2002

["Dosis solum facit venenum" also for herbal products].

A report of severe hepatitis due to the use of material from the plant Chelidonium majus, reminds us that herbal products can be much more life-threatening than many people realise. The widespread use of plants for food has reinforced the idea that eating plants promotes health. With the development of organic chemistry in the 19th century it became possible for the first time to purify and identify pharmacologically active plant constituents and later on to synthesize related compounds with an even stronger activity. The development of the antimalarial artemotil from Artemisia plants is a recent example. The activity, safety and composition of such compounds can be controlled in just the same manner as purely synthetic compounds. However, some people still believe that traditional plants are much safer and better than modern synthetic pharmaceuticals. The qualitative and quantitative composition of such herbal medicines from alternative medical sources, are not covered by public health legislation. Whereas phytotherapists consider plants to be a source of useful drugs, regular physicians maintain that the composition of a preparation and not the provenance, determines its effects.

Artemisia↗
PubMed1989

Bioassays in whole animals.

The basis for whole animal bioassays as practised today was laid down by Paul Ehrlich in 1894. He introduced the concepts of a stable standard preparation and of the unit of activity as the activity of a defined mass of that standard preparation in the assay performed. Such assays have often provided a way of quantifying newly discovered active principles of biological origin, so that they could be applied in clinical medicine. Whole animal bioassays can be applied not only for the quantitative analysis of a biological product (analytical assays), but also for the comparison of different products intended for the same clinical indication (comparative or research assays). As such they have been the model for controlled clinical trial. For some products many different types of bioassay have been developed. They may produce heterogeneous results when more than one active principle is involved, and these are present in standard preparation and in the unknown preparation in different relative concentrations. In addition the precision of different assay methods for the same substance may vary markedly. An important source of variation in whole animal bioassays is the influence of some environmental factors on the individual animals during the assay. Thus the number of rats per cage markedly influences the variation of the response of rats to serum gonadotrophin. Careful studies are required to detect the discriminatory environmental factors in a particular whole animal bioassay. Keeping these discriminatory factors constant at their optimal level may increase the precision of the assay markedly and thus reduce the number of animals required to attain the precision specified, e.g. in pharmacopoeial tests.

Animals↗
PubMed1988

An accurate method for estimating an approximate lethal dose with few animals, tested with a Monte Carlo procedure.

A reliable but not necessarily precise indication of the toxicity of a chemical product is frequently needed for the determination of its class of toxicity. Estimations of the LD50 carried out for this purpose often have a precision which is higher than necessary and so is the number of laboratory animals used. Alternative methods estimating an approximate lethal dose (ALD) have been proposed, but too little is known about their accuracy and precision. The method of Deichmann and LeBlanc (1943) for estimating an ALD has a systematic error, dependent upon the magnitude of the unknown variance of the log tolerance. A new method was developed in which this systematic error was removed. Its performance was tested in a model with Monte Carlo techniques. The model is based on the log-normal distribution of individual tolerance, i.e. the lowest dose that is lethal for an individual of the species under study. A hypothetical substance was created with a mean tolerance between 1 and 5,000 mg per kg and a standard deviation of log tolerance between 0.1 and 1.5 (in natural logarithms). This substance was then subjected to a sequential test, by repeatedly drawing a random element from the population of normally distributed log tolerance values and testing whether this element is smaller or greater than the dose administered according to the method's protocol. The method of Lorke (1983) was tested with a similar simulation model. In series of 100 simulations no systematic error was found. For a standard deviation of log tolerance exceeding 0.85 the new method was less precise than that of Lorke, but for smaller values the new method was more precise; it required on average less than ten animals, against 13 required in Lorke's method.

Animals↗
PubMed1988

Quality assurance of products manufactured by recombinant DNA technology. Introduction and elements of a philosophy.

The risk of gene technology has been overrated, leading to regulations which are unnecessarily strict. Industry can contribute to relaxation of such controls by making its experiences in production available to the authorities concerned. Good manufacturing practice (GMP) for large scale operations mainly covers the risks of gene technology in industrialised countries; to what extent this also applies to developing countries is not yet certain. Quality assurance of recombinant DNA technology derived products requires control of the starting materials (host organism and DNA vector), manufacturing process and final product. The host organism and DNA vector are beyond pharmacopoeial control; this control must be exercised by the competent national authorities, concerned with licensing of pharmaceutical production. The same applies to the validation of methods designed to exclude viral contamination during manufacture. The risk of introducing DNA-engineered organisms into the environment remains to be studied. Application of gene technology in the development and production of pharmaceutical products does not call for rigid directives, but for guidelines and lists of "Points to consider".

Biotechnology↗
PubMed1986

Reduction of animal use for toxicological evaluation: the Netherlands Health Council report on the LD50.

In 1981 the Health Council of the Netherlands installed a committee to report on the scientific value of the LD50 and on ways of obtaining the information needed for the toxicological evaluation of chemical products at the expense of less experimental animals and of less suffering. This was done at the request of the Minister of Public Health and Environmental Hygiene. The first four reports have been published. The first one discusses the different methods for estimating the median lethal dose, and stresses that a high precision is seldom needed. A limit test would suffice in many cases. The test for abnormal toxicity of the European Pharmacopoeia (General method) has a power of discrimination of 0.96 when the dose injected in fact is equal to the LD50; the power of the version of this test intended for immunosera and vaccines is even higher. The second report deals with pharmaceutical preparations, immunosera and vaccines. The types of toxicity data and the precision required differ in the successive stages of screening, selection, development up to registration and quality control. Determination of an LD50 with a high precision is required only for preparations with a narrow therapeutic margin, and in very exceptional cases for quality control.

Animal Testing Alternatives↗
PubMed1985

Parallel line assays of endotoxins with the LAL chromogenic substrate method.

All endotoxins from the gram negative microorganisms studied sofar contain lipid A, which is considered to be responsible for the biological activity. Endotoxins may therefore react in a similar way in quantitative assays. The varying non-lipid A part of different endotoxins may potentiate or reduce the activity of the identical lipid A part without changing the slope of the log-dose vs. response curve of these endotoxins. To test whether 13 endotoxins from different microorganisms react similarly with amoebocyte lysate (LAL) log-dose response curves were made using a chromogenic substrate method. A balanced incomplete block design with 13 blocks and four replications of each endotoxin was applied. A group of eight endotoxins with a common slope was defined with the Student-Newman-Keuls procedure. Two independent potency estimates of these endotoxins were in good agreement.

Analysis of Variance↗
PubMed1983

Protective effects of prostaglandins against ulcerogenic activity of indomethacin during different stages of erosion development in rat stomach. Role of acid and bicarbonate secretion.

Prostaglandin E2 (PGE2) and PGF2 beta decreased the gastric erosive activity of orally administered indomethacin in a dose-dependent manner, when given as a continuous intravenous infusion in the conscious rat. PGE2 protected both during the initial stage of erosion induction and during the later outgrowth to larger erosions. Moreover PGE2 was able to stop the eroding process at any stage as long as the infusion continued. Both PGs were protective only in doses which also reduced the histamine-stimulated acid secretion. PGE2 protected the stomach against indomethacin-induced erosions even in the presence of exogenously administered acid. An infusion of PGE2 stimulated the secretion of bicarbonate in the stomach during some minutes but had no effect during prolonged infusion. These results suggest that, although effects on secretion of acid and bicarbonate were found, these effects cannot be the (only) explanation for the cytoprotective effects observed. Furthermore the protective effect of PGE2 is not confined to any specific stage of the development of indomethacin-induced gastric injury.

Animals↗
PubMed1983

The influence of paracetamol on the anti-inflammatory, the anti-pyretic and the analgesic activity of indomethacin.

Interactions between indomethacin (INDO) and paracetamol (PAR) with regard to their anti-inflammatory, anti-pyretic and analgesic activities were studied in rats. The anti-inflammatory and anti-pyretic effects of INDO and PAR were additive. Although antagonism was observed in the analgesic test, the effect of the combination was not inferior to that of PAR alone.

Acetaminophen↗
PubMed1982

The influence of paracetamol on the erosive activity of indomethacin in the rat stomach.

Indomethacin induced erosions in the glandular part of the rat stomach in a dose-dependent manner. Gastric erosions became apparent about 15 min after administration of indomethacin and the damage was maximal at about 4 h. The erosive activity of indomethacin administered subcutaneously was similar to that after oral administration, confirming the data of other authors. The erosive activity of subcutaneously applied aspirin, however, was far less than that of oral administered aspirin and it was not dose dependent. In a dose-dependent manner, paracetamol reduced the incidence of gastric erosions induced with indomethacin; this effect was independent of the route of administration of either drug. Paracetamol was also effective when given 0.5 or 1 h before indomethacin. Orally administered paracetamol also reduced the incidence of gastric erosions induced with aspirin but after subcutaneous administration, paracetamol had no protective effect. The differences between the erosive activities of indomethacin and aspirin are discussed with emphasis on the differentiating influence of paracetamol on the incidence of gastric erosions. Direct contact with the mucosa is apparently more important for the erosive activity of aspirin than for that of indomethacin. Possible mechanisms by which paracetamol exerts its protective activity are proposed.

Acetaminophen↗
PubMed1981

The anti-inflammatory, analgesic and antipyretic activities of non-narcotic analgesic drug mixtures in rats.

The effects of non-narcotic analgesics have been examined, separately and in admixture, on carrageenan-induced hind paw oedema and on yeast-induced hyperalgesia and hyperthermia in adult rats. The efficacy of the drugs was evaluated using the kinetics of drug-receptor interaction. In addition, the hypothesis was tested that the anti-inflammatory, analgesic and antipyretic activities of the drug mixtures used equal the addition of the activities of the individual drugs and could be predicted from their intrinsic activities and affinities. Dose-dependent inhibition of paw oedema, hyperalgesia and hyperthermia was observed after oral administration of acetylsalicylic acid (aspirin), paracetamol, phenacetin (60, 125, 250 and 500 mg.kg--1), and caffeine (12.5, 25, 50 and 100 mg.kf--1). Over the dose-ranges used, the anti-inflammatory activities of paracetamol, phenacetin and caffeine tended to be smaller than that of aspirin. The dose producing a semi-maximal effect for caffeine was lower than that for aspirin which in turn was comparable to that for paracetamol or phenacetin. The analgesic activities of phenacetin and caffeine were classified as stronger than that of aspirin, whereas the efficacy of paracetamol was similar. Paracetamol and aspirin were comparable as antipyretics. The antipyretic activity of phenacetin was higher but that of caffeine was lower than that of aspirin. For caffeine the dose producing a semi-maximal effect was lower than that of aspirin. Within the dose-ranges used, low doses of mixtures of aspirin with either paracetamol, phenacetin or caffeine exhibited anti-inflammatory, analgesic and antipyretic activities which were not different from the activities expected on the basis of addition. Incidentally, at some of the higher dose levels potentiation of the activity of the drugs was found. Low doses of the triple combinations: aspirin + paracetamol + caffeine and aspirin + phenacetin + caffeine showed anti-inflammatory and antipyretic activities which were not different from those expected on the basis of addition, but the activities observed with higher doses of these combinations indicated potentiation. It is concluded that, in the rat, the anti-inflammatory, analgesic and antipyretic activities of dual and triple combinations of aspirin, paracetamol, phenacetin and caffeine at least equal the activities expected on the basis of addition.

Analgesics↗