Biomedical subjects

J W van der Laan

Publications and source records attributed to J W van der Laan.

At least 19 recordsLinked to original sources

PubMed2003

Assessing immunotoxicity: guidelines.

Over the last couple of years the assessment of immunotoxic potential of human pharmaceuticals has drawn considerable attention worldwide. Regulatory agencies entrusted with the registration of pharmaceuticals (or other compounds) found an increased need for guidance on this issue. This has resulted in the release of guidance documents on immunotoxicity in Europe, USA and Japan in close succession. In Europe the CPMP has released their immunotoxicity guidance documents that are now in force. The FDA and the Japanese Authorities are in the process of doing so, and will shortly enforce them. Immune suppression and stimulation, hypersensitivity, photosensitivity, drug-induced autoimmunity and developmental immunotoxicity are the focus of regulatory testing. This review discusses these kinds of immunotoxicity and their clinical implications. The three regional guidelines and screening tools for detection are discussed. Additionally, the scientific background on which these guidelines are based is briefly highlighted.

Adjuvants, Immunologic↗

PubMed2001

Xpa and Xpa/p53+/- knockout mice: overview of available data.

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Academies and Institutes↗

PubMed2000

Current status and use of short/medium-term models for assessment of carcinogenicity of human pharmaceuticals: regulatory perspectives.

In the summer of 1997 international governmental organizations and industry partners agreed upon a new document on 'Testing for Carcinogenicity of Pharmaceuticals'. The most important element in the new guidance was the acceptability of only one life-time carcinogenicity study in a rodent species (preferably the rat). In addition a choice could be made to test the pharmaceutical in one of the newly developed models, i.e. the newborn mouse assay or one of the various transgenic mouse assays. In the present paper the strengths and weaknesses of various models are discussed from a regulatory point of view. The aim of the new animal models would eventually be replacing animal life-span studies without compromizing human safety. Such studies should supplement the life-span studies and provide additional information not readily available from the long-term assay. At present there is insufficient information to predict or offer guidance on which of the models may be the most suitable. New models are not useful to test the carcinogenic potential of biotechnological products.

Animals↗

PubMed2000

Disturbance of cardiovascular circadian rhythms by pertussis vaccine in freely-moving rats.

Vaccination of young children with diphtheria, tetanus, poliomyelitis and pertussis (DTPoP) vaccine is effective in preventing outbreaks of whooping cough but adverse events sometimes occur. This pilot study shows that in freely-moving rats, multiple treatment with DTPoP (at day 0 and day 5, 6 ml/kg i.v.) increased heart rate (HR) for 5 days after the first treatment and decreased diastolic blood pressure (DBP) for at least 26 days after the first treatment and inhibited the circadian rhythm of HR and DBP for at least 10 days. DTPo vaccine, containing no pertussis vaccine, was free of such effects. Thus, in rats, the pertussis component of DTPoP acts on the cardiovascular system and disturbs its circadian rhythm. The contribution of these findings to clinical adverse effects is as yet unknown and needs further research.

Animals↗

PubMed1998

New perspectives for alternative approaches to carcinogenicity testing: a regulator viewpoint.

Genotoxic compounds are thought more likely to be transspecies carcinogens inducing carcinomas in more than one species, implying a hazard to humans. Non-genotoxic compounds will have a certain threshold concentration below which they are definitely not carcinogenic. What are we looking for in the case of pharmaceuticals? New animal models would be helpful to enhance the quality of assessment of carcinogenic potential, based on 'weight of evidence', in order to reach the goal of replacing animal life span studies without compromising human safety. Such studies should supplement life span studies and provide additional information not readily available from the long-term assay. Short- or medium-term assays may be helpful in confirming the transspecies character of carcinogens.

Animals↗

PubMed1998

[Cognitive and psychotic effects after cessation of chronic cannabis use].

Establishment of residual cognitive and psychotic effects (effects present at the time that all active cannabinoids are eliminated from the body) putatively produced by prolonged heavy cannabis use is difficult, because of many confounding variables like slow elimination of active cannabinoids, lack of supervision during abstinence, poor use of well-matched control groups and the presence of withdrawal symptoms. Residual cognitive effects were observed in some but not in all tests after prolonged heavy cannabis use. The effects were mostly mild. The relationship of cannabis use, psychotic effects and schizophrenia was unclear; the cannabis conceivably gave relief, but it also appeared that cannabis caused schizophrenia in young people and (or) enhanced the symptoms, especially in young people poorly able to cope with stress or in whom the antipsychotic therapy was unsuccessful.

Adolescent↗

PubMed1998

The effect of pertussis toxin and whole-cell pertussis vaccine on haemodynamics and autonomic responsiveness in the rat depends on route of administration and age.

Vaccination of children with Diphtheria, Tetanus, Poliomyelitis and pertussis vaccine (DTPoP-vaccine) containing the whole-cell pertussis component is known to be associated with manifestation of side-effects such as acute encephalopathy, convulsions and hypotensive-hyporesponsive episodes. In young and adult rats the effects of pertussis toxin and DTPoP-vaccine on haemodynamics and autonomic responsiveness are evaluated following treatment with high dose via different routes of administration (s.c., i.p. and i.v.). The effect of pertussis toxin is dose-dependent (between 1 and 20 micrograms kg-1) and largest responses are observed after i.v. administration. At 20 micrograms kg-1, i.v. pertussis toxin decreases baseline diastolic blood pressure and increases baseline heart rate by 31% and inhibits autonomic responsiveness (salbutamol-induced increase in diastolic blood pressure and arecoline-induced decrease in heart rate). In adult rats DTPoP-vaccine induces generally more prominent effects than in young rats. In adult rats DTPoP-vaccine reduces baseline diastolic blood pressure by 25% while no response is observed in young rats. In adult rats DTPoP inhibits the adrenergic response though less compared to treatment of pertussis toxin. After treatment with DTPoP-vaccine (single or twice) only minor differences are observed between young and adult rats. Present results show that adult rats are more sensitive to pertussis toxin and pertussis vaccine than young rats and that the responses depend on the route of administration.

Aging↗

PubMed1998

Repeated administration of whole-cell and acellular pertussis vaccines affects haemodynamics and autonomic responsiveness.

Rats were treated in a repetitive way one to four times with either pertussis toxin, combined Diphtheria-Tetanus-Poliomyelitis-Pertussis vaccine (DTP-IPV vaccine, which includes inactivated polio virus and whole-cell pertussis), DT-IPV vaccine (lacking the whole-cell pertussis component) or acellular pertussis (aP) vaccine or Haemophilus influenzae type b vaccine. Baseline diastolic blood pressure, baseline heart rate and adrenergic and cholinergic responses were evaluated 4 days after last treatment. Pertussis toxin decreased baseline diastolic blood pressure (28-43%) and increased baseline heart rate (28-40%). Adrenergic and cholinergic response were inhibited by 65-75% and 70-78%. Multiple treatments were grossly as effective as single treatment. Similar results were obtained with DTP-IPV, while DT-IPV did not affect any of the four responses measured. Acellular pertussis vaccine did not affect baseline diastolic blood pressure, but significantly increased baseline heart rate (14%) and inhibited the adrenergic (19-23%) and cholinergic response (39-50%). This indicates that the acellular vaccine tested contains pharmacologically active pertussis toxin. As the effects were less pronounced compared to DTP-IPV, it is concluded that acellular pertussis retains less residual toxicological effects than whole-cell pertussis vaccine and may therefore be a safer vaccine. The observed effects on haemodynamics and autonomic control seem to be specific for pertussis toxin and pertussis-related vaccines as Haemophilus influenzae type b vaccine is in this respect virtually inactive.

Animals↗

PubMed1995

Immunotoxicological screening of morphine and methadone in an extended 28 day study in rats.

Drug addicts are prone to infection with viruses including hepatitis-B and HIV. Besides indirect effects as a consequence of lifestyle, heroin and methadone may also enhance the risk of infections by a direct immunotoxic effect affecting resistance. In addition to general toxicological screening, we therefore performed a screening for potential immunotoxicity of morphine and methadone. Rats treated orally with different dosages of morphine or methadone for 6 weeks showed only a minor effect of overt toxicity on liver and spleen at the high dose, whereas at lower doses an increase in the relative weight of the mesenteric lymph nodes and an increase in cell density in the medullary cords were observed histopathologically, indicating a specific effect on humoral immunity. This specific immunotoxic effect was corroborated by an increased IgG concentration in serum (significant for the methadone-treated group). Further immunotoxicological research is needed aimed at revealing the potential risk of opiate use with respect to immune function. In conclusion, the present paper showed the toxicological profile of morphine and methadone in an extended 28 day subchronic study. Specific immunotoxicological effects were observed at doses where no effects were seen in routine toxicological evaluation, suggesting that the immune system is sensitive to opiates.

Animal Feed↗

PubMed1993

Tolerance and withdrawal after chronic lorazepam treatment in rats.

The purpose of the study was to develop an animal model for benzodiazepine tolerance and dependence on the basis of oral administration, using lorazepam as the test drug. We have used the continuous measurement of locomotor activity in home cages to obtain a narrow estimation of the time course of withdrawal related hyperactivity as an observer-independent symptom. Acute administration of lorazepam (9.5-37.5 mg/kg body weight/day) resulted in the first week in a dose-dependent muscle relaxation on the accelerod and sedation in the open field. The most striking manifestation of sedation, however, was the decrease of nocturnal locomotor activity in home cages. After 5 weeks of administration tolerance to the sedative effect had developed. In a second study, using a lower dose range (2.5-9.5 mg/kg body weight/day), a decrease of nocturnal locomotor activity was also observed as was the development of tolerance. The latter can be partly explained by dispositional tolerance, i.e., decreased serum concentrations after administration of lorazepam for more than 2 weeks. Withdrawal of lorazepam in the experiment using high doses led to three symptoms, i.e., a decrease in food intake, loss of body weight and an increase in daytime locomotor activity. The decrease in food intake and the loss of body weight were maximal on the first day of withdrawal. The increase in the daytime locomotor activity was present in the high dose experiment only, with a maximum on days 2-3 and a duration of at least 1 week. The increase however, was not dependent on the dose previously administered. The symptoms 'loss of body weight' and 'decrease in food intake' appeared to be more sensitive in benzodiazepine withdrawal: they were dose dependently present over the whole dosage range (2.5-37.5 mg/kg body weight/day). It is concluded that the model represents a sensitive model to measure lorazepam tolerance and dependence in animals. Comparative studies with other benzodiazepines are in progress.

Animals↗

PubMed1993

Pharmacokinetic differences of desmethyldiazepam in three outbred Wistar strains related to differences in liver enzyme activities.

Various strains of rats differ in their sensitivities towards benzodiazepines suggesting that variations in biological features are responsible for these differences. All reports concern inbred strains. We have studied male rats of three outbred Wistar strains with regard to the pharmacokinetics of desmethyldiazepam given as a single intravenous dose. The elimination half-life of desmethyldiazepam was longer in the Riv:TOX(M) (from the National Institute of Public Health and Environmental Protection) and in the Cpb:WU strain than in the Crl:(WI)BR strain. This strain difference in elimination of desmethyldiazepam may be related to differences in liver enzyme activities.

Animals↗

PubMed1992

Chronic infusion of clonidine does not alleviate spontaneous morphine withdrawal symptoms in rats.

Opiate withdrawal is associated with behavioural symptoms and a sympathetic hyperactivity, the latter being sensitive to clonidine. The central question is whether behavioural symptoms would be also sensitive to clonidine. A rat model was used in which the locomotor activity was measured 24 h a day during the morphine withdrawal phase. Spontaneous withdrawal of morphine reduced strongly the high nocturnal locomotor activity, concomitantly decreasing food intake and body weight. Chronic infusion of clonidine (30-120 micrograms/kg/day) using osmotic minipumps had no effect on the withdrawal symptoms. Higher dosages (250-1000 micrograms/kg/day) potentiated rather than alleviated the withdrawal symptoms, suggesting an alpha 1-adrenergic effect of clonidine rather than an alpha 2-action. Therefore, we studied the action of a more specific alpha 2-agonist UK-14.304. UK-14.304 was less potent than clonidine in naive animals. It slightly alleviates the decrease of nocturnal activity during spontaneous morphine withdrawal. Furthermore, we have tested whether the effects of high dosages of clonidine could be altered by a specific alpha 1-antagonist doxazosine. Doxazosine reduced only slightly the potentiation in the decrease in food intake by clonidine during morphine withdrawal. For the other symptoms no interaction between doxazosine and clonidine was found. The data suggest that the use of clonidine in the detoxification of opiate dependent people is based on the suppression of the sympathetic hyperactivity rather than on symptoms with a more behavioural character.

Adrenergic alpha-Agonists↗

PubMed1992

Benzodiazepines preferentially affect mesolimbic dopamine turnover in rats.

Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional depressions, which can be treated with dopamine-antagonistic drugs. Withdrawal of benzodiazepines in rats induces a strong hyperactivity during daytime, leaving the nighttime activity relatively undisturbed. This hyperactivity may be related to an enhanced dopaminergic activity in the mesolimbic area, especially in the nucleus accumbens. Mesolimbic dopaminergic activity may be specifically involved in the development of benzodiazepine withdrawal. Acute administration of benzodiazepines in otherwise non-treated rats, has been described not to affect the dopamine-turnover in the nucleus accumbens, measured by synthesis inhibition. However, activation by administration of haloperidol (feedback activation) can be suppressed by benzodiazepines effectively. Five different benzodiazepines viz. desmethyldiazepam (DMD), lorazepam (LRZ), brotizolam (BTZ), triazolam (TRZ) and flunitrazepam (FNZ) have been compared with respect to their acute effects. Using a 3-fold increase in dopamine turnover (determined by measuring the DOPAC-concentration), benzodiazepines were capable to reduce this increase maximally for 70-80% in the nucleus accumbens. The results point to a selective effect of benzodiazepines in the nucleus accumbens. The increase induced by haloperidol in the corpus striatum was found to be much less sensitive to benzodiazepines. In contrast to the other compounds lorazepam appeared to have no effect on haloperidol-induced increase in DOPAC concentration. Flunitrazepam and brotizolam did affect not only the haloperidol-induced DOPAC increase but also the basal DOPAC concentrations. Linear dose-response curves could not be obtained for the compounds, but minimal effective doses could be assessed. Flunitrazepam and triazolam appeared to be the most active compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Differences in the duration of sedative and anxiolytic effects of desmethyldiazepam in two outbred Wistar strains.

Different sensitivities to benzodiazepines have been described for various strains of both rats and mice suggesting that variations in biological features of the animals are responsible for these differences. Since all reports concern inbred strains, we studied two outbred Wistar strains which are used routinely in several research disciplines. The pharmacodynamics of desmethyldiazepam (DMD), the main active metabolite of diazepam in man, were compared for male rats of the Riv:TOX strain (from the National Institute of Public Health and Environmental Protection) and the Crl:(WI)BR strain. The duration of sedative action of DMD after oral administration, as derived from suppression of the nocturnal locomotor activity, was longer in the Riv:TOX strain than in the Crl:(WI)BR strain. Accordingly, suppression of novelty-induced corticosterone release as an index of anxiolytic action was observed 11 hours after DMD administration in Riv:TOX rats but not in Crl:(WI)BR rats. At that time, serum DMD concentration was shown to be higher in the Riv:TOX strain than in the Crl:(WI)BR strain. The data are discussed in relation with possible metabolic differences between the two strains.

Animals↗

PubMed1988

The concentration of morphine in serum of rats made dependent using a drug-admixed food method.

The present study reports on the induction of physical dependence in rats using morphine-admixed food and addresses the question of the resulting concentration of morphine in serum. The stability of morphine in food is good, since no decrease in concentration could be observed. The concentration of morphine in serum during the experiment was measured using a radioimmunoassay technique. A correlation was found between the food intake during a 7-hour period and the concentration of morphine in the serum at the end of that period, both for a 1 g/kg and a 2 g/kg batch of morphine-admixed food. The concentration of morphine in serum was also found to be dose-related during a period of 6-23 days when the rats were fed for a prolonged period. After long-term administration of 1 g/kg morphine in food a steady-state level of about 0.5 mg/l serum was obtained. Similarly with 2 g/kg morphine in food a steady-state level of 0.8-1.1 mg/l serum was reached. After withdrawal of morphine the serum concentration of morphine dropped to 0.1 mg/l within 24 hours and to below the detection limit within 48 hours. During the withdrawal period sharp drops were noted in body weight (20%) and food intake (50%) after one day.

Animal Feed↗

PubMed1988

Changes in locomotor-activity patterns as a measure of spontaneous morphine withdrawal: no effect of clonidine.

The anti-withdrawal action of clonidine was studied in a model of spontaneous morphine withdrawal in rats. After withdrawal the behaviour of the animals was registered continuously for several days. In the initial phase of induction of dependence the locomotor activity was enhanced during daytime. Partial tolerance to this increase developed in the course of 3 weeks. In morphine withdrawn animals the activity decreased strongly at night, and this effect was maximal on the second night after removal of morphine. After four nights the nightly activity was restored. Treatment with clonidine (100 micrograms/kg s.c. twice daily) changed neither the observed decrease in nightly locomotor activity nor other withdrawal symptoms such as a decrease in food intake and loss of body weight. In non-dependent animals clonidine induced a biphasic effect in locomotor activity, i.e. a decrease in the first few hours of the night and an increase in the second part of the night. The latter can be interpreted as a rebound phenomenon occurring after only three injections. It was concluded that clonidine was not effective as an anti-withdrawal compound in a model for spontaneous morphine abstinence. The low incidence of symptoms relating to a hyperactive sympathetic system during spontaneous withdrawal may be an explanation for the absence of an effect of clonidine.

Animals↗

PubMed1986

The potentiation of morphine-withdrawal jumping by clonidine is antagonized by m-chlorophenylpiperazine and not by haloperidol.

Administration of naloxone (0.5 mg/kg i.p.) to morphine-dependent rats induced a strong withdrawal syndrome consisting of body shakes, escape jumping and various autonomic signs. Clonidine (750 micrograms/kg s.c.) had a dual action on naloxone-precipitated withdrawal symptoms in rats: a suppressive action on body shakes and a potentiating action on jumping. Both actions were found to be mediated by alpha 2-receptors which generally are responsible for sedative effects. Therefore, the action of alpha 2-agonists such as clonidine and azepexole was studied more extensively. Since both serotonergic and dopaminergic systems have been suggested to be involved in morphine-withdrawal jumping, the interaction of clonidine and azepexole with serotonergic and dopaminergic drugs was studied. Neither haloperidol (0.3 mg/kg i.p.) nor the benzamides sulpiride (40 mg/kg p.o.) and metoclopramide (8 mg/kg i.p.) affected the jumping potentiated by the alpha 2-agonists. However, the serotonin-agonist m-chlorophenylpiperazine (2.5 mg/kg i.p.) suppressed the effects of clonidine. Precipitation of jumping in morphine-dependent animals was more effective using bremazocine (1.0 mg/kg i.p.). This effect again could be potentiated by clonidine (750 micrograms/kg s.c.). A low dose of m-chlorophenylpiperazine (0.03 mg/kg i.p.) antagonized the clonidine-effect without affecting the basal jumping response. The data suggest that clonidine potentiates naloxone-precipitated jumping by decreasing serotonergic output while the administration of m-chlorophenylpiperazine can counteract this lack of serotonergic activity.

Adrenergic alpha-Antagonists↗

PubMed1985

Effects of inhibitors of GABA-transaminase on hole-board exploration and on temperature. Relation with effects on quasi-morphine abstinence behaviour induced by sodium dipropylacetate.

Four inhibitors of gamma-aminobutyric acid transaminase (GABA-T) were investigated together with respect to their effects on hole-board exploration and temperature and the relation with effects on quasi-morphine-abstinence behaviour induced by dipropylacetate (DPA) in rats. Amino-oxyacetic acid (AOAA), gamma-acetylenic-GABA (GAG), gamma-vinyl-GABA (GVC) and ethanolamine-O-sulfate (EOS) were found to reduce hole-board exploration especially in the higher doses used, although the time-course of the effect was different for the compounds. For EOS and GVG the decrease in hole-board exploration paralleled a strong hypothermic effect. The compounds AOAA and GAG exerted a less and more transient hypothermic effect. However, the decrease in hole-board exploration did not fall in with this decrease in temperature. AOAA and GAG were found to decrease DPA-induced body shakes and locomotor activity, while GVG and EOS had no effect on body shakes and transient effects but opposite to each other, on locomotor activity. The efficacy of the GABA-T-inhibitors was measured biochemically, and the influence on the activity of glutamate decarboxylase (GAD) was also determined. AOAA and GAG were found to be strong inhibitors of GABA-T whereas the other two compounds were less efficient in the used doses. In addition AOAA and GAG influenced the activity of GAD strongly, while using GVG only a small decrease was found. The results suggest that the anti-quasi-withdrawal, the sedative and the hypothermic effects are not related to each other nor related to an effect on GABA-T. The suppressive effects on quasi-withdrawal body shakes, however, could be related to the inhibition of GAD and a hypothesis involving a compartmentalized action of DPA on GABA-metabolism has been proposed.

4-Aminobutyrate Transaminase↗