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A review of preclinical assessment reports on immunomodulatory biopharmaceuticals submitted to the European Agency for Evaluation of Medicinal Products from 1995 to the middle of 1999 was conducted. Questions regarding the rationale for the preclinical development programmes were often put to the applicants. Effects mediated via changes of the immune function, including risks of reproductive toxicity and tumorigenicity, were of particular concern. This review indicates the need to further develop methods for safety testing of immunomodulatory biopharmaceuticals.

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Long-term studies of antipsychotic-induced oral movements may serve as a rat model of acute and tardive movement disorders. Vacuous chewing movements (VCM), tongue protrusions (TP), and jaw tremors (TR) were studied in rats during acute and chronic administration of two potential antipsychotics, amperozide and FG5803. Comparisons were made with haloperidol and vehicle. Single intraperitoneal injections of amperozide (0.2, 1, or 5 mg/kg) or FG5803 (1.2, 6, or 30 mg/kg) were without effect on oral behaviors. During long-term drug administration, withdrawal and readministration, endpoint analysis was focused on changes in supranormal oral movements. The maximal mean control frequencies found at 29 sessions during 14 months experiment +2 standard deviations were used to define the upper limit of the normal range. FG5803 (1.2, 6, or 30 mg/kg per day) administered via the drinking water for 12 months, did not produce significant deviations from this normal range with respect to VCM, TP, or TR, and this drug was not studied further. Rats receiving amperozide (0.2, 1, or 5 mg/kg per day) showed dose-related increases in oral movements over the year. The changes began after 3 months of treatment with amperozide 1 and 5 mg/kg per day, but became statistically significant only during the second half of the treatment year. Amperozide 0.2 mg/kg per day did not produce significant changes in oral movements during administration for a year, but drug withdrawal resulted in a significant rise in TP behavior. Haloperidol (1 mg/kg per day) produced increases in supranormal oral movements which tended to level out after 9 months. In all groups with significant elevations (i.e. haloperidol and amperozide 1 and 5 mg/kg per day), there was a persistence of such movements during a month of drug withdrawal. During treatment with amperozide (1 or 5 mg/kg per day), some rats developed a high frequency chewing behavior up to 175 VCMs/min. It is concluded that long-term treatment with amperozide, but not FG5803, produced a tardive pattern of supranormal oral movements. The importance of these findings for the clinical future of amperozide is difficult to predict, due to the unexpected finding of high-frequency chewing, which has not been noticed before during extensive studies of classical neuroleptics.

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Rats were pretreated for 11 months with vehicle or with chronic haloperidol (HAL), administered either continuously (in the drinking water) or intermittently (via weekly injections). During this time the animals were habituated to an enclosed tube and periodically monitored by a computerized video device which measured their oral movements. The rats were then withdrawn from chronic HAL and bilateral cannulae were implanted in the ventrolateral striatum (VLS) and substantia nigra (SN). One week later oral movements were observed in an open cage and then measured by the computerized video device following bilateral infusions into VLS of the muscarinic agonist pilocarpine or the dopamine D1 agonist SKF38393, or following infusions of the GABA antagonist bicuculline into SN. Agonist infusions into VLS had different effects depending upon the prior regimen of chronic HAL. Infusions of pilocarpine into VLS led to an exaggeration of the distinctive oral movement form which follows continuous HAL but an attenuation of the different oral syndrome in the intermittent chronic HAL animals. Infusions of SKF38393 into VLS had similar, but considerably smaller effects. Infusions of bicuculline into SN did not induce either effect. These results indicate differences exist in either striatum or its output circuitry in the neurochemical mechanisms which mediate the different oral movement forms induced by different chronic neuroleptic regimens.

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Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 micrograms ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the ibotenic acid injection and markers of gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VA/VL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The ibotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.

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The purpose of the following experiments was to describe some of the neurochemical changes that occur in the basal ganglia of rats exposed chronically to a classical neuroleptic, fluphenazine, and to relate these changes to extrapyramidal motor dysfunction. For these studies a combination of behavioural, receptor autoradiographic and in situ hybridization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris-citrate buffer increased the number of binding sites labelled by [3H]muscimol by over 120% without affecting binding affinity or selectivity. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements compared to controls. In the striatum, changes in GABA transmission were observed in fluphenazine-treated rats with increases in glutamate decarboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [3H]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatment increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated animals. Autoradiographic analysis of excitatory amino acid binding showed that fluphenazine exposure decreased [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding in entopeduncular nucleus and in the ventrolateral thalamic nucleus and decreased [3H]dizocilpine maleate binding in the medial geniculate nucleus. These experiments show that in addition to altering GABA transmission, chronic neuroleptic exposure alters excitatory amino acid transmission in specific regions of the basal ganglia-thalamocortical motor system. The neuroleptic dependent increases in glutamate decarboxylase mRNA levels in the entopeduncular nucleus may reflect changes in neurotransmission in the indirect pathway connecting the major input and output nuclei of the basal ganglia. Changes in some of these brain regions may be related to the occurrence of extrapyramidal motor disturbances.

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Bilateral intranigral infusions of three different peptide agonists were made in rats exposed to fluphenazine decanoate, 30 mg/kg/month (FLU) or vehicle (CON) for seven months. Oral movements were monitored repeatedly during the neuroleptic pretreatment period, as well as before the intranigral infusion and during a 90-min period postinfusion. The FLU group had an increased frequency of vacuous chewing movements (VCM) during the pretreatment period in comparison to controls. Intranigral infusion of the neurokinin-1 (NK1) receptor agonist, [Pro9]Substance P (2.5 nmol on each side), 5-7 weeks after the last FLU injection, caused a significant increase of VCM in both pretreatment groups, lasting 7 min after the infusion. The VCM response to [Pro9]Substance P in the FLU group was significantly higher than in the CON group. A NK2 agonist [Lys5, MeLeu9, Nle10]Neurokinin A(4-10) (2.5 nmol) failed to produce significant changes in oral activity. A Leu-enkephalin analogue [D-Ala2,D-Leu5]enkephalin (3.8 nmol) induced a massive biting behavior in both FLU and CON rats. Using VCM as a behavioral assay, an increased nigral sensitivity to a NK1 agonist is demonstrated in rats chronically exposed to neuroleptics. No corresponding alterations could be ascribed for the NK2 receptor agonist or the Leu-enkephalin analogue.

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Bilateral infusion of 5-hydroxytryptamine (5-HT) agonists into the substantia nigra pars reticulata (SNr) of awake rats was shown to influence oral behavior. The 5-HT1A agonist (R)-8-hydroxy-2-(di-propylamino)- tetralin (8-OH-DPAT) (1.3-13 nmol on each side) produced a dose-dependent depression of vacuous chewing movements (VCMs) that lasted about 20 min. The (R)-8-OH-DPAT-induced depression of VCMs was blocked by the simultaneous intranigral infusion of a specific 5-HT1A antagonist [(-)-(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin HCl (UH-301)], which had no effect when given alone. Another 5-HT1A agonist [(5-methoxy-N,N-dimethyltryptamine hydrogen oxalate (5-MeO-DMT)] also reduced VCM frequencies. Intranigral infusion of the nonspecific 5-HT-agonists 1-(3-triflouro-methylphenyl) piperazine (TFMPP) and 1(m-chlorophenyl)-piperazine (mCPP) and a 5-HT3 agonist [2-methyl-5-hydroxytryptamine (2-Me-5-HT)] increased VCM after 5- to 10-nmol doses. Another 5-HT3 agonist (1-phenylbiguanide) and a 5-HT2 agonist [1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane (DOB)] had no significant effect. As most 5-HT receptors in the SNr are of the 5-HT1B subtype, these results suggest that the increased VCM frequency was mediated via nigral 5-HT1B receptors. The importance of 5-HTergic mechanisms in the development of drug-induced dyskinesias is discussed.

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Bilateral intranigral infusion of selective neurokinin NK1 and NK2 receptor agonists were made in freely moving rats followed by measurements of vacuous chewing frequencies for 30 min post-infusion. The NK1 receptor agonist, [Pro9] substance P, induced an immediate dose-related elevation of non-object directed vacuous chewing movements. There was a linear dose-response relation in the 0.5-5 nmol dose range. In experiments with the NK2 receptor agonist, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10), the highest dose, 4.8 nmol, caused a less intensive but longer lasting increase of the vacuous chewing movement frequency. These findings may imply a role for neurokinins in the regulation of oral movements.

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The neural mechanisms that mediate a primate model of tardive dyskinesia have been investigated using the 2-deoxyglucose (2-DG) uptake technique. Three groups of Cebus monkeys were used. Some of the animals received long-term neuroleptic treatment. These animals were allotted to one of two groups depending on whether they developed tardive dyskinesia or not. A third group of animals served as untreated controls. The neuroleptic-treated dyskinetic animals showed reduced uptake of 2-DG in the medial segment of the globus pallidus and in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus relative to that seen in the equivalent structures in the neuroleptic-treated nondyskinetic and untreated control animals. The data are interpreted as suggesting that tardive dyskinesia is mediated by underactivity of the pathways from the subthalamic nucleus to the medial pallidal segment and the substantia pars nigra pars reticulata, which in turn result in a loss of gamma-aminobutyric acid-ergic inhibition of the VA and VL thalamic nuclei. This suggests that tardive dyskinesia shares a common underlying neural mechanism with other hyperkinesias such as chorea and ballism.

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Synthetic agonists for the tachykinin NK1 and NK3 receptors were bilaterally infused at three dose levels (4.2, 0.17, and 0.007 nmol) into each substantia nigra of freely moving rats and oral behaviors were monitored for 30 min postinfusion. It was found that all doses of senktide, an agonist at the NK3 receptor, induced a significant increase of nonobject-directed chewing, vacuous chewing movements (VCM). The highest dose of senktide produced the greatest effect (p less than 0.001) and precipitated wet shakes for about 15 min after infusion. Septide, selective at the NK1 receptor, was without effect on oral behavior. The present results suggest that NK3 receptor-active peptides might be symptom inducers in oral dyskinesia.

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Bilateral microinjection of kainic acid (30-117 pmol) into the substantia nigra induced convulsive seizures resembling those elicited from limbic system structures. The convulsive seizures, which consisted of facial and forelimb clonus with rearing and falling, developed after a latency of more than 30 min and were preceded by wet dog shakes and non-convulsive seizure activity registered electroencephalographically. The convulsant effect of intranigral kainic acid was strictly dose-dependent (ED50 = 60 pmol) and anatomically site-specific. Stimulation of nigral neurons by focal application of agonists for NMDA or quisqualate receptors, or by focal application of the GABA antagonist, bicuculline, was without convulsant effects. The convulsant action of intranigral kainic acid was prevented by the focal application of kynurenic acid (100 nmol) but not by 2-amino-7-phosphonoheptanoic acid (AP-7) (25 nmol) or 7-chlorokynurenic acid (20 nmol), suggesting that the convulsant effect of kainic acid in the substantia nigra does not depend upon activation of NMDA receptors in this region.

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Leu- and Metenkephalin (Lenk and Menk) and their more stable analogues D-Ala-Leu- and D-Ala-Metenkephalin (DALenk and DAMenk) as well as D-Ala-D-Leu- and D-Ala-D-Metenkephalin (DADLenk and DADMenk) were infused bilaterally into substantia nigra in awake rats and oral movements were recorded for 90 min. DADLenk and DADMenk elicited dose-dependent biting dyskinesias with a chewing rate of about 90 jaw movements/min. DALenk produced a similar but weaker effect, whereas DAMenk, Lenk and Menk were ineffective in the doses given. These findings suggest a possible enkephalinergic mechanism underlying neuroleptic-induced tardive dyskinesias.

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