Paul A. J. Janssen

Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats.

We produced unilateral photochemical infarcts in the hindlimb sensorimotor neocortex of 186 rats by intravenous injection of the fluorescein derivative rose bengal and focal illumination of the intact skull surface. Infarcted rats showed specific, long-lasting deficits in tactile and proprioceptive placing reactions of the contralateral limbs, mostly the hindlimb. Placing deficits were most prominent during transition to immobility and/or when independent limb movements were required. Administration of flunarizine, a Class IV calcium antagonist, 30 minutes after infarction resulted in marked sparing of sensorimotor function in 30 rats. In contrast to 20 vehicle-treated rats, which remained deficient for at least 21 days, 15 (75%) of the rats treated with 1.25 mg/kg i.v. flunarizine showed normal placing on Day 1 after infarction, whereas the remaining five (25%) recovered within 5 days. Oral treatment of 10 rats with 40 mg/kg flunarizine was also effective. Neocortical infarct volume and thalamic gliosis, assessed 21 days after infarction, did not differ between 30 flunarizine- and 30 vehicle-treated rats. However, when 4-hour-old infarcts were measured in 16 rats, posttreatment with intravenous flunarizine reduced infarct size by 31%. In combination with appropriate behavioral analyses, photochemical thrombosis may constitute a relevant stroke model, in which flunarizine preserved behavioral function during a critical period, corresponding to the spread of ischemic damage.

TMC125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1

ABSTRACT Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 μM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of α1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.

Minireview A systematic study of the pharmacological activities of dopamine antagonists

Abstract The so-called dopamine (DA)-antagonists possess a wide variety of pharmacological activities. The present paper analyses some comparative data that were obtained in the Janssen Research Laboratories, using a large series of DA-antagonists in a representative set of pharmacological tests. This study illustrates the relative importance of the different pharmacological properties of these compounds, provides a tool for further meaningful pharmacological and biochemical research in this area, and discusses the therapeutic potential of these drugs.

Evolution of anti-HIV drug candidates. Part 3: diarylpyrimidine (DAPY) analogues

The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.

Inhibition of 5-hydroxytryptamine-induced and-amplified human platelet aggregation by ketanserin (R 41 468), a selective 5-HT2-receptor antagonist

Ketanserin, a selective 5-HT2-receptor antagonist, inhibits the reversible aggregation induced by 5-hydroxytryptamine (5-HT) in human platelet-rich plasma (PRP). In this respect, the compound is equipotent to cyproheptadine and more active than methysergide (IC50: 1.66×10−8M, 1.44×10−8M and 5.62×10−8M respectively). Ketanserin is active against 5-HT-induced platelet aggregation after bothin vitro and oral administration to human volunteers. At concentrations up to 500 times in excess of the IC50 for 5-HT-induced platelet reactions, ketanserin does not affect the aggregation induced by ADP, epinephrine, collagen or Thrombofax®, the prostaglandin biosynthesis of thrombin-stimulated platelets, nor the active uptake of14C-5-HT by platelets.5-Hydroxytryptamine amplifies the human platelet aggregation induced by threshold concentrations of ADP, collagen, epinephrine, norepinephrine and induced irreversible aggregation of platelets pre-sensitized with Thrombofax®. This amplification by 5-hydroxytryptamine results in a platelet response typical for the potentiated agonist; for the combination of the monoamine with collagen, the serotonergic amplification results in enhanced aggregation, release of β-TG and PF4 and excessive formation of TXB2. Ketanserin, after bothin vitro and oral administration to man reduces the amplified response to the level of the potentiated agonist.The present evidence suggests the presence of functional 5-HT2 receptors on the human platelet, different from those involved in the uptake of the monoamine.

Theoretical and methodological considerations on drug discrimination learning

A method is described which allows the assessment of discriminative stimulus properties of drugs, and the ability of amphetamine (0.16 mg/kg, s.c), chlordiazepoxide (5 mg/kg, p.o.), desipramine (5 mg/kg, s.c), and haloperidol (0.02 mg/kg, s.c.) to produce a discriminative stimulus complex (DSC) is evidenced. The method is found to yield clear-cut data that are specifically related to drug discrimination learning without being possibly confounded by state dependent effects. In addition, the experimental procedure is designed so as to provide an appropriate measurement of operant response modulating drug effects.

In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus Microbicides

ABSTRACT The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV.

Discriminative stimulus properties of cocaine: Neuropharmacological characteristics as derived from stimulus generalization experiments ☆ ☆☆

The experiments reported here were undertaken to examine the neuropharmacological characteristics of drugs inducing stimulus generalization with cocaine as a cue. Experiment 1 indicated that d-amphetamine (ED50: 0.17 mg/kg), 1-amphetamine (0.45 mg/kg), methylamphetamine (0.15 mg/kg), methylphenidate (0.55 mg/kg) and nomifensine (0.32 mg/kg) induce stimulus generalization with cocaine in rats trained to discriminate 10 mg/kg cocaine from saline; this generalization occurred in 100% of the animals, proceeded along steep slopes (s: 1.27 to 1.88 in log-probit plots), and was not associated with behaviorally toxic effects. Amantadine (57.8 mg/kg; s=1.85), apomorphine (0.33 mg/kg; s=1.77), piribedil (8.4 mg/kg; s=10.6) and bromocryptine (>40 mg/kg) also induced stimulus generalization to some extent, but this generalization was partial in some cases, proceeded along a shallow slope with piribedil, and was invariably associated with severe rate depressant effects. Ten mg/kg, but not 1.25 mg/kg hydroxyamphetamine induced generalization in 3 out of 8 rats. Experiment 2 revealed that tranylcrypromine (2.5 mg/kg; s=1.7), fentanyl (0.068 mg/kg; s=1.34), morphine (>10 mg/kg), phencyclidine (0.81 mg/kg; s=1.43), and benztropine (9.2 mg/kg) induce stimulus generalization with cocaine, whereas lidocaine, procaine, chlordiazepoxide, imipramine, desipramine, mescaline, LSD, isopropamide, and atropine do not. Experiment 3 shows that propranolol (1.25 to 40 mg/kg) and isoproterenol (0.63 to 2.5 mg/kg) induce a biphasic generalization with cocaine. Experiment 4 discloses that rats trained to discriminate 10 mg/kg propranolol from saline generalize their training drug along a linear gradient, but generalize cocaine along a biphasic gradient. It is suggested (a) that stimulus generalization with cocaine may be contingent upon increasing the functional availability of endogenous dopamine and, perhaps, of norepinephrine irrespective of the presynaptic mechanism from which such increase may result and (b) that differential stimulus generalization of drugs with cocaine (in terms of dose, subjects, slope, and rate effects) may parallel their differential primary reinforcing properties.

Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT2 receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT2 receptor antagonist ritanserin injected intraperitoneally (IP) (0.04–2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT2 receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16–2.5 mg/kg) or with cinanserin (2.5–5 mg/kg), another 5-HT2 receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT1 receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16–2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT2 receptors are involved in this action. In addition it is suggested that 5-HT1 receptor subtypes are unlikely to interact with 5-HT2 receptors in the sleep-wakefulness modulation mediated through 5-HT2 receptors.

Effect of serotonin antagonism in schizophrenia: A pilot study with setoperone

The new antipsychotic drug setoperone is pharmacologically characterized by its potent serotonin and moderate dopamine receptor blocking properties. Forty chronic schizophrenic patients were included and 34 completed this pilot study. Following a drug free period of 1 week the patients received setoperone 5 mg t.i.d. After 1 month of treatment, the psychotic symptoms, as measured by the BPRS, improved by approximately 50% (P<0.001) as compared with the condition under previous neuroleptic medication. Blockade of serotonin receptors may be related to improvement of autistic behaviour, dysphoria, and parkinson-like symptoms. In residual schizophrenic patients, the need for dopamine blockade, which is normally correlated with the therapeutic effect on positive symptoms, can be reduced substantially.