Pralsetinib for the treatment of non-small cell lung cancer.

The identification of oncogenic drivers and the subsequent development of targeted therapies have been established as biomarker-based care for metastatic non-small cell lung cancer (NSCLC) patients. Rearranged during transfection (RET) events have been reported to be oncogenic drivers in NSCLC and were more common in patients who i) were young; ii) had adenocarcinoma histology; and iii) had never smoked. Phase II studies indicated the limited efficacy of multi-targeted tyrosine kinase inhibitors in patients with NSCLC that have a confirmed RET event. Consequently, there has been ongoing research to develop more potent and specific RET tyrosine kinase inhibitors. Recently, a novel and specific RET inhibitor, pralsetinib (BLU-667), has been reported to have excellent efficacy and low off-target toxicity in RET cancer patients. In this review, we summarize the clinical data regarding the use of pralsetinib in NSCLC patients.

Lurbinectedin for the treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive, aggressive metastatic and lethal subtype of lung cancer. Unfortunately, there has been little progress regarding the development of novel treatments for SCLC. However, lurbinectedin, a transcriptional inhibitor, has emerged as a potential novel treatment for cancer. It produces antitumor efficacy by inhibiting oncogenic transcription activity, inducing the accumulation of DNA double-strand breaks and modulating the tumor microenvironment (TME). Data from phase I/II trials indicates that lurbinectedin has significant antitumor efficacy and tolerable adverse effects in SCLC patients. Furthermore, lurbinectedin is efficacious in platinum-sensitive and platinum-resistant SCLC patients and in those with SCLC relapse after second-line treatment. In 2020, the U.S. Food and Drug Administration (FDA) approved lurbinectedin for the treatment of adult patients with metastatic SCLC or for patients that have received platinum-based chemotherapy. In this review, we discuss the molecular profile and the preclinical and clinical studies of lurbinectedin in the treatment of SCLC patients.

Paritaprevir/ritonavir/ombitasvir+dasabuvir plus ribavirin therapy and inhibition of the anticoagulant effect of warfarin: a case report.

WHAT IS KNOWN AND OBJECTIVE: Paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD) is a direct-acting antiviral (DAA) approved for the treatment of chronic hepatitis C virus. We report on a probable interaction between PrOD with ribavirin and warfarin. CASE DESCRIPTION: Two weeks after the start of PrOD with ribavirin, the patient's international normalized ratio (INR) became subtherapeutic. Eleven weeks into therapy and following a 125% total increase in the weekly warfarin dose, therapeutic INR was achieved. Thirteen days after DAA therapy was completed and discontinued, the patient's INR became critically supratherapeutic. WHAT IS NEW AND CONCLUSION: Patients on PrOD plus ribavirin with warfarin should have INR followed closely upon initiation and discontinuation of therapy due to a probable drug interaction.

Study of brain uptake and biodistribution of [11C]toluene in non-human primates and mice.

Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain phamacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [11C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radio-tracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.

Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission.

To explore the role of endogenous GABA in NMDA antagonist induced dopamine (DA) release, we used in vivo microdialysis to study the effects of pretreatment with gamma-vinyl GABA (GVG) on phencyclidine (PCP)-induced DA release in terminal regions of midbrain DA neurons. GVG, an irreversible inhibitor of the GABA catabolizing enzyme GABA-AT, significantly reduced the DA response to PCP (7.0 mg/kg) in freely moving animals. Preferential increases in PCP-induced DA release in the PFC (four-fold those of NAcc) were dose-dependently inhibited by acute pretreatment with GVG at doses of 150 (51% inhibition), 300 (68% inhibition), and 500 (82% inhibition) mg/kg, whereas NAcc PCP-induced DA activity was unresponsive to 150 mg/kg and only partially inhibited by 300 and 500 mg/kg. Subchronic treatment with GVG did not enhance the inhibitory capacity of the GABAergic system. While GVG evidently modulates PCP-induced increases in mesocorticolimbic DA transmission, the character of this modulation is regionally specific, with cortical NMDA-antagonist induced increases appearing more sensitive to inhibition by endogenous GABA than subcortical areas.

The selective sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(phenylpropyl)piperazine (SA4503), blocks the acquisition of the conditioned place preference response to (-)-nicotine in rats.

We examined the effect of the sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(phenylpropyl)piperazine (SA4503), on the acquisition of the conditioned place preference response to subcutaneously administered (-)-nicotine in rats. (-)-Nicotine, but not SA4503 or vehicle, produced a significant conditioned place preference response. Pretreatment of animals with either 1 or 3 mg/kg of SA4503 significantly attenuated the conditioned place preference response to (-)-nicotine.

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats.

We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting.

Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADASE).

In this study we examined the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and GPI 5693, selective inhibitors of the enzyme N-Acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21), which cleaves glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG), on the conditioned place preference (CPP) response to cocaine in male rats. The i.p. administration of 15 mg/kg of cocaine produced a significant CPP response. The acquisition and expression of the CPP response to cocaine was blocked by the i.p. administration of 100 mg/kg of 2-PMPA and the p.o. administration of 30 mg/kg of GPI 5693. In contrast, neither 2-PMPA nor GPI 5693 produced a CPP or conditioned place aversion response when administered alone. Furthermore, neither 2-PMPA or GPI 5693 altered the expression of the CPP response to food. These results indicate that NAALADase inhibitors block the incentive motivational value of cocaine, suggesting that such agents may be of use in treating cue-induced craving in cocaine addicts.

Intracerebroventricular administration of NMDA-R1 antisense oligodeoxynucleotide significantly alters the activity of ventral tegmental area dopamine neurons: an electrophysiological study.

In this study, we determined the activity of midbrain dopamine (DA) neurons in male albino rats following the intracerebroventricular (i.c.v.) administration of antisense oligodeoxynucleotide (aODN) against the mRNA for the NR1 subunit of the NMDA receptor. In addition, the effect of aODN on the specific binding of the NMDA receptor ligand [(3)H]MK-801 was also examined in various brain areas, including the midbrain. Antisense ODN against the NR1 mRNA, the corresponding sense ODN (sODN) or saline was continuously administered into the right ventricle of rats by osmotic minipumps for 7 days (20 nmol/day). Autoradiographic binding studies indicated that aODN significantly reduced the density of [(3)H]MK-801 binding by an average of 20-30% in several forebrain regions, including the anterior cingulate cortex, caudate putamen, and nucleus accumbens. However, [(3)H]MK-801 binding was not significantly altered in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNC). Subsequently, using the technique of extracellular single-unit recording, the number, as well as the firing pattern, of spontaneously active DA neurons was determined in the VTA and SNC. The administration of aODN did not significantly alter the number of spontaneously active VTA and SNC DA neurons compared to saline- of sODN-treated animals. Furthermore, the firing pattern of spontaneously active SNC DA neurons was not significantly altered. However, for spontaneously active VTA DA neurons, the administration of aODN significantly decreased the percent events in bursts, number of bursts, and percentage of DA neurons exhibiting a bursting pattern compared to saline- and sODN-treated animals, i.e., neurons show less bursting activity. The present results suggest that subchronic aODN treatment against the mRNA for the NR1 subunit of the NMDA receptors can reduce NMDA receptor number and can result in an altered activity of spontaneously active VTA DA neurons in anesthetized rats.

Effectiveness of ECT combined with risperidone against aggression in schizophrenia.

Aggressive behavior in schizophrenic patients can often be problematic not only for the patients themselves, but for their families and others. This study examined the effect of electroconvulsive therapy (ECT) in combination with risperidone in an open trial in 10 male schizophrenic patients with significant aggressive behaviors. Patients were given bilateral ECT five times a week in combination with risperidone. The mean total number of times of ECT was 6.6 (range 5-9). The aggressive behavior in five of the six patients, who showed positive symptoms, was rapidly ameliorated within 12 days. The ECT/risperidone regimen also eliminated aggressive behavior in four patients showing no positive symptoms within 10 days. These treatment effects lasted for at least 6 months in 9 (of the 10) patients. The results suggest that ECT, combined with risperidone, produce a rapid and effective elimination of aggressive behaviors in schizophrenic patients. In addition, there was a resolution of aggression in four patients with no positive symptoms. This suggests that aggression in some schizophrenic patients develops as a primary symptom of schizophrenia and is not related to other positive symptoms of the disease or the patient's personality traits.

GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine.

Environments previously associated with drug use can become one of the most common factors triggering relapse to drug-seeking behavior. To better understand the neurochemical mechanisms potentially mediating these cues, we measured nucleus accumbens dopamine levels in animals exposed to environmental cues previously paired with cocaine administration. In animals exposed to a cocaine-paired environment nucleus accumbens dopamine increased by 25%. When administered 2.5 h prior to presentation of the environmental trigger, racemic vigabatrin (an irreversible inhibitor of gamma-aminobutyric acid (GABA)-transaminase) abolished this cue-induced increase. Conversely, R-(-)-vigabatrin, the inactive enantiomer, had no effect. Combined with our earlier findings, these studies support the potential therapeutic benefit of this enzyme-based GABAergic strategy to modulate brain dopamine and the subsequent treatment of drug addiction.

Acute and repeated administration of the selective 5-HT(2A) receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: an in vivo electrophysiological study.

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT(2A) receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01-0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats.

Effect of the repeated administration of (+/-)-3,4-methylenedioxymethamphetamine on the behavioral response of rats to the 5-HT1A receptor agonist (+/-)-8-hydroxy-(di-n-propylamino)tetralin.

In this study, we examined the effect of the subcutaneous administration (twice daily for 4 consecutive days) of 3,4-methylenedioxymethamphetamine (MDMA, 20 mg/kg) or saline (1 ml/kg) on the response of rats to the behavioral effects of the 5-HT1A agonist (+/-)-8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) 30 days after the last saline or MDMA treatment. The reciprocal forepaw treading elicited by the 0.25-mg/kg dose of 8-OH-DPAT was significantly lower in animals pretreated with MDMA compared to vehicle-treated animals. However, there were no significant differences between the MDMA- and vehicle-treated animals in flat body posture, locomotor activity and rectal temperature measured after the systemic administration of 8-OH-DPAT. Overall, our results suggest that the depletion of 5-HT levels by the repeated administration of MDMA does not produce a supersensitivity of central 5-HT1A receptors in the rat as determined via our approach.

Intravenous biperiden in akathisia: an open pilot study.

OBJECTIVE: Antipsychotic-induced akathisia can be distressing and unendurable for prolonged periods. It has been shown that intramuscular biperiden is a relatively rapid and effective treatment for akathisia. However, the intravenous administration of biperiden may provide a more rapid effect, although this remains to be definitively proven. METHOD: The subjects obtained for this study met the diagnostic criteria for schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The therapeutic effect of i.v. and i.m. biperiden was studied in an open clinical trial in twenty-three (12 male and 11 female) patients who developed antipsychotic-induced acute akathisia as defined by the research criteria of the DSM-IV. Following the development of akathisia, 5 mg of biperiden was intravenously injected in seventeen patients and intramuscularly in six patients. The therapeutic effect of biperiden on akathisia was clinically assessed by using the rating scale of Barnes. RESULTS: Following i.v. administration on biperiden, the mean time to onset and maximum effect occurred 1.6 (SD = 1.9) and 9.2 minutes (SD = 6.0), respectively. Furthermore, at the time of maximal effect, akathisia was completely ameliorated in all patients. The side effects reported were mild and transient. Following i.m. administration, the mean time to onset and maximum effect were 30.5 (SD = 5.9) and 50 minutes (SD = 7.4), respectively. Thus, the time to maximal effect was significantly less (40 minutes) after i.v. compared to i.m. administration. CONCLUSION: These results suggest that i.v. administration of 5 mg of biperiden could be used to provide a rapid and effective treatment for patients with severe akathisia.

Acute and chronic administration of the selective D(3) receptor antagonist SB-277011-A alters activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study.

This study examined the effect of acute and repeated p.o. administration of the selective D(3) receptor antagonist SmithKline Beecham (SB)-277011-A (1, 3, or 10 mg/kg) on the activity of spontaneously active midbrain dopamine (DA) neurons in anesthetized, male Sprague-Dawley rats. This was accomplished with the technique of in vivo extracellular single-unit recording. A single administration of either 3 or 10 mg/kg SB-277011-A produced a significant increase in the number of spontaneously active substantia nigra pars compacta (or A9) DA neurons compared with vehicle-treated (2% methylcellulose) animals. The 10-mg/kg dose of SB-277011-A produced a significant increase in the number of spontaneously active A10 DA neurons compared with vehicle-treated animals. The acute administration of SB-277011-A produced a significantly greater alteration in the firing pattern of spontaneously active A10 DA neurons, particularly at the 3- and 10-mg/kg doses, compared with vehicle-treated animals. The i.v. administration of SB-277011-A (0.01-1.28 mg/kg) did not significantly alter the firing rate or firing pattern of either A9 or A10 DA neurons. The repeated p.o. administration of 1, 3, or 10 mg/kg SB-277011-A once a day for 21 days produced a significant decrease in the number of spontaneously active A10 DA neurons. The repeated administration of SB-277011-A produced a greater effect on the firing pattern of spontaneously active A10 DA neurons, particularly at the 3-mg/kg dose, compared with A9 DA neurons. Overall, our results indicate that SB-277011-A alters the activity of midbrain DA neurons in rats.

The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats.

In this study, we assessed the effects of the acute administration of various 5-HT receptor antagonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges, respectively, and the latency of secondary discharge was also determined. The administration of either the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-c yclohe xanecarboximimde 3 HCl (WAY 100635, 0.1-1 mg/kg i.p.), the selective 5-HT(3) receptor antagonist granisetron (0.3-3 mg/kg i.p.), the selective 5-HT(2A) receptor antagonist R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidine-methanol (MDL 100907, 0.3-3 mg/kg i.p.) or the 5-HT(2B,C) receptor antagonist antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea HCl (SKB 200646A, 5-50 mg/kg i.p.) did not alter the pulse number threshold compared to vehicle-treated animals. However, the acute administration of WAY 100635 (0.3 mg/kg) and M100907 (1 mg/kg) significantly increased, whereas granisetron (1 mg/kg) decreased, the primary afterdischarge duration compared to vehicle-treated animals. The latency of secondary after discharge was significantly decreased by WAY 100635 (1 mg/kg) and granisetron (3 mg/kg) compared to vehicle-treated animals. These results suggest that in this model, the antagonism of 5-HT(1A), 5-HT(2A), 5-HT(3) or 5-HT(2B,C) receptors do not lower or raise seizure threshold. However, the antagonism of 5-HT(1A) receptors may increase or augment seizure severity.

Heterogeneity of the mesotelencephalic dopamine fibers: physiology and pharmacology.

The mesotelencephalic dopamine (DA) system is heterogeneous with respect to nuclei, terminal loci, DA receptor subtypes, electrophysiological characteristics and response patterns, and neuropharmacological response to a range of agents. The majority of mesocortical and mesolimbic DA neurons originate in the ventral tegmental area. Mesostriatal DA neurons originate in substantia nigra pars compacta. DA neurons originating from the retrorubal field primarily innervate subcortical limbic and neostriatal loci. Mesostriatal terminal loci have relatively low densities of D3 and D4 receptors, compared to mesolimbic and mesocortical loci. The D1 and D2 receptors appear more homogeneously distributed. Electrophysiologically, mesostriatal DA neurons show more regularity in firing pattern (fewer bursting events), and a lower basal firing rate than mesolimbic or mesocortical neurons. Neuropharmacologically, mesocortical DA neurons are less responsive to intravenous d-amphetamine, (+)apomorphine, and chronic antipsychotic drug treatment. Mesocortical DA neurons are also relatively insensitive to iontophoretically applied DA, a finding congruent with their reported relative lack of somatodendritic autoreceptors. Neurochemically, mesoaccumbens DA neurons are more sensitive to systemic administration of drugs with addictive liability.

Enhancement of conditioned place preference response to cocaine in rats following subchronic administration of 3, 4-methylenedioxymethamphetamine (MDMA).

In this study, we measured conditioned place preference (CPP) responses to cocaine following subchronic administration of the recreationally abused drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in male Sprague-Dawley rats. Animals were given either vehicle (1 ml/kg of distilled water, s.c.) or MDMA (20 mg/kg, s.c.) twice a day for 4 consecutive days. Two weeks later, CPP responses to cocaine (5, 10, or 20 mg/kg, i.p.) were measured. The MDMA-treated animals showed a significantly greater CPP response to cocaine than the vehicle-treated animals. Since conditioned place preference is believed to be a measure of appetitive behavior, these results suggest that MDMA abuse could lead to an increased vulnerability to the rewarding actions of cocaine and, hence, to increased vulnerability to cocaine addiction and dependence.

Gamma-vinyl GABA inhibits methamphetamine, heroin, or ethanol-induced increases in nucleus accumbens dopamine.

We examined the acute effect of the irreversible GABA-transaminase inhibitor, gamma-vinyl GABA (GVG, Sabril((R)), Vigabatrin((R))) on increases in nucleus accumbens (NAc) dopamine (DA) following acute administration of methamphetamine, heroin, or ethanol. Methamphetamine (2.5 mg/kg) produced a dose-dependent increase (2, 700%) in NAc DA. GVG preadministration (300 or 600 mg/kg), however, inhibited this response by approximately 39 and 61%, respectively. The lower dose of methamphetamine (1.25 mg/kg), increased DA by 1, 700%. This response was inhibited to a similar extent (44%) regardless of the GVG dose preadministered (300 or 600 mg/kg). In addition, heroin-induced increases in NAc DA (0.5 mg/kg, 170%) were inhibited or completely abolished by GVG (150 or 300 mg/kg, 65 and 100%, respectively). Finally, at half the dose necessary for heroin, GVG (150 mg/kg) also completely abolished ethanol-induced increases in NAc DA following a 0.25 g/kg challenge dose (140%). Taken with our previous findings using nicotine or cocaine as the challenge drug, these results indicate that GVG attenuates increases in NAc DA by a mechanism common to many drugs of abuse. However, it appears unlikely that an acute dose of GVG can completely inhibit increases in NAc DA following challenges with a drug whose mechanism of action is mediated primarily through the DA reuptake site.

Acute and chronic administration of the selective sigma1 receptor agonist SA4503 significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study.

In this study, we examined the effect of the acute and repeated administration of the selective sigma (sigma)1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on the number and firing pattern of spontaneously active dopamine (DA) neurons in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single unit recording. The intravenous administration of SA4503 (0.01-1.28 mg/kg) did not significantly alter the firing rate or pattern of spontaneously active DA neurons in either the SNC or VTA. A single injection of either 0.1 or 0.3 mg/kg i.p. of SA4503 did not alter the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of 1 mg/kg i.p. of SA4503 produced a significant decrease and increase in the number of spontaneously active SNC and VTA DA neurons, respectively. Overall, the firing pattern parameters of spontaneously active SNC DA neurons were altered more significantly than those of spontaneously active VTA DA neurons following the acute administration of SA4503. The repeated administration (one injection per day for 21 days) of 0.3 and 1 mg/kg i.p. of SA4503 produced a significant increase in the number of spontaneously active VTA DA neurons. In addition, the repeated administration of SA4503 produced a greater alteration of the firing pattern of spontaneously active VTA compared to SNC DA neurons. Our results suggest that the administration of SA4503 significantly alters the activity of spontaneously active midbrain DA neurons, particularly those in the VTA following repeated administration.