A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168)

Hepatocellular carcinoma (HCC) remains a lethal treatment-resistant cancer with a median survival of <6 months in patients not considered candidates for radical surgical treatments. SB-715992 is a novel cytotoxic agent implicated in the inhibition of mitotic kinesin spindle protein (KSP). Based on evidence from preclinical models and phase I trials, we conducted a phase II trial of SB-715992 in chemo-na?ve patients with advanced HCC. A non-randomized, non-blinded multicentre two-stage phase II study was completed examining the efficacy, toxicity, and pharmacokinetics of SB-715992 at 18 mg/m2 IV q 3 weeks, in patients with measurable locally advanced, metastatic or recurrent HCC. The predictive value of KSP in archival tumour was assessed. Fifteen patients with metastatic HCC received a median of 3 cycles of SB-715992. The most common grade 3+ toxicities were granulocytopenia, leukocytopenia, diarrhea and liver transaminase rise. Overall confirmed response rate was 0%. Seven (46%) patients had a best response of stable disease at the 8-week evaluation (median duration 3.9 months) Median time to progression was 1.61 months (95%CI = 1.31-3.94 months) SB-715992 plasma concentrations were comparable to those observed in the phase I studies. Expression of KSP by immunohistochemistry was observed in only four of eight evaluable samples with strong expression reported in only two. No correlation was observed between intensity of KSP staining and clinical outcome. Among these patients with preserved hepatic function and good performance status, SB-715992 was generally well tolerated. However, no conclusive evidence of benefit was seen with SB-715992 monotherapy in HCC.     

GSK-3 beta inhibition and prevention of mitochondrial apoptosis inducing factor release are not involved in the antioxidant properties of SB-415286

The antioxidant effects of lithium and SB-415286, two glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors, were studied in cerebellar granule neurons by measuring changes in 2, 7-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. GSK-3 beta inhibitors inhibit apoptosis mediated by serum and potassium withdrawal (S/K withdrawal) and GSK-3 beta activation, as measured by beta-catenin degradation. Furthermore, as both drugs prevent mitochondrial apoptosis inducing factor (AIF) release, these data indicate that GSK-3 beta inhibitors prevent caspase-independent apoptosis in cerebellar granule neurons induced by S/K withdrawal. While the most specific GSK-3 beta inhibitor, SB-415286, demonstrated antioxidant effects, Li+ 10 mM did not. These results indicate that lithium 10 mM and SB-415286 20 microM exert anti-apoptotic effects in cases of S/K withdrawal mediated by GSK-3 beta inhibition. However, these antioxidant properties are independent of GSK-3 beta inhibition and prevention of mitochondrial AIF release.     

Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin₁ receptors

BACKGROUND AND PURPOSE

The enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment. Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin₁ receptor antagonist SB-334867 in inbred alcohol-preferring rats.

EXPERIMENTAL APPROACH

Rats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n= 11, delayed n= 11) or SB-334867 (20 mg·kg⁻¹ i.p.; immediate n= 6, delayed n= 11). Fos expression was compared between each group and to animals that underwent extinction only.

KEY RESULTS

SB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra-limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices.

CONCLUSIONS AND IMPLICATIONS

Cue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence.     

Antagonism of orexin-1 receptors attenuates swim- and restraint stress-induced antinociceptive behaviors in formalin test

Orexin (ORX) plays an important role in pain modulation. ORX receptors have been found in many brain structures and are known to be involved in pain processing. It is well-established that the acute and chronic forms of stress could induce hormonal and neuronal changes that affect both pain threshold and nociceptive behaviors. The role of OX1R receptors in stress-induced analgesia (SIA) has not been fully elucidated. In the present study, using the formalin test, attempts were made to evaluate the effects of acute immobilization restraint stress and swimming stress on pain behavioral responses following OX1R antagonist administration in rats. Animals received OX1R antagonist (SB-334867), vehicle, or naloxone before exposure to acute restraint stress (30 min) or swimming stress test (6 min, 20 ± 1 °C), and immediately submitted to hind paw formalin injection (50 μl, 2%). Acute 30-min exposure to restraint stress as well as 6-min exposure to swim stress could significantly reduce the formalin-induced nociceptive behaviors in rats. This antinociceptive effect with either restraint stress or swim stress was fully prevented by OX1R antagonist (SB-334867), while the SB-334867 alone had no effect. However, the opioid receptor antagonist naloxone could not totally reverse the antinociception effect with either form of stress. It is suggested that OX1R might be involved in antinociception behaviors induced by these two forms of stress. These data highlight the significant role of OX1R as a novel target for treatment of stress-related disorders.     

Serotonin 5-HT6 receptor blockade reverses the age-related deficits of recognition memory and working memory in mice

Studies have shown that the blockade of 5-HT6 receptors (5-HT6R) can improve memory processes and reverse age-related spatial episodic like memory deficits. Since normal aging in the human is associated with a decline in episodic and working memory, we assessed the effect of the 5-HT6R blockade (SB-271046) on recognition memory (object recognition task) (a component of episodic like memory) in parallel to working memory (spontaneous alternation task in the T-maze) performances in young, adult, aged and senescent mice. Deficits in consolidation of non spatial recognition memory that were observed in 17- and 21-month-old mice were found to be reversed by 5-HT6R blockade. Deficits in working memory performances were only apparent as late as at 25 months of age; again, these deficits were reversed by 5-HT6R blockade. This study revealed in the mouse that, as in humans, working memory is more lately altered than recognition memory during aging and that such memory deficits could be counteracted by the use of 5-HT6R antagonists.     

SB-239063, a Potent and Selective Inhibitor of P38 Map Kinase: Preclinical Pharmacokinetics and Species-Specific Reversible Isomerization

Purpose. A series of studies was conducted to evaluate the preclinical pharmacokinetics of SB-239063 (trans-1-(4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [(2-methoxy) pyrimidin-4-yl] imidazole), a potent and selective p38 MAP kinase inhibitor. Methods. SB-239063 was administered both i.v. and p.o. in the rat, dog, cynomolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data. Results. Initial rat studies suggested possible nonlinear disposition; however, assay refinement revealed an in vivo trans-cis isomerization of SB-239063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavailability in the rat and dog, but poor bioavailability in the cynomolgus monkey. Substantial in vivo trans-cis isomerization occurred in the rat and cynomolgus monkey, but occurred to a far lesser extent in the dog. The isomerization reaction was reversible, with a recycled fraction of 0.20 and 0.0003 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bioavailability was also poor, but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilance in conducting high-throughput analytical method development, and the importance of using a variety of preclinical species when evaluating the disposition of new drug candidates.     

Profile of SB-204269, a mechanistically novel anticonvulsant drug,in rat models of focal and generalized epileptic seizures

1. Earlier optimization of structure-activity relationships in a novel series of 4-(benzoylamino)-benzopyrans, led to the discovery of SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3R-ol, hemihydrate), a potent orally-active anticonvulsant in the mouse maximal electroshock seizure threshold (MEST) test.
2. Studies have now been undertaken to determine the effects of SB-204269 in a range of seizure models and tests of neurological deficits in rats. In addition, the compound has been evaluated in a series of in vitro mechanistic assays.
3. SB-204269 proved to be an orally-effective anticonvulsant agent, at doses (0.1–30 mg kg⁻¹) devoid of overt behavioural depressant properties, in models of both electrically (MEST and maximal electroshock (MES)) and chemically (i.v. pentylenetetrazol (PTZ) infusion)-evoked tonic extension seizures. However, the compound did not inhibit PTZ-induced myoclonic seizures at doses up to 30 mg kg⁻¹, p.o.
4. SB-204269 also selectively reduced focal electrographic seizure activity in an in vitro elevated K⁺ rat hippocampal slice model at concentrations (0.1–10 μM) that had no effect on normal synaptic activity and neuronal excitability.
5. In all of these seizure models, SB-204269 was equivalent or better than the clinically established antiepileptic drugs carbamazepine and lamotrigine, in terms of anticonvulsant potency and efficacy.
6. Unlike SB-204269, the corresponding trans 3S,4R enantiomer, SB-204268, did not produce marked anticonvulsant effects, an observation in accord with previous findings for other related pairs of trans enantiomers in the benzopyran series.
7. In the rat accelerating rotarod test, a sensitive paradigm for the detection of neurological deficits such as sedation and motor incoordination, SB-204269 was inactive even at doses as high as 200 mg kg⁻¹, p.o. This was reflected in the excellent therapeutic index (minimum significantly effective dose in the rotarod test/ED₅₀ in the MES test) for SB-204269 of >31, as compared to equivalent values of only 7 and 13 for carbamazepine and lamotrigine, respectively.
8. At concentrations (⩾10 μM) well above those required to produce anticonvulsant activity in vivo (i.e. 0.1 μM in brain), SB-204269 did not interact with many of the well known mechanistic targets for established antiepileptic drugs (e.g. Na⁺ channels or GABAergic neurotransmission). Subsequent studies have shown that the anticonvulsant properties of SB-204269 are likely to be mediated by a novel stereospecific binding site present in the CNS.
9. The overall efficacy profile in rodent seizure models, together with a minimal liability for inducing neurological impairment and an apparently unique mechanism of action, highlight the therapeutic potential of SB-204269 for the treatment of refractory partial and generalized tonic-clonic seizures.

     

5-HT7 receptor modulators: a medicinal chemistry survey of recent patent literature (2004 – 2009)

Importance of the field: The 5-HT₇ receptors are discretely localized within the CNS (thalamus, hypothalamus, limbic and cortical regions). The 5-HT₇ receptors are also present in smooth muscle cells from blood vessels and have been reported in gastrointestinal tract as well as in rat lumbar dorsal root and sympathetic ganglia. The 5-HT₇ receptors have been implicated in depression, disorders related to circadian rhythms, pain and migraine. Thus, there is a great interest in developing potent and selective 5-HT₇ receptor modulators.

Areas covered in this review: This review article highlights the research advances published in the patent literature between January 2004 and December 2009, giving emphasis to the medicinal chemist's standpoint.

What the reader will gain: Readers will rapidly gain an overview of the various 5-HT₇ receptor modulators reported in the patent literature in the past 6 years. Furthermore, the readers will learn which structure type can interact with 5-HT₇ receptor and also the different companies that are the main players in the field.

Take home message: Although no 5-HT₇ modulator has entered clinical trials, the development and future use of different agonists and antagonists suitable for use in vivo seem very promising.     

Exploring California’s new law eliminating personal belief exemptions to childhood vaccines and vaccine decision-making among homeschooling mothers in California

Background

California’s Senate Bill 277 (SB-277) law eliminated the personal belief exemption to school immunization requirements. A potential consequence may be that parents choose homeschooling to avoid immunization. Vaccine attitudes and behaviors have not been well studied among the home-schooling population. This study explored the effect of SB-277 and vaccine decision-making among California home schoolers.