Preclinical Evidence

GABA is the predominant inhibitory neurotransmitter in the CNS. Baclofen acts centrally as an agonist at the GABAb receptor, which increases inhibition of nerves. 3-Aminopropylphosphinic acid (3-APPi) has been shown experimentally to act as an antitussive at peripheral nerves and preclinical evidence suggests that baclofen indeed has antitussive actions clinically [3]. 

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

GHB treatment in mice, tolerance develops to both the hypolocomotion and cataleptic effects of the drug (Itzhak and Ali 2002). There is also preclinical evidence of cross-tolerance and cross-dependence of GHB with alcohol (Colombo et al. 1995 Fadda et al. 1989). As described in the earlier section on clinical pharmacology, GHB and its analogues have been used in humans in the treatment of alcohol withdrawal. Nicholson and Balster (2001) reviewed the evidence for cross-tolerance and cross-dependence of GHB with alcohol. 

Determining the underlying therapeutic mechanisms of a drug makes pharmacology a powerful tool for understanding biological phenomena. This chapter reviews the preclinical evidence of the impact of some neurotransmitter systems and related drugs on sleep and wakefulness. 

Roberts D.C. Preclinical evidence for GABA(B) agonists as a pharmacotherapy for cocaine addiction. Physiol. Behav. 86 18, 2005. 

Another creative trial design was performed for the pivotal trial for approval of the monoclonal antibody cetuzimab (Erbitux). The clinical trial was based on the preclinical evidence. Erbitux was synergistic in animal model systems. 

As for HER-2, preclinical evidence exists to support targeting EGFR (HER-1) with a therapeutic intent in epithelial neoplasms. First, the expression of EGF receptors is elevated in many epithelial tumors and this overexpression has been associated with poor clinical outcome (28). Second, coexpression of high levels of EGFR and its ligands, EGF... 

Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. There is considerable preclinical evidence that hyperalgesia and allody-nia following peripheral tissue or nerve injury is not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depends on NMDA receptor-mediated central changes in synaptic excitabihty (Zieglgansberger and Tolle 1993 Sandkiihler and Liu 1998 Hide 2000 Parsons 2001 Fundytus 2001). 

A limited number of studies have evaluated the consequences of early-life stress in adults (Table 9.1). Although there is evidence for increased 24-hour urinary cortisol excretion in abused women with PTSD (Lem-ieux and Coe, 1995), findings on basal plasma or salivary cortisol levels in women with a history of childhood abuse are conflicting, likely because of methodological differences (Heim and Nemeroff, 2001). There is evidence for increased HPA feedback sensitivity in abused women with PTSD (Stein et al., 1997a). Given the preclinical evidence for a sensitization of the... 

McCann, U., Hatzidimitriou, G., Ridenow, A., Fischer, C., Yuan, S., Katz, J., and Ricaurte, G. (1994) Dexfenfluramine and serotonin neurotoxicity further preclinical evidence that clinical caution is indicated./ Pharmacol Exp Ther 269 792-798. 

Substantial preclinical evidence exists that 5-HTj, receptor agonists possess anxiolytic activity in animal screens of anxiety. Clinical studies with the... 

Preclinical evidence indicates that knockdown of BRCAl by small interference RNA (siRNA) in T47D cells leads to a 50-fold increase in resistance to paclitaxel. The increased sensitivity to paclitaxel observed in BRCAl reconstituted cells correlated with the activation of the mitotic checkpoint and an increase in apoptosis (40,55). 

Colombo G et al The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence Preclinical evidence. Mol Neurobiol 2007 36 102. [PMID 17952655]... 

Despite the compelling preclinical evidence about the feasibility and efficacy of gene therapy in the treatment of CVDs, only a few small-scale trials have been carried out (55). Of the 918 trials that have been finished or currently under way worldwide, only 8,3% are CVDs, The majority of these trials evaluated the therapeutic efficacy of angiogenic gene transfer... 

TABLE 19.3 Preclinical evidence of carcinogenic risk with erythropoiesis stimulating agents... 

Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 2000 48(8) 740-54. 

As far as hjtpertension is concerned, there is a substantial body of preclinical evidence of the potential efficacy of endothelin antagonists in hypertension, and this has been extensively reviewed (10). Circulating endothelin concentrations are not increased in hypertension, but it is postulated that there is an imbalance between the vaso-dilatory effects of nitric oxide and the vasoconstrictor effects of endothelin at a local vascular level, resulting in increased endothelin vasoconstrictor tone and endo-thelin-mediated end-organ damage (11,12). 

Biradar S, Joshi H, Chheda T (2014) Biochanin-A ameliorates behavioural and neurochemical derangements in cognitive-deficit mice for the betterment of Alzheimer s disease. Hum Exp Toxicol. 33 369-382. Han K, Jia N, Li J, Yang L, Min LQ (2013) Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer s disease. Mol Med Rep 8 737-740. Matsumoto K, Zhao Q, Niu Y, Fujiwara H, Tanaka K, Sasaki-Hamada S et al (2013) Kampo formulations, chotosan, and yokukan-san, for dementia therapy Existing clinical and preclinical evidence. J Pharmacol Sci 122 257-269... 

The biological rationale, preclinical evidence, and early clinical results demonstrate the potential for small-molecule IAP protein antagonists in the treatment of cancer. It has been gratifying for us to participate in an effort that has taken a program from... 

Preclinical evidence suggests selective Nay 1.8 inhibitors may provide relief from inflammatory pain conditions without mechanism-based cardiac and CNS side effects. To date, this hypothesis has been validated in rodent models of pain using targeted genetic disruption (Akopian et al. 1999 Laird et al. 2002), antisense oligonucleotide-mediated depletion (Villarreal et al. 2005), a p-conotoxin less than tenfold selective for Nayl.8 over other sodium channels (Ekberg et al. 2006), and, most recently, a small molecule with nanomolar potency and more than 100-fold selectivity over other sodium channels (Jarvis et al. 2007). 

In the United States in 1960, Richardson-Merrell sought marketing approval for thalidomide under the brand name Kevadon. It never reached the market because of the resistance of an FDA medical reviewer. Dr. Francis Kelsey. It is said that she was influenced by her previous experience with the antimalarial drug quinidine, which had teratogenic activity. Her misgivings were based on concerns that peripheral neuritis had been observed in adults. This mixture of concern about safety and previous experience combined to overrule the considerable body of preclinical evidence that the drug was safe. Kelsey... 

Derosa G, Maffioli P, Cicero AFG. Berberine on metabolic and cardiovascular risk factors An analysis from preclinical evidence to clinical trials. Expert Opin Biol r cr2012 12(8) 1113-24. 

There is a wealth of preclinical evidence of the protective effects of nitroalkenes, OA-NO2 in particular, in various animal models of metabolic and inflammatory disorders (reviewed in Francisco J. Schopfer, Cipollina, and Freeman 2011). These are now being developed for the treatment of diseases associated with kidney injury, inflammation and metabolic disorders, the initial clinical target being contrast imaging dye-induced nephropathy. 

Phase II clinical trials have all involved perillyl alcohol. Results demonstrated that despite preclinical evidence, there appeared to be no anticarcinogenic activity in cases of advanced ovarian cancer (Bailey et al., 2002), metastatic colorectal cancer (Meadows et al., 2002), and metastatic breast cancer (Bailey et al., 2008). Only one trial has demonstrated antitumor activity as evidenced by a reduction of tumor size in patients with recurrent malignant gliomas (Orlando da Fonseca et al., 2008). 

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