The central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolic enzymes. This blood-CNS barrier (BCNSB) plays a pivotal role in the pathophysiology of multiple sclerosis (MS). It binds and anchors activated leukocytes to permit their movement across the BCNSB and into the CNS. Once there, these immune cells target particular self-epitopes and initiate a cascade of neuroinflammation, which leads to the breakdown of the BCNSB and the formation of perivascular plaques, one of the hallmarks of MS. Immunomodulatory drugs for MS are either biologics or small molecules, with only the latter having the capacity to cross the BCNSB and thus have a propensity to cause CNS side effects. However, BCNSB penetration is a desirable feature of MS drugs that have molecular targets within the CNS. These are nabiximols and dalfampridine, which target cannabinoid receptors and potassium channels, respectively. Vascular cell adhesion molecule-1, present on endothelial cells of the BCNSB, also serves as a drug discovery target since it interacts with α4-β1-integrin on leucocytes. The MS drug natalizumab, a humanized monoclonal antibody against α4-β1-integrin, blocks this interaction and thus reduces the movement of immune cells into the CNS. This paper further elaborates on the role of the BCNSB in the pathophysiology and pharmacotherapy of MS. 1. Introduction Multiple sclerosis (MS) is an acquired autoimmune disease that affects both the brain and the spinal cord leading to a variety of symptoms, including changes in motor function, sense perception, and mental function, along with fatigue [1–3]. The disease presents in different forms that follow distinct patterns of evolution and rates of disability progression [4]. The most common form is relapsing-remitting MS (RRMS), which affects about 85% of people with MS (pwMS), is more common in females than males (by a ratio of 2 to 1), and has an average age at diagnosis of 29 years [5]. RRMS is characterized by acute attacks (relapses) followed by partial or full recovery (remission) and contrasts with primary progressive MS (PPMS), which affects about 10–15% of pwMS, is diagnosed (on average) at age 40, has no gender bias, and is characterized by a steady and irreversible progression of functional impairments [6–8]. These two forms of MS also differ in their onset as PPMS begins insidiously, whereas the harbinger of RRMS is usually a transient impairment in motor or sensory function, together with white matter abnormalities shown by magnetic resonance
References
[1]
Y. Bol, J. Smolders, A. Duits, I. M. J. Lange, and R. Hupperts, “Fatigue and heat sensitivity in patients with multiple sclerosis,” Acta Neurologica Scandinavica, vol. 126, no. 6, pp. 384–389, 2012.
[2]
A. Compston and A. Coles, “Multiple sclerosis,” The Lancet, vol. 372, no. 9648, pp. 1502–1517, 2008.
[3]
A. M. Palmer, “Pharmacotherapeuetic options for the treatment of Multiple sclerosis,” Clinical Medicine Insights, vol. 4, pp. 145–168, 2012.
[4]
F. D. Lublin and S. C. Reingold, “Defining the clinical course of multiple sclerosis: results of an international survey,” Neurology, vol. 46, no. 4, pp. 907–911, 1996.
J. Antel, S. Antel, Z. Caramanos, D. L. Arnold, and T. Kuhlmann, “Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?” Acta Neuropathologica, vol. 123, no. 5, pp. 627–638, 2012.
[7]
M. Koch, E. Kingwell, P. Rieckmann, and H. Tremlett, “The natural history of primary progressive multiple sclerosis,” Neurology, vol. 73, no. 23, pp. 1996–2002, 2009.
[8]
D. H. Miller and S. M. Leary, “Primary-progressive multiple sclerosis,” Lancet Neurology, vol. 6, no. 10, pp. 903–912, 2007.
[9]
K. Pandey and F. D. Lublin, “Clinically isolated syndrome and multiple sclerosis: rethinking the arsenal,” Current Treatment Options in Neurology, vol. 11, no. 3, pp. 193–202, 2009.
[10]
C. Forn, M. A. Rocca, P. Valsasina et al., “Functional magnetic resonance imaging correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of multiple sclerosis at presentation: an activation and connectivity study,” Multiple Sclerosis, vol. 18, no. 2, pp. 153–163, 2012.
[11]
L. K. Fisniku, P. A. Brex, D. R. Altmann et al., “Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis,” Brain, vol. 131, no. 3, pp. 808–817, 2008.
[12]
M. Koch, E. Kingwell, P. Rieckmann et al., “The natural history of secondary progressive multiple sclerosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 9, pp. 1039–1043, 2010.
[13]
M. Rovaris, C. Confavreux, R. Furlan, L. Kappos, G. Comi, and M. Filippi, “Secondary progressive multiple sclerosis: current knowledge and future challenges,” Lancet Neurology, vol. 5, no. 4, pp. 343–354, 2006.
[14]
M. Trojano and D. Paolicelli, “The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes,” Neurological Sciences, vol. 22, supplement 2, pp. S98–S102, 2001.
[15]
A. Ceccarelli, R. Bakshi, and M. Neema, “MRI in multiple sclerosis: a review of the current literature,” Current Opinion in Neurology, vol. 25, no. 4, pp. 402–409, 2012.
[16]
M. Filippi and M. A. Rocca, “MR imaging of multiple sclerosis,” Radiology, vol. 259, no. 3, pp. 659–681, 2011.
[17]
M. Filippi, M. A. Rocca, F. Barkhof et al., “Association between pathological and MRI findings in multiple sclerosis,” The Lancet Neurology, vol. 11, no. 4, pp. 349–360, 2012.
[18]
J. H. Simon, D. Li, A. Traboulsee et al., “Standardized MR imaging protocol for multiple sclerosis: consortium of MS Centers consensus guidelines,” American Journal of Neuroradiology, vol. 27, no. 2, pp. 455–461, 2006.
[19]
C. H. Polman, S. C. Reingold, G. Edan et al., “Diagnostic criteria for multiple sclerosis: 2005 Revisions to the “McDonald Criteria”,” Annals of Neurology, vol. 58, no. 6, pp. 840–846, 2005.
[20]
A. Faridar, G. Eskandari, M. A. Sahraian, A. Minagar, and A. Azimi, “Vitamin D and multiple sclerosis: a critical review and recommendations on treatment,” Acta Neurologica Belgica, vol. 112, no. 4, pp. 327–333, 2012.
[21]
D. G. Haegert, “Multiple sclerosis: a disorder of altered T-cell homeostasis,” Multiple Sclerosis International, vol. 2011, Article ID 461304, 6 pages, 2011.
[22]
S. S. Ousman, B. H. Tomooka, J. M. Van Noort et al., “Protective and therapeutic role for αB-crystallin in autoimmune demyelination,” Nature, vol. 448, no. 7152, pp. 474–479, 2007.
[23]
E. K. Mathey, T. Derfuss, M. K. Storch et al., “Neurofascin as a novel target for autoantibody-mediated axonal injury,” Journal of Experimental Medicine, vol. 204, no. 10, pp. 2363–2372, 2007.
[24]
A. M. Burrell, A. E. Handel, S. V. Ramagopalan, G. C. Ebers, and J. M. Morahan, “Epigenetic mechanisms in multiple sclerosis and the major histocompatibility complex (MHC),” Discovery Medicine, vol. 11, no. 58, pp. 187–196, 2011.
[25]
G. C. Ebers, D. E. Bulman, and A. D. Sadovnick, “A population-based study of multiple sclerosis in twins,” New England Journal of Medicine, vol. 315, no. 26, pp. 1638–1642, 1986.
[26]
L. F. Barcellos, S. Sawcer, P. P. Ramsay et al., “Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis,” Human Molecular Genetics, vol. 15, no. 18, pp. 2813–2824, 2006.
[27]
P.-A. Gourraud, H. F. Harbo, S. L. Hauser, and S. E. Baranzini, “The genetics of multiple sclerosis: an up-to-date review,” Immunological Reviews, vol. 248, no. 1, pp. 87–103, 2012.
[28]
P. I. W. De Bakker, “Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci,” Annals of Neurology, vol. 70, no. 6, pp. 897–912, 2011.
[29]
S. Sawcer, G. Hellenthal, N. A. Patsopoulos et al., “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis,” Nature, vol. 476, no. 7359, pp. 214–219, 2011.
[30]
A. E. Handel, G. Giovannoni, G. C. Ebers, and S. V. Ramagopalan, “Environmental factors and their timing in adult-onset multiple sclerosis,” Nature Reviews Neurology, vol. 6, no. 3, pp. 156–166, 2010.
[31]
A. E. Handel, A. J. Williamson, G. Disanto, R. Dobson, G. Giovannoni, and S. V. Ramagopalan, “Smoking and multiple sclerosis: an updated meta-analysis,” PLoS ONE, vol. 6, no. 1, Article ID e16149, 2011.
[32]
A. E. Handel, A. J. Williamson, G. Disanto, L. Handunnetthi, G. Giovannoni, and S. V. Ramagopalan, “An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis,” PLoS ONE, vol. 5, no. 9, Article ID e12496, pp. 1–5, 2010.
[33]
D. M. Wingerchuk, “Environmental factors in multiple sclerosis: Epstein-Barr virus, vitamin D, and cigarette smoking,” Mount Sinai Journal of Medicine, vol. 78, no. 2, pp. 221–230, 2011.
[34]
N. J. Abbott, A. A. K. Patabendige, D. E. M. Dolman, S. R. Yusof, and D. J. Begley, “Structure and function of the blood-brain barrier,” Neurobiology of Disease, vol. 37, no. 1, pp. 13–25, 2010.
[35]
B. Engelhardt, “The blood-central nervous system barriers actively control immune cell entry into the central nervous system,” Current Pharmaceutical Design, vol. 14, no. 16, pp. 1555–1565, 2008.
[36]
A. M. Palmer, “The role of the blood-CNS barrier in CNS disorders and their treatment,” Neurobiology of Disease, vol. 37, no. 1, pp. 3–12, 2010.
[37]
A. Mahringer, M. Ott, I. Reimold, V. Reichel, and G. Fricker, “The ABC of the blood-brain barrier—regulation of drug efflux pumps,” Current Pharmaceutical Design, vol. 17, no. 26, pp. 2762–2770, 2011.
[38]
S. Shen and W. Zhang, “ABC transporters and drug efflux at the blood-brain barrier,” Reviews in the Neurosciences, vol. 21, no. 1, pp. 29–53, 2010.
[39]
M. Cereijido, J. Valdés, L. Shoshani, and R. G. Contreras, “Role of tight junctions in establishing and maintaining cell polarity,” Annual Review of Physiology, vol. 60, pp. 161–177, 1998.
[40]
A. M. Palmer, “Brain disorders, brain medicines and the blood-brain barrier,” in Horizons in Neuroscience Research, A. Costa and E. Villalba, Eds., vol. 6, pp. 97–122, Nova Science Publishers, 2012.
[41]
A. M. Palmer and M. S. Alavijeh, “Translational CNS medicines research,” Drug Discovery Today, vol. 17, no. 19-20, pp. 1068–1078, 2012.
[42]
R. Gandhi, A. Laroni, and H. L. Weiner, “Role of the innate immune system in the pathogenesis of multiple sclerosis,” Journal of Neuroimmunology, vol. 221, no. 1-2, pp. 7–14, 2010.
[43]
L. H. Kasper and J. Shoemaker, “Multiple sclerosis immunology: the healthy immune system vs the MS immune system,” Neurology, vol. 74, supplement 1, pp. S2–S8, 2010.
[44]
T. Holm？y and F. Vartdal, “The immunological basis for treatment of multiple sclerosis,” Scandinavian Journal of Immunology, vol. 66, no. 4, pp. 374–382, 2007.
[45]
P. Conlon, J. R. Oksenberg, J. Zhang, and L. Steinman, “The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system,” Neurobiology of Disease, vol. 6, no. 3, pp. 149–166, 1999.
[46]
I. Galea, I. Bechmann, and V. H. Perry, “What is immune privilege (not)?” Trends in Immunology, vol. 28, no. 1, pp. 12–18, 2007.
[47]
C. Larochelle, J. I. Alvarez, and A. Prat, “How do immune cells overcome the blood-brain barrier in multiple sclerosis?” FEBS Letters, vol. 585, no. 23, pp. 3770–3780, 2011.
[48]
D. A. Carlow, K. Gossens, S. Naus, K. M. Veerman, W. Seo, and H. J. Ziltener, “PSGL-1 function in immunity and steady state homeostasis,” Immunological Reviews, vol. 230, no. 1, pp. 75–96, 2009.
[49]
A. E. R. Hicks, S. L. Nolan, V. C. Ridger, P. G. Hellewell, and K. E. Norman, “Recombinant P-selectin glycoprotein ligand-1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect,” Blood, vol. 101, no. 8, pp. 3249–3256, 2003.
[50]
K. D. Patel, S. L. Cuvelier, and S. Wiehler, “Selectins: critical mediators of leukocyte recruitment,” Seminars in Immunology, vol. 14, no. 2, pp. 73–81, 2002.
[51]
M. Sperandio, C. A. Gleissner, and K. Ley, “Glycosylation in immune cell trafficking,” Immunological Reviews, vol. 230, no. 1, pp. 97–113, 2009.
[52]
W. A. Sheremata, A. Minagar, J. S. Alexander, and T. Vollmer, “The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications,” CNS Drugs, vol. 19, no. 11, pp. 909–922, 2005.
[53]
B. Engelhardt, B. Kempe, S. Merfeld-Clauss et al., “P-selectin glycoprotein ligand 1 is not required for the development of experimental autoimmune encephalomyelitis in SJL and C57BL/6 mice,” Journal of Immunology, vol. 175, no. 2, pp. 1267–1275, 2005.
[54]
I. Bartholom？us, N. Kawakami, F. Odoardi et al., “Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions,” Nature, vol. 462, no. 7269, pp. 94–98, 2009.
[55]
B. Engelhardt, “Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines,” Journal of the Neurological Sciences, vol. 274, no. 1-2, pp. 23–26, 2008.
[56]
T. Holm？y, “The immunology of multiple sclerosis: disease mechanisms and therapeutic targets,” Minerva Medica, vol. 99, no. 2, pp. 119–140, 2008.
[57]
H. Wekerle, “Immune pathogenesis of multiple sclerosis,” Neurological Sciences, vol. 26, supplement 1, pp. S1–S2, 2005.
[58]
L. Filli, P. Kuster, S. Traud et al., “Spatiotemporal distribution of white matter lesions in relapsing-remitting and secondary progressive multiple sclerosis,” Multiple Sclerosis, vol. 18, no. 11, pp. 1577–1584, 2012.
[59]
M. P. Pender and J. M. Greer, “Immunology of multiple sclerosis,” Current Allergy and Asthma Reports, vol. 7, no. 4, pp. 285–292, 2007.
[60]
M. Sospedra and R. Martin, “Immunology of multiple sclerosis,” Annual Review of Immunology, vol. 23, pp. 683–747, 2005.
[61]
A. Kutzelnigg, C. F. Lucchinetti, C. Stadelmann et al., “Cortical demyelination and diffuse white matter injury in multiple sclerosis,” Brain, vol. 128, no. 11, pp. 2705–2712, 2005.
[62]
C. M. P. Vos, J. J. G. Geurts, L. Montagne et al., “Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis,” Neurobiology of Disease, vol. 20, no. 3, pp. 953–960, 2005.
[63]
J. Huppert, D. Closhen, A. Croxford et al., “Cellular mechanisms of IL-17-induced blood-brain barrier disruption,” FASEB Journal, vol. 24, no. 4, pp. 1023–1034, 2010.
[64]
H. Kebir, K. Kreymborg, I. Ifergan et al., “Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation,” Nature Medicine, vol. 13, no. 10, pp. 1173–1175, 2007.
[65]
E. Miller, “Multiple sclerosis,” Advances in Experimental Medicine and Biology, vol. 724, pp. 222–238, 2012.
[66]
F. Luessi, V. Siffrin, and F. Zipp, “Neurodegeneration in multiple sclerosis: novel treatment strategies,” Expert Review of Neurotherapeutics, vol. 12, no. 9, pp. 1061–1077, 2012.
[67]
D. Baker, W. Gerritsen, J. Rundle, and S. Amor, “Critical appraisal of animal models of multiple sclerosis,” Multiple Sclerosis, vol. 17, no. 6, pp. 647–657, 2011.
[68]
C. S. Constantinescu, N. Farooqi, K. O'Brien, and B. Gran, “Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS),” British Journal of Pharmacology, vol. 164, no. 4, pp. 1079–1106, 2011.
[69]
R. Gold, C. Linington, and H. Lassmann, “Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 Years of merits and culprits in experimental autoimmune encephalomyelitis research,” Brain, vol. 129, no. 8, pp. 1953–1971, 2006.
[70]
T. A. Yednock, C. Cannon, L. C. Fritz, F. Sanchez-Madrid, L. Steinmann, and N. Karin, “Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin,” Nature, vol. 356, no. 6364, pp. 63–66, 1992.
[71]
N. Tubridy, P. O. Behan, R. Capildeo et al., “The effect of anti-α4 integrin antibody on brain lesion activity in MS,” Neurology, vol. 53, no. 3, pp. 466–472, 1999.
[72]
E. Pucci, G. Giuliani, A. Solari et al., “Natalizumab for relapsing remitting multiple sclerosis,” Cochrane Database of Systematic Reviews, no. 10, Article ID CD007621, 2011.
[73]
S. M. Kerfoot, M. U. Norman, B. M. Lapointe, C. S. Bonder, L. Zbytnuik, and P. Kubes, “Reevaluation of P-selectin and α4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis,” Journal of Immunology, vol. 176, no. 10, pp. 6225–6234, 2006.
[74]
R. Bill, A. D？ring, U. Deutsch, and B. Engelhardt, “PSGL-1 is dispensible for the development of active experimental autoimmune encephalomyelitis in SJL/J mice,” Journal of Neuroimmunology, vol. 232, no. 1-2, pp. 207–208, 2011.
[75]
I. Osmers, D. C. Bullard, and S. R. Barnum, “PSGL-1 is not required for development of experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 166, no. 1-2, pp. 193–196, 2005.
[76]
A. D？ring, M. Wild, D. Vestweber, U. Deutsch, and B. Engelhardt, “E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice,” Journal of Immunology, vol. 179, no. 12, pp. 8470–8479, 2007.
[77]
L. Battistini, L. Piccio, B. Rossi et al., “CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1,” Blood, vol. 101, no. 12, pp. 4775–4782, 2003.
[78]
B. Bahbouhi, L. Berthelot, S. Pettré et al., “Peripheral blood CD4+ T lymphocytes from multiple sclerosis patients are characterized by higher PSGL-1 expression and transmigration capacity across a human blood-brain barrier-derived endothelial cell line,” Journal of Leukocyte Biology, vol. 86, no. 5, pp. 1049–1063, 2009.
[79]
M. S. Alavijeh and A. M. Palmer, “Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds,” Neurobiology of Disease, vol. 37, no. 1, pp. 38–47, 2010.
[80]
K. Hellwig and R. Gold, “Progressive multifocal leukoencephalopathy and natalizumab,” Journal of Neurology, vol. 258, no. 11, pp. 1920–1928, 2011.
[81]
T. A. Yousry, E. O. Major, C. Ryschkewitsch et al., “Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy,” New England Journal of Medicine, vol. 354, no. 9, pp. 924–933, 2006.
[82]
D. Pelletier and D. A. Hafler, “Fingolimod for multiple sclerosis,” New England Journal of Medicine, vol. 366, no. 4, pp. 339–347, 2012.
[83]
J. Chun and H. P. Hartung, “Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis,” Clinical Neuropharmacology, vol. 33, no. 2, pp. 91–101, 2010.
[84]
A. M. Palmer, “Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis,” Current Opinion in Investigational Drugs, vol. 11, no. 11, pp. 1313–1323, 2010.
[85]
M. C. Claussen and T. Korn, “Immune mechanisms of new therapeutic strategies in MS—teriflunomide,” Clinical Immunology, vol. 142, no. 1, pp. 49–56, 2011.
[86]
T. Limsakun and F. Menguy-Vacheron, “Pharmacokinetics of oral teriflunomide, a novel oral disease-modifying agent under investigation for the treatment of multiple sclerosis,” Neurology, vol. 74, p. A415, 2010.
[87]
D. H. Miller, R. Grove, O. Graff et al., “Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial,” The Lancet Neurology, vol. 11, no. 2, pp. 131–139, 2012.
[88]
A. R. Blight, “Treatment of walking impairment in multiple sclerosis with dalfampridine,” Therapeutic Advances in Neurological Disorders, vol. 4, no. 2, pp. 99–109, 2011.
[89]
A. D. Goodman, T. R. Brown, K. R. Edwards et al., “A phase 3 trial of extended release oral dalfampridine in multiple sclerosis,” Annals of Neurology, vol. 68, no. 4, pp. 494–502, 2010.
[90]
A. D. Goodman and M. Hyland, “Dalfampridine in multiple sclerosis,” Drugs of Today, vol. 46, no. 9, pp. 635–639, 2010.
[91]
G. Damsma, P. T. M. Biessels, B. H. C. Westerink, J. B. De Vries, and A. S. Horn, “Differential effects of 4-aminopyridine and 2.4-diaminopyridine on the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis,” European Journal of Pharmacology, vol. 145, no. 1, pp. 15–20, 1988.
[92]
M. Lemeignan, H. Millart, and D. Lamiable, “Evaluation of 4-aminopyridine and 3,4-diaminopyridine penetrability into cerebrospinal fluid in anesthetized rats,” Brain Research, vol. 304, no. 1, pp. 166–169, 1984.
[93]
D. R. Cornblath, E. J. Bienen, and A. R. Blight, “The safety profile of dalfampridine extended release in multiple sclerosis clinical trials,” Clinical Therapeutics, vol. 34, no. 5, pp. 1056–1069, 2012.
[94]
T. E. Pikoulas and M. A. Fuller, “Dalfampridine: a medication to improve walking in patients with multiple sclerosis,” Annals of Pharmacotherapy, vol. 46, no. 7-8, pp. 1010–1015, 2012.
[95]
J. Sastre-Garriga, C. Vila, S. Clissold, and X. Montalban, “THC and CBD oromucosal spray (Sativex) in the management of spasticity associated with multiple sclerosis,” Expert Review of Neurotherapeutics, vol. 11, no. 5, pp. 627–637, 2011.
[96]
G. Pryce and D. Baker, “Potential control of multiple sclerosis by cannabis and the endocannabinoid system,” CNS and Neurological Disorders, vol. 11, no. 5, pp. 624–641, 2012.
[97]
S. Deiana, A. Watanabe, Y. Yamasaki et al., “Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour,” Psychopharmacology, vol. 219, no. 3, pp. 859–873, 2012.
[98]
D. Wade, “Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough?” Expert Review of Neurotherapeutics, vol. 12, no. 4, supplement, pp. 9–14, 2012.
