Detailed Pharmacology Review of Neuroprotective agents for ALS
TABLE OF CONTENTS Page
1. AEOL10150 ..2 2. Arimoclomol ..7 3. Ceftriaxone 10 4. Celastrol 14 5. CGP3446 18 6. Copaxone 21 7. Coenzyme Q10 25 8. Insulin Growth Factor-1 - AAV 31 9. Insulin Growth Factor-1 34 10. Memantine 38 11. Minocycline 41 12. NAALADase Inhibitors 47 13. NBQX 50 14. Nimesulide 53 15. Nimodipine 56 16. ONO2506 60 17. Sodium Phenylbutyrate 63 18. Riluzole 68 19. Scriptaid 73 20. Talampanel 76 21. Tamoxifen 79 22. Thalidomide 83 23. Trehalose 86 24. Vitamin E 89 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
AEOL 10150
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Catalytic antioxidant
Manufacturer Incara Pharmaceuticals, Inc. RTP, NC (Aeolus Pharmaceuticals) Regulatory Approval Status Investigational
Mechanism of Antioxidant – downstream reduction in protein nitration and oxidation Action
CASE FOR USE IN ALS Rationale Ongoing oxidative stress may be involved in the pathogenesis of ALS.
Clinical Data None
Animal Data Kiael M, 2004 (Abstract Only): AEOL 10150 (2.5 mg/kg/day, i.p.) was administered to G93A transgenic mice from the time of symptom onset, which was determined by a combination of tests (i.e., Rotarod performance at 15 rpm, appearance of tremor of the hind legs, and gait abnormalities). AEOL 10150 treatments attenuated weight loss, enhanced motor performance and increased the survival interval (time from symptom onset to death) by 38% in G93A mice. AEOL 10150 treatments also extended the survival in these mice by 14%.
Crow JP, 2004 (presented at AAN): In four separate studies in two academic medical centers,
2 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
AEOL 10150 was compared to control in a transgenic mouse model of ALS. The drug was initiated at symptom onset at 2.5 mg/kg/day IP. The treated mice experienced a survival interval ratio of 2.98, p<0.01 (they lived 3 times longer). Also, when added to an already proven effective combination of rofecoxib and creatine, AEOL 10150 resulted in a further doubling of survival time.
In Vitro Data None
HUMAN USE PROFILE Examined ALS Indications
Safety/Tolerability Aeolus Pharmaceuticals, Inc Press Release (www.focusonals.com): Currently being studied in a Phase I dose-ranging, PK study in ALS patients.
PK/Drug Pharmacokinetics: Interactions Unknown in humans
Sheng H, 2004: In a spinal cord injury model in mice, only when the drug was given intrathecally (compared to IV) was it effective in improving performance and reducing injury. The IV dose in this study was 0.5 mg/kg bolus followed by 1 mg/kg/h x 24 h.
However, in the Crow study, IP administration of 2.5 mg/kg daily was effective in improving
3 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. survival in ALS.
Drug Interactions
Unknown
4 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Sheng H, 2004: Intrathecal AEOL 10150, administered 5 minutes after spinal cord injury in mice, improved outcome.
Bowler RP, 2002: IV AEOL 10150, administered 5 minutes after reperfusion in a model of cerebral ischemia (MCAO for 60 minutes), reduced the expression of inflammatory genes.
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Pharmacokinetics and BBB penetration in humans 2. Therapeutic concentrations in animal model 3. Human safety REFERENCES www.focusonals.com www.aeoluspharma.com
Bowler RP, Sheng H, Enghild JJ, Pearlstein RD, Warner DS, Crapo JD. A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke. Free Rad Biol Med 2002; 33(8):1141-1152.
Kiael M, Kipiani K, Petri S, Chen J, et al. A novel catalytic antioxidant, manganese (AEOL 10150) slows disease progression and extends lifespan in transgenic mouse model. ALS/MND 2004; 5(suppl 2):91. (Abstract Only).
Sheng H, Spaspjevic I, Warner DS, Batinic-Haberle I. Mouse spinal cord compression injury is ameliorated by
5 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. intrathecal cationic manganese (III) porphyrin catalytic antioxidant therapy. Neurosci Lett 2004; 366:220-225.
6 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
ARIMOCLOMOL
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Heat shock protein inducer; may have as neurotrophic factor
Manufacturer Cytrx Regulatory Approval Status Investigational (maybe preclinical only)
Mechanism of Lindquist S, 1986: Interacts with, and amplifies the heat shock protein response, which has Action been shown to be a powerful cytoprotective mechanism.
CASE FOR USE IN ALS Rationale Kieran D, 2004: Heat shock proteins (HSPs) are upregulated in ALS, but in motor neurons, there is evidence that they have reduced availability. Increasing HSP levels may protect motor neurons from apoptosis in ALS.
Clinical Data None
Animal Data Kieran D, 2004: Arimoclomol (10 mg/kg IP daily), starting at 35 days or 70 days (after symptoms emerged) in SOD mutant mice, resulted in a 22% increase in lifespan and improved hindlimb muscle function. The animals receiving the treatment also had significantly preserved body weight compared to controls. Delay of treatment until after the emergence of symptoms (70 days) did not impair the efficacy of the intervention!
7 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In Vitro Data None
HUMAN USE PROFILE Examined None Indications
Safety/Tolerability Unknown
PK/Drug Unknown Interactions
8 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Kalmar B, 2002: BRX-220 (is this arimoclomol??) pretreatment, improved the survival of motor neurons at 14 days after sciatic crush injury in rat pups
BIMOCLOMOL (advanced Phase II in 1997 – Vigh, 1997) – close relative, also developed by Biorex R&D
Biro k, 1997: ameliorates peripheral neuropathy in rats Erdo F, 1998: reduces vascular consequences of SAH in rats Biro K, 1998: improves early signs of retinopathy in diabetic rats Jednakovits A, 2000: prevents vascular changes in SHRs Lubbers NL, 2002: pretreatment decreased infarct size in a rat model of coronary ischemia and reperfusion
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Pharmacokinetics and BBB penetration in humans 2. Therapeutic concentration in animal model 3. BBB penetration in mouse 4. Human Safety
REFERENCES
Kieran D, Kalmar B, Dick JRT, Riddoch-Contreras J, et al. Treatment with arimoclomol, a coninducer of heat shock proteins, delays disease progression in ALS mice. Nature Medicine. 2004 Apr. 10(4):402-405.
9 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
CEFTRIAXONE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Antibacterial; cephalosporin
Manufacturer Roche - Rocephin Regulatory Approval Status Approved
Mechanism of Action Rothstein, 2005: Antiexcitatory and antioxidant (discovered through the NDSC program of 1040 compounds, of which 16 were cephalosporins). The cephalosporins seem to be antiglutamatergic by increasing astrocytic uptake of glutamate by the EAAT2 transporter (increased activity of the transporter).
CASE FOR USE IN ALS Rationale Rothstein, 2005: NINDS in vitro assays of EAAT2 transporter and motor neurons demonstrated potential activity of the cephalosporins. Ceftriaxone was chosen for further study because of its superior penetration into the CNS and its long t ½.
Clinical Data None
10 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data Rothstein, 2005: G93A SOD1 mice were treated daily with 200 mg/kg IP, starting at 12 weeks of age and survival was prolonged 10 days (8%) over saline treated animals (122 days) (p>0.006). When the treatment was initiated at 6 weeks of age, the survival was similarly increased (10%- 122 vs 135 days). Treated animals also demonstrated improved body weight retention and grip strength. Rats given 200 mg/kg IP x 5 days had a 3-fold increase in GLT1 protein (glutamate transporter).
In Vitro Data Rothstein, 2005: Increases EAAT2 activity and enhances synaptic glutamate clearance. - increased EAAT2 promoter in astroglial cell lines - lower concentrations (1 µM) required to increase EAAT2 than to protect motor neurons from toxicity in culture (100 µM)
HUMAN USE PROFILE Examined Indications MD consult, 2004: Bacterial infections including meningitis, septicemia, etc
Safety/Tolerability MD consult, 2004: Generally well-tolerated; side effects similar to other cephalosporins: superinfections, diarrhea (up to 50%), skin and blood dyscrasias.
No serious adverse events when 4 g/day (maximum approved dose) was administered x 10-14 days.
11 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Guglielmo, 2000: In 21 patients receiving 2 g q24 of ceftriaxone for 6-7 weeks for the treatment of osteomyelitis, no adverse effects were documented (no diarrhea or biliary symptoms).
PK/Drug Pharmacokinetics: Interactions Patel, 1981: t ½ =4-6 hours in serum and is linear. Nau, 1993: t ½ = up to 18 hours in CSF. Chandrasekar, 1983: In humans with uninflamed meninges, 2 gm IV resulted in average peak concentrations in plasma of 262.4 mg/L and the peak in the CSF was 2.12 mg/L (about 1%), which occurred 3-4 hours post dose MD consult, 2004: t ½ increased to 12-15 hours in renal impairment; no dosage adjustment needed in hepatic dysfunction.
Drug Interactions: MD consult, 2004: May prolong the PT, therefore may increase the tendency of warfarin to cause bleeding.
Summary: One might expect after 4 g daily of ceftriaxone, concentrations of 4-8 mg/L in the CSF (equivalent to up to 12 µM)
12 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS
SUMMARY:
Needed prior to development as a treatment in ALS:
1. Long term human toxicity studies
REFERENCES
Rothstein JD, Patel S, Regan MR, Haenggell, Huang YH, Bergles DE, Jin L, Hoberg MD, Vidensky S, Chuung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB. ? -Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-77
MD Consult ; Ceftriaxone monograph, 2004
Gugliemo BJ, Luber AD, Paletta D, Jacobs RA. Ceftriaxone therapy for staphylococcal osteomyelitis: A Review. CID 2000;30:205-207
Nau R, Prange HW, Muth P, Mahr G, Menck S, Kolenda H, Sorgel. Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges. Antimicrob Agents Chemother 1993;37:1518-1524
Patel IH, et al. Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother 1981;20:634-641
Chandrasekar P et al. Penetration of ceftriaxone into human cerebrospinal fluid. Clin Res 1983; 31:628 (abstract)
Spector R. Ceftriaxone pharmacokinetics in the central nervous system. J Pharm Exp Ther 1986;236:380-383
13 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Celastrol (triterpine)
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Herbal medicine Derivative of the Celastraceae family of plants
Manufacturer Various Regulatory Approval Status Mechanism of Nagase, et al. 2003: Celastrol has been reported to have antitumor activity, antitumor Action promoting activity, anti-inflammatory activity, suppression of adjuvant arthritis, suppression of TNF-a and IL1-b, decrease of the induced expression of class II MHC molecules, and inhibition of NF-kB activation, NO production, and lipid peroxidation.
CASE FOR USE IN ALS Rationale Allison, et al. 2001: The potent antioxidant and anti-inflammatory activities of celastrol, and its effects on cognitive function, suggest that the drug may be useful to treat neurodegenerative diseases accompanied by inflammation.
Clinical Data No data available
Animal Data Kipiani, et al. 2004 (abstract only): Celastrol was administered to G93A SOD1 mice starting at 4 weeks of age. Celastrol significantly improved weight loss, rotorod performance and survival. Cell counts of lumbar spinal cord motor neurons confirmed a protective effect.
In Vitro Data No data available
14 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
HUMAN USE PROFILE Examined Indications
Safety/Tolerability Allison, et al. 2001: Short-term administration to animals has not revealed serious toxicities, and extracts containing celastrol have been administered for many years to Chinese patients without evidence of carcinogenicity or other limiting side effects.
PK/Drug Allison, et al. 2001: Celastrol is bioavailable following oral administration, as indicated by oral Interactions doses of 3 mg/kg were found to suppress joint swelling and other manifestations of adjuvant arthritis, and to oppose weight loss.
15 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS
Cleren, et al. 2004 (abstract only): Mice received injections of celastrol (3 mg/kg i.p., q 12h x 2 injections) before and after administration of MPTP (15 mg/kg, i.p., q 2h x 4 injections). Tyrosine hydroxylase immunostaining revealed that MPTP induced a 48% loss of dopaminergic neurons within the substantia nigra pars compacta, which was totally prevented (p<0.01) by the celastrol treatment. HPLC revealed that MPTP induced a 37% depletion in dopamine concentrations within the striatum which was totally prevented (p<0.05) by the celastrol treatment.
Westerheide, et al. 2004: HeLa cells and SH-SY5Y cells were pretreated with either 3 um celastrol or a 42°C heat shock for one hour, recovered for 5 h, then given a 20 or 40 min heat treatment. A 35 min at 45°C heat stress was performed and cells were assayed 24 h later for cytosolic nucleosomes, an indicator of apoptotic cell death. Celastrol pretreatment protected HeLa cells from apoptosis (1.7-fold), and similar results were obtained for SH- SY5Y neuroblastoma cells.
SUMMARY:
Needed prior to development for ALS:
1. Animal model BBB penetration (presumed due to effects in PD / AD models) 2. Human pharmacokinetics / BBB penetration 3. Therapeutic concentration in animal model
REFERENCES
Allison AC, Cacabelos R, Lombardi VRM, Alvarez XA, et al. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s Disease. Prog Neuro-Psychopharmacol & Biol. Psychiat. 2001; 25:1341-1357.
16 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Kippiani K, Kiaei M, Chen J, Calingasan NY, et al. Celastrol blocks motor neuron cell death and extend life in transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004; 90(Suppl 1):92.
Westerheide SD, Bosman JD, Mbadugha BNA, Kawahara TLA, et al. Celastrols as inducers of the heat shock response and cytoprotection.
17 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
CGP 3466
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Kragten et al., 1998: CGP 3466 is a structurally related analog of R-(-) deprenyl (Selegiline)
LeWitt P, 2004: CGP 3455 is also designated in laboratory research reports as CGP3446B or TCH346. Manufacturer Novartis Regulatory Preclinical only Approval Status
Mechanism of Berry et al., 2000: The binding of CGP 3446 occurs in the channel region running through the center of Action the tetrameric form of GAPDH, resulting in the splitting of the tetramer into two dimmers. This action prevents the nuclear accumulation of GADPH, which is associated with the initiation of apoptosis. CASE FOR USE IN ALS Rationale Sagot et al., 2000: CGP 3446, an orally delivered anti-apoptotic compound, binds to GAPDH in an animal model with motorneuron degeneration.
Clinical Data None
Animal Data Sagot et al., 2000: CGP 3446 was delivered orally by direct injection into the stomach of pmn/pmn mice. Four concentrations were tested with a delivery schedule of three days per week (M,W, F) at 1 nmol/kg, 10 nmol/kg, 100 nmol/kg, and 1000 nmol/kg. An additional group of mice were treated with 100 nmol/kg of CGP 3446 five days a week (M-F). A separate group of mice were treated with riluzole at a concentration of 100 mcg/ml in the drinking water. At 10 nmol/kg and 100 nmol/kg, CGP 3446 significantly slowed down the diease progression by 30% as compared to untreated pmn/pmn mice. There was a 57% increase in the life-span of the mice treated five times per week as compared to untreated mice. Riluzole treated mice exhibited no effect on survival. Following the appearance of the disease symptoms, the body weight of untreated mice ceased to increase. Mice treated at 100 nmol/kg three times per week increased their body weight by 20%, this effect was even more pronounced with a treatment of 5 times per week. When CGP 3446
18 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
was administered 5 times per week at 100 nmol/kg, the surviving 62 day-old treated mice walked normally; at this age, all mice in the other treatment groups had already died.
In Vitro Data None
HUMAN USE PROFILE Examined None Indications Safety/Tolerability Unknown
PK/Drug No information found on BBB penetration Interactions
19 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
LeWitt P, 2004: In vitro testing of CGP3446 has been carried out in rhesus monkeys rendered parkinsonian by MPTP injections. With s.c. administration of CGP3446 2 hours after the second MPTP treatment and continuing twice daily for 2 weeks (0.0142 mg/kg), this compound almost completely blocked the development of parkinsonian features. CGP3446 treatment resulted in sparing of the usual loss caused by MPTP in substantia nigra neurons and their dopaminergic projections to the striatum.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Peer-review of failed clinical trial 2. Human pharmacokinetics and safety
REFERENCES
LeWitt P. Clinical trials of neuroprotection for Parkinson’s disease. Neurology. 2004 Oct. 63(7)
20 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
COPAXONE (Glatiramer Acetate)
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Immunosuppressant
Manufacturer Teva Regulatory Approval Status Approved for MS (1997)
Mechanism of Immune modulation – After administration, suppressor T cells are induced and activated in the Action periphery.
CASE FOR USE IN ALS Rationale Angelov, 2003: The protective T-cell mediated response can be activated by glatiramer acetate. This may increase motor neuron survival.
Clinical Data None
21 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data Schwalenstoecker, 2004 (Abstract Only): Male (SOD-1-G93A) mice were crossed with non- transgenic B6SJL females. The 20 offspring were used for the study and treated with 75 mcg Cop-1 (1 mcg/mcl) subcutaneously, followed by 75 12.5 mg/kg/day Cop-1 dissolved in drinking water. Control animals were treated with vehicle. Motor activity did not change significantly in response to Cop-1 (male and female). Cop-1 was able to extend lifespan (+ 7days) of female hybrid mice to 140 +/- 9 days compared to the female vehicle control group (133 +/- 14). In male mice, however, Cop-1 treatment had no effect on survival time.
Angelov, 2003: COP-1 immunization 7 days prior to facial nerve axotomy in mice, resulted in significantly preserved numbers of motor neurons (766 vs. 1172) and improved function (whisking) (p<0.05). Also, life expectancy in SOD mutant mice was significantly prolonged (263 vs. 211 days) in COP-1 -immunized mice (at 60 days) followed by oral administration of COP-1 in the drinking water (? activity by this route)
In Vitro Data None
HUMAN USE PROFILE Examined Indications MS
Safety/Tolerability MD Consult, 2004: Most common adverse reactions to 20 mg sc daily include: injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia and hypertonia.
22 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In MS clinical trials, 8% of patients had adverse reactions causing discontinuation of the drug. These were: injection site reactions (6.5%), vasodilation, depression, dyspnea, urticaria, tachycardia, dizziness, tremor.
21% of patients complain of chest pain, usually starts one month after initiation of treatment.
PK/Drug Pharmacokinetics: Interactions MD Consult, 2004: A substantial portion of the subcutaneous dose is hydrolyzed locally. The intact or partially intact hydrolyzed compound is presumed to enter the lymphatic circulation. Some of the drug MAY enter the systemic circulation (probably not necessary for its effect).
- only dose approved is 20 mg daily sc (do not give IV).
Angelov, 2003: Since the effect desired in ALS is markedly different than in MS, the administration route and dose may need to be entirely different.
Drug Interactions:
None known
23 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Berner EJ, 2004: protects DA neurons in mouse PD
Kipnis J, 2004: inhibits progression of secondary degeneration after crush injury of rat optic nerve.
MISCELLANEOUS SUMMARY:
Needed prior to development for ALS:
Nothing (BBB penetration in humans probably not necessary for activity)
REFERENCES
“Copaxone.” Drug monograph. MD Consult, 2004. www.mdconsult.com.
Schwalenstoecker B, Danzelsen R, Ludolph AC. Copaxone treatment in a mouse model of ALS: effect of gender and genetic background. ALS/MND 2004; 5(suppl 2):91-92 (Abstract Only).
24 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Coenzyme Q10
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Nutraceutical
Manufacturer Various Regulatory Approval Status Mechanism of Crone et al., 2001: During oxidative phosphorylation, coenzyme Q10 acts as an important cofactor of the Action electron transport chain. Coenzyme Q10 also reforms the reduced form of vitamin E, an important cellular antioxidant.
Matthews et al., 1998: Coenzyme Q10 serves as an important antioxidant in both mitochondria and lipid membranes.
CASE FOR USE IN ALS Rationale Matthews et al., 1998: If defects in energy metabolism and oxidative damage play a role in the pathogenesis of neurodegenerative diseases, then treatment with coenzyme Q10 could exert beneficial therapeutic effects. An early pathologic finding in mice expressing SOD1 mutation is mitochondrial swelling and vacuolization, suggesting that mitochondrial dysfunction may contribute to the pathogenesis of ALS.
Clinical Data None
Animal Data Matthews et al., 1998: Mice expressing SOD1 mutation were administered 200 mg/kg Coenzyme Q10 via supplemented rat chow (n=16) or unsupplemented rat chow (n=13). Treatment was started 50 days after birth and continued until death. Oral supplementation with coenzyme Q10 produced a significant increase in survival from a mean of 135-141 days (P<0.05).
25 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In Vitro Data None
HUMAN USE PROFILE Examined Crone et al., 2001: Congestive heart failure, Huntington’s disease, and Parkinson’s disease. Indications Kagan et al.: Ischemic heart disease, hypertension, HIV infection, mitochondrial encephalomyopathies, and human cancer.
Safety/Tolerability Ferrante et al., 2004 (Abstract Only): In a 9-month trial of patients with ALS, Co Q10 was given to patients, and increased monthly until the daily for the first three months until the dose reached 3000 mg/day. Patients took 3000 mg/day from month 3 to month 8 then tapered their dose during month 9. The subjects tolerated the high dose well. No serious adverse events or unexpected adverse events have been related to its use.
Crone et al., 2001: Doses of up to 200 mg/day in human trials have produced infrequent side effects, mainly nausea, emesis, epigastric pain, and headaches. Infrequently, supplementation with higher than 200 mg/day of coenzyme Q10 has been linked to mild elevations in liver transaminases unaccompanied by serious hepatotoixicity.
Shults et al., 2002: Parkinson disease patients were treated with placebo or coenzyme Q10 at doses of 300, 600, or 1200 mg/d. Co Q10 was well tolerated and no dosage reductions were needed in any of the treatment groups. Most adverse events were mild.
Shults et al., 2004 (Abstract Only): Parkinson disease patients were treated with coenzyme Q10 at doses of 1200, 1800, 2400, and 3000 mg/day with a stable dosage of vitamin E 1200 IU/day. Adverse effects were typically considered to be unrelated to coenzyme Q10.
PK/Drug PHARMACOKINETICS Interactions Crone et al., 2001: Coenzyme Q10 is widely distributed across tissues, but is concentrated in the cells of organs with higher metabolic rates, such as kidneys, pancreas, heart, and liver. With a half-life of
26 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. approximately 35 hours, it is eliminated mainly via the biliary tract. Coenzyme Q10 is lipophilic and crosses the blood-brain barrier.
Matthews et al., 1998: Oral supplementation with coenzyme Q10 at a dose of 200 mg/kd to 12-month- old Sprague-Dawley rats produced a significant increases in Coenzyme Q10, coenzyme Q9H2, and total coenzyme Q9 and Q10 levels in cerebral cortex. Increases were in the 30% range. Oral supplementation with coenzyme Q10 resulted in progressive increases in brain mitochondrial concentrations of coenzyme Q10 at 7, 30, and 60 days, with increases at 60 days being significant as compared to control levels.
Shults et al., 2004: Parkinson disease patients were treated with coenzyme Q10 at doses of 1200, 1800, 2400, and 3000 mg/day with a stable dosage of vitamin E 1200 IU/day. The plasma level of coenzyme Q10 reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage.
DRUG INTERACTIONS Crone et al., 2001: There are cases noting an interaction between coenzyme Q10 and warfarin, which is thought to relate to the former having procoagulant effects.
Passi et al., 2003: Endogenous CoQ 10 levels were measured in 42 male, hypercholesterolemic patients treated for 3 months with different doses of three different statins: atorvastatin 10 mg (n=10) and 20 mg (n=7), simvastatin 10 mg (n=5) and 20 mg (n=10), and pravastatin 20 mg (n=5) and 40 mg (n=5). The statins produced a dose dependent plasma depletion of the levels of total cholesterol and CoQ 10.
Rundek et al., 2004: CoQ 10 levels were measured in 34 patients with elevated LDL cholesterol level before and after exposure to atorvastatin, 80 mg/d, for 14 and 30 days. There was a 45% reduction in baseline CoQ 10 levels after 14 days of atorvastatin therapy and a 49% reduction from baseline after 30 days of atorvastatin therapy. The decrease in CoQ 10 levels could be explained by an inhibition of CoQ 10 synthesis by “statin” drugs through a widespread inhibition of cholesterol synthesis.
Lexi-Natural Products: Drugs which can cause depletion of CoQ10: hydralazine, thiazide diuretics, HMG-CoA reductase inhibitors, sulfonylureas, beta blockers, tricyclic antidepressants, chlorpromazine,
27 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al. clonidine, methyldopa, diazoxide, biguanides, haloperidol. CoQ10 may decrease response to warfarin.
28 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Shults et al., 2002: Oral supplementation with coenzyme Q10 reduced the loss of dopamine and dopaminergic axons in the striatum in 1-year-old mice treated with MPTP.
Matthews et al., 1998: Oral administration of co Q10 significantly attenuated lesions produced by intrastriatal administration of malonate in rats, as well as malonate-induced depletions of ATP and increases in lactate concentrations.
Crone et al., 2001: Increased lactate levels in the cerebral cortex and basal ganglia of Huntington’s patients may contribute to neuronal degeneration and ultimate cell death. Co Q10 has been shown to produce significant reductions in cortical lactate concentrations.
MISCELLANEOUS
Sohmiya, 2005: Plasma samples were collected from 20 healthy volunteers (controls) and 20 patients with sALS. Blood was drawn from fasted patients, and plasma levels of ascorbic acid, uric acid, and unconjugated bilirubin were determined. Plasma levels of CoQH2-10, CoQ 10, vitamin E (mixture of alpha and gamma-tocopherols), and total cholesterol were determined by a published method. There were no significant differences in plasma levels of uric acid, ascorbic acid, unconjugated bilirubin, vitamin E, CoQH2-10, total CoQ 10, and CoQH2-10/total cholesterol between sALS patients and control volunteers. Plasma levels of CoQ 10 (p=0.0002) and CoQ 10/total cholesterol (p<0.0001) were significantly higher in sALS patients than those in controls. In addition, %CoQ 10 values were significantly higher (p<0.0001) in sALS patients than in controls. A significant correlation was observed between %CoQ 10 values and the duration of illness (p=0.494, p=0.0315), however, there was no correlation between %CoQ 10 values and the ALS score.
SUMMARY:
Needed prior to development in ALS:
Nothing REFERENCES
Beal, MF. Therapeutic effects of coenzyme Q10 in neurodegenerative diseases. Quinones and Age-Related Diseases. 473-
29 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
487.
Crone C, Gabriel G, Wise TN. Non-herbal nutritional supplements – the next wave. Psychosomatics. 2001 July- Aug;42(4):285-299.
Ferrante KL, Shefner JM, Betensky RA, O’brien ML, et al. C34 clinical trial of coenzyme Q10 in patients with amyotrophic lateral sclerosis. ALSMNS. 2004; 5(suppl 2):25.
Lexi-Natural Products. Coenzyme Q10. 2004.
Kagan T, Davis C, Lin L, Zaker Z. Coenzyme Q10 can in some circumstances block apoptosis, and this effect is mediated through Mitochondria. Ann NY Acc Sci. 31-47.
Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad. 1998 July;95:8892-8897.
Passi S, Stancato A, Aleo E, Dmitrieva A, et al. Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA. Biofactors. 2003; 18:113-124.
Rundek T, Naini A, Sacco R, Coates K, et al. Atorvastatin decreases the coenzyme Q10 levels in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol. 2004 June;61:889-892.
Shults CW, Oakes D, Kieburtz K, Beal MF, et al. Effects of coenzyme Q10 in early Parkinson disease. Arch Neurol. 2002 Oct;59:1541-1550.
Sohmiya, M, Tanaka M, Suzuki Y, Tanino Y, et al. An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients. J Neur Sci. 2005 228:49-53.
30 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
VIRAL DELIVERY OF IGF-1
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Insulin growth factor
Manufacturer Ceregene Regulatory Approval Status Investigational
Mechanism of Kaspar et al., 2003: increase the phosphorylated state of Akt, a protein kinase activated by insulin and Action various growth factors that is involved in blocking proapoptotic pathways through receptor-mediated phosphatidylinositol 3-kinase signaling.
CASE FOR USE IN ALS Rationale Kaspar et al., 2003: Past studies have suggested that many different neurotrophic factors are motor neuron protective. At the cellular and biochemical level, gliosis is believed to contribute to ALS disease progression, with resultant insults including excitotoxicity. Previous in vitro data have demonstrated that IGF-1 can prevent excitotoxic motor neuron degeneration.
Clinical Data None
Animal Data Kaspar et al., 2003: Adeno-associated virus (AAV) was injected into G93A SOD1 mice to test the efficacy of two neurotrophic factors, insulin growth factor 1 (IGF-1) and glial cell line-derived neurotrophic factor (GDNF). Trial 1: AAV vector expressing GDNF or IGF-1 or control vector were injected bilaterally into the hindlimb quadriceps and intercostals muscles before disease onset (at 60 days of age), with a dosage of 1 x 10^10 particles per injection. IGF-1 treatment delayed the onset by 31 days compared to a 16- day delay of onset in GDNF treated animals. IGF-1 treated animals showed a larger, significant improvement in life-span, with a 37-day increase in median survival time compared to controls (160 days versus 123 days). The maximal life-span of IGF-1 treated animals was 265 days compared to
31 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
140 days in the control group. Trial 2: Injections of GDNF or IGF-1 or control vectors were injected into the hind limb quadriceps and intercostal muscles at the same time as disease onset (90 days of age) with the same dose as in trial 1. IGF-1 treatment extended median life-span by 22 days compared to the control group (146 days versus 124 days). Between 100 and 110 days of age, control animals showed a marked decrease in performance, whereas the IGF-1 treated animals displayed the greatest deficits ~20 days later. IGF-1 treated animals maintained their weights over a longer period of time, compared to a 15% weight loss in the control group. IGF-1 treatment had hypertrophic and protective effects against muscle atrophy, resulting in a 20% higher muscle mass in IGF-1 treated animals compared to control at 115 days of age. Trial 3: Histological evaluation of the lumbar spinal cord revealed that IGF-1 treatment prevented the pathological changes typical of the transgenic disease model. An estimate of the total number of motor neurons in the lumbar spinal cord showed an that IGF-1 promoted a 78% increase in motor neuron survival when compared to the control group. The most vulnerable motor neurons in ALS, the large motor neurons, were also significantly preserved in the IGF-1 treated animals, with a 66% increase in survival compared to the control group. At the end-stage, animals treated with IGF-1 continued to have 34% more large neurons as compared to control. IGF-1 also significantly reduced the amount of astrogliosis, as assessed by glial fibrillary acidic protein (GFAP) staining.
In Vitro Data None
HUMAN USE PROFILE Examined None Indications Safety/Tolerability None
PK/Drug None Interactions
32 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Kaspar et al, 2003: A dose response for retrograde transport to the spinal cord by injection AAV at titers between 4 x 10^7 and 3 x 10^10 viral particles into the quadriceps muscles was found by performing PCR for vector sequences on the lumbar spinal cord. A dose of 1 x 10 ^10 viral particles was required to achieve transport to the lumbar spine. Up to 1.1% of the virus injected at a dose of 1 x 10^10 viral particles was transported to the lumbar region of the spinal cord, as assessed by quantitative PCR.
MISCELLANEOUS SUMMARY:
Needed prior to development for ALS:
1. Human safety and BBB penetration
REFERENCES
Kaspar BK, Llado J, Sherkat N, Rothstein JD, et al. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science. 2003 Aug;301(8):839-842.
33 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
IGF-1
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Insulin-like growth factor
Manufacturer Cephalon Regulatory Approval Status Mechanism of Not known Action CASE FOR USE IN ALS Rationale Borasio et al., 1998: Insulin-like growth factor 1, a pleiotropic polypeptide, has been shown to exert a trophic effect on motor neurons in vitro and in vivo.
Hantai et al., 1995: IGF-1 promotes neuritic growth, influences the maintenance and regulation of neuronal development and regeneration and has neuroprotective properties.
Clinical Data Borasio et al., 1998: 183 patients from 8 European centers were randomized to receive either placebo (n=59) or rhIGF-1 0.1 mg/kg/day (n=124) subcutaneously for 9 months. The AALS total score at baseline was 68.6 +/- 1.8 for the placebo group, and 68.9 +/- 1.3 for the rhIGF-1 group. The mean change in AALS total score form baseline of the patients treated with rhIGF-1 was 21.9 +/- 1.5 versus 25.2 +/- 2.3 for the placebo group. No significant difference between treatment groups was found in the Sickness Index Profile (SIP) scores.
Lai et al., 1997: 266 patients with sporadic ALS were treated divided into three groups: 1) receive 0.05 mg/kg/day, s.c., rhIGF-1, 2) receive 0.1 mg/kg/day, s.c., rhIGF-1, or 3) receive placebo for 9 months. In this study, 141 patients completed the 9 month trial and 67 reached early termination (AALS score >=115 or FVC <39%). A dose-response relationship was observed in that the AALS slope in the low- dose group (3.8 +/- 0.3 points per month) was greater than in the high-dose group (3.1 +/- 0.3 points per
34 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
month). Thus, the high dose group experienced a 1.1 points per month, or 26% slower rate of symptom progression when compared to placebo.
Animal Data Hantai et al., 1995: Mutant Wobbler mice were administered 1 mg/kg of rhIGF-1 or vehicle once a day during 6 weeks at the time of phenotypic diagnosis. After 21 days of treatment, the IGF-1 treated mice showed a (x4) weight increase compared to placebo. After 25 days of treatment, the IGF-1 treated mice showed an increase in grip strength whereas the control group showed a decrease in grip strength (40% difference between the two groups). When wobbler mutants were treated with IGF-1, a shift of the muscle fiber diameter to the right was observed when compared with placebo treated mutants. There was no statistically different number of motoneurons in the spinal cord between IGF-1 and placebo treated mice.
In Vitro Data None
HUMAN USE PROFILE Examined None Indications Safety/Tolerability Borasio et al., 1998: Out of 183 patients treated with placebo or rhIGF-1 0.1 mg/kg/day subcutneously for 9 months, the most frequent adverse experiences were weakness, injection site pain, dyspnea, sweating, dysarthria, headache, and dysphagia. The incidence of adverse experiences was not significantly different between treatment groups.
Lai et al., 1997: There were no clinically significant adverse experiences associated with s.c. administration of rhIGF-1 at dosages of 0.05 mg/kg/day and 0.1 mg/kg/day or placebo. Injection related complaints, typically mild, were reported by 232 of the 266 patients tested, and were evenly distributed among the three treatment groups. Injection site inflammation and non-specific reactions were more frequent in the rhIGF-1-treated patients, most notably in the low dose group. Injection site inflammation, hair changes, knee pain, face edema, lung disorders, sinusitis, and joint swelling were more frequent with rhIGF-1 treatment, although not in a consistent dose-related pattern.
PK/Drug None identified Interactions
35 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Rosenthal et al., 2004 (Abstract Only): In retinal pigment epithelium cells, IGF-1 stimulated the second messengar Ca(2+) and increases vascular endothelial growth factor which, in turn, induces neovascularization.
Corse et al., 1999 (Abstract Only): Using organotypic spinal cord cultures from postnatal rats, IGF-1 significantly increased choline acetyltransferase activity, indicating IGF-1’s neuroprotective properties.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Human BBB penetration - Better delivery method? (Clinical trials already performed in ALS)
REFERENCES
Borasio GD, Robberect W, Leigh PN, Emile J, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. Neurology. 1998 Aug; 51(2):583-586.
Corse AM, Bilak MM, Bilak SR, Lechar M, et al. Preclinical testing of neuroprotective neurotrphic factors in a model of chronic motor neuron degeneration. Neurobiol. 1999 Oct;6(5):335-346 (Abstract Only).
Hantai D, Akaaboune M, Lagord C, Murawsky M, et al. Beneficial effects of insulin-like growth factor-1 on wobbler mouse motoneuron disease. J Neurol Sci. 1995;129(Suppl)122-126.
Lai EC, Felice KJ, Festoff BW, Gawel MJ, et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS: A placebo-controlled study. Neurology. 1997 Dec; 49(6):1621-1630.
36 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Rosenthal R, Wohlleben H, Malek G, Schlinchting L, et al. Insulin-like growth factor-1 contributes to neovascularization in age-related macular degeneration. Biochem Biophys Res Commun. 2004 Oct;323(4):1203-1208 (Abstract Only).
37 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
MEMANTINE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class NMDA receptor antagonist
Manufacturer Forest Regulatory Approved for Alzheimer’s Disease Approval Status
Mechanism of Prevents excitotoxic glutamate transmission Action
CASE FOR USE IN ALS Rationale There is evidence that impaired glutamate metabolism is involved in the pathogenesis of ALS.
Clinical Data None
Animal Data None
In Vitro Data None
38 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
HUMAN USE PROFILE Examined Alzheimer’s Disease and Vascular Dementia Indications
Safety/Tolerability MD Consult, 2004:
In placebo-controlled trials in which dementia patients received doses of memantine HCl up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the memantine HCl group as in the placebo group. No individual adverse event was associated with the discontinuation of treatment in 1% or more of memantine HCl treated patients and at a rate greater than placebo.
The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate to severe Alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population. They include headache, fatigue, pain, confusion, agitation, etc.
PK/Drug Pharmacokinetics: Interactions Efficacy in AD patients at tolerated doses supports adequate penetration across the BBB.
MD Consult, 2004: Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 hours.
Parsons, 1999: In male rats, clinically relevant doses have been shown to result in brain levels
39 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
sufficient to affect NMDA receptors.
MD Consult, 2004 Drug Interactions: In vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. These data indicate that no pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
The combined use of memantine HCl with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
RELEVANT PRECLINICAL DATA
Forrest Labs (Internal Data): Evidence of neuroprotection in rodents (ischemia, beta amyloid)
MISCELLANEOUS SUMMARY:
Needed prior to development for ALS:
1. Animal model or in vitro data supporting activity in ALS REFERENCES
MD Consult : Memantine monograph; 2004
40 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
MINOCLYCLINE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Antibiotic, a second generation tetracycline Manufacturer Various Regulatory Lexi-Drugs: Approval Status Approved for the treatment of susceptible bacterial infections of both gram-positive and gram-negative organisms; treatment of anthrax (inhalational, cutaneous, and gastrointestinal); acne; meningococcal carrier state; Rickettsial diseases (including Rocky Mountain spotted fever, Q fever); nongonococcal urethritis; gonorrhea; acute intestinal amebiasis
Mechanism of Lexi-Drugs: Action Inhibits bacterial protein synthesis by binding with the 30S and possibly the 50S ribosomal subunit(s) of susceptible bacteria; cell wall synthesis is not affected
CASE FOR USE IN ALS Rationale Kriz et al.,2002: There is evidence of the potential role for microglia activation in ALS pathogenesis; minocycline has been shown to inhibit microglial activatin in an animal model of cerebral ischemia.
Zhu et al. , 2002: Minocycline inhibits the activity of caspase-1, caspase-3, inducible forms of nitric oxide syntyetase (iNOS), and p38 mitogen-activated protein kinase (MAPK); these factors are important in ALS.
Clinical Data Gordon et al., 2004: Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. Trial 1: 19 patients received 200 mg/day or placebo for 6 months. The primary outcome comprised the safety and tolerability data. There were no significant differences in minor or severe adverse effects or laboratory abnormalities. Trial 2: 23 patients received up to 400 mg/day in a 8-month crossover trial. The starting dose was 100 mg twice daily and doses were increased by 50 mg bid until reaching the highest tolerated dose of 400
41 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
mg/day. There was a trend toward gastrointestinal symptoms while taking higher doses of minocycline. Elevations of BUN and AST/ALT while taking minocycline were statistically significant, though not clinically significant.
Animal Data Kriz et al., 2002: Transgenic mice overexpressing SOD1G37R by ~5-fold were administered minocycline (1 g/kg) in the special Custom Made Rodent Diet. Treatment with minocycline increased the average life span by 3 weeks. For ~70% of tested mice, treatment increased longevity by 5 weeks. Treatment delayed significantly the decline of motor strength of SOD1G37R mice during the slower declining stage until end-stage disease. Treatment delayed the onset of axonal degeneration. Minocycline was shown to delay the onset of Cdk5 deregulation, by examining spinal cord sections of the mice at early symptomatic and end-stage of disease.
Zhu et al., 2002: Minocycline (10 mg/kg/day) was injected into mutant hSOD1G93A transgenic mice. Onset of impaired motor performance in minocycline-treated mice was delayed 109 +/- 1.5 days of age as compared to 90.3 +/- 2.2 days in saline-treated mice. Survival was extended from 125.6 +/- 3.4 days from 136.8 +/- 1.2 days. In another experiment, hSOD1 mice were injected with 11 mg/kg/day. Mortality of saline-treated mice was 126.3 +/- 2.7 days as compared to 139 +/- 2.1 days of the minocycline-treated mice.
Zhang et al., 2003: Mice carrying the human SOD1G93A mutant gene were fed a diet supplemented with 2% creatine and injected intraperitoneally with 22 mg/kg/day of minocycline. Survival was extended by 13%, 12%, and 25% in the minocycline, creatine, and minocycline-creatine groups, respectively. Disease onset was delayed to 113 and 111 days, respectively, in the minocycline- and creatine-treated groups as compared with 94 days in the control group. Survival was delayed in the minocycline and creatine groups to 142 and 141 days, respectively, as compared with 126 days in the control group. Minocycline-creatine combination resulted in disease onset detected at 122 days and mortality at 157 days.
Van Den Bosch et al., 2002: Female mice with the G93A human SOD1 mutation were treated every weekday with an i.p. injection of two different doses of minocycline: 25 mg/kg and 50 mg/kg. The group treated with 50 mg/kg concentration delayed the mean onset of clinical symptoms by 18 days. The lower dose of minocycline increased the mean survival time by 11% and the higher dose by 16%.
42 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In Vitro Data None
HUMAN USE PROFILE Examined Gordon et al., 2004: Minocycline has neuroprotective effects in animal models of stroke/ischemic injury Indications and neurodegenerative disorders including Huntington disease and the MPTP model of Parkinson disease.
Safety/Tolerability Lexi-Drugs: Common adverse reactions: Discoloration of teeth (in children), lightheadedness, vertigo, photosensitivity, nausea, diarrhea Less frequent adverse reactions: Acute renal failure, anaphylaxis, angioedema, diabetes insipidus, eosinophilia, erythema multiforme, hemolytic anemia, hepatitis, neutropenia, pericarditis, rash, Stevens- Johnson syndrome, drug-induced SLE, thrombocytopenia, tinnitus, vomiting
PK/Drug PHARMACOKINETICS Interactions Mandell: Principles and Practice of Infectious Disease, 5th ed, 2000: Minocycine is the most lipophilic of the tetracyclines. 26% of plasma levels are achieved in the CSF.
Saivin: Clinical Pharmacokinetics 1988; 15:355-366: Levels in the CSF are between 11 and 56% of blood concentrations, but there is not clear correlation with the degree of inflammation of the meninges. Concentrations in the CSF do not exceed 0.5 mg/L even though minocycline is the tetracycline that diffuses best through the BBB. The absorption of minocycline is between 95 and 100%.
Lexi-Drugs: Distribution: majority for extended periods in fat; crosses placenta; enters breast milk. Protein binding: 70-75%. Half-life elimination: 15 hours. Excretion: urine
DRUG INTERACTIONS Lexi-Drugs: Increased Effect/Toxicity: Minocycline may increase the effect of warfarin
43 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Decreased Effect: Decrease effect with antacids (divalent cations), bismuth salts, sodium bicarbonate, barbiturates, carbamazepine, hydantoins. Food Interactions: Minocycline serum concentrations are not altered if taken with dairy products. Herb Interactions: Avoid don quai, St. John’s wort Test Interactons: May cause false elevations with fluorescence test for urinary catecholamines
44 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Kriz et al., 2002: In experimental model of cerebral ischemia, minocycline inhibited microglial activation, reduced inflammation, and decreased the size of infarct. It also inhibits caspase-1 and inducible nitric oxide synthetase (iNOS) upregulation.
Van Den Bosch et al., 2002: Minocycline inhibits caspase-1 and caspase-3 expression, decreases iNOS activity and delays mortality in a transgenic mouse model of Huntington’s disease. Minocycline protects against excitotoxicity by inhibitng activagtion and proliferation of microglia in primary spinal cord cultures.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
Nothing
REFERENCES
Gordon PH, Moore DH, Gelinas DF, Qualls C, et al. Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology. 2004 May;62:1845-1847.
Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobio Dis. 2002; 10:268-278.
Lexi-Drugs. Minocycline. 2004.
Mandell. Principles and Practice of Infectious Disease, 5th ed, 2000.
Saivin. Clinical Pharmacokinetics 1988; 15:355-366
45 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuropharm Neurotox. 2002 June; 13(8):1067-1070.
Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003; 53:267-270.
Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nauture. 2002 May;417:74-78.
46 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
NAALADase Inhibitors
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class N-acetylated alpha-linked acidic dipeptidase (NAALADase) – antiglutamatergic
Manufacturer Guillford Pharmaceuticals Inc. Regulatory Approval Status Investigational
Mechanism of Inhibits the enzyme that hydrolyzes NAAG to liberate glutamate. Action
CASE FOR USE IN ALS Rationale Thomas AG, 2003: There is evidence that there is upregulation of NAALADase in the motor cortex in ALS tissue and increased levels of NAAG and glutamate in the CSF of ALS patients. Chronic glutamate toxicity may result from the hydrolysis of NAAG by NAALADase.
Ghanashyam, et al., 2003: Activation of mGluR3 by N-acetylaspartylglutamate (NAAG) has been shown to inhibit glutamate release, increase release of transforming growth factor b (TGFB) from glial cells, and provide neuroprotection. NAAG is hydrolyzed to N-acetylaspartate and glutamate by glutamate carboxypeptidase II (CPII), an enzyme localized on the plasma membrane of glial cells with its catalytic region facing the synapse. Inhibition of CPII would be expected to provide neuroprotection by means of both decreasing glutamate and increasing NAAG.
Clinical Data None
47 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data Ghadge, et al. 2003: Starting from 37-39 days of age, G93A FALS transgenic mice received a daily oral dose of either 30 mg/kg of 2-(3- mercaptopropyl)pentanedioic acid (2-MPPA) or vehicle. There was a statistically significant prolongation in median survival, from 190 days in the vehicle-treated group to 219 days in the 2-MPPA-treated group, a 15% increase in the mean life span (p=0.0059).
In Vitro Data Thomas AG, 2003: In an in vitro model of chronic glutamate-mediated motor neuron degeneration, 2-PMPA (a NAALADase inhibitor) was neuroprotective as demonstrated by CAT activity, motor neuron count and morphology preservation.
HUMAN USE PROFILE Examined None Indications
Safety/Tolerability Unknown
PK/Drug Unknown Interactions
48 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Vornov JJ, 1999: 2-PMPA dramatically reduced extracellular glutamate concentrations during rat cerebral ischemia (MCAO) and an increase in NAAG during reperfusion.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Human safety and BBB penetration
REFERENCES
Vornov JJ, Wozniak K, Lu M, Jackson P, Tsukamoto T, Wang E, Slusher B. Blockade of NAALADase: a novel neuroprotective stragety based on limited glutamate and elevating NAAG. Ann NY Acad Sci 1999;890:400-405
Thomas AG, Corse AM, Coccia CF, Bilak MM, Rothstein JD, Slusher BS. NAALADase inhibition protects motor neurons against chronic glutamate toxicity. Eur J Pharmacol 2003;471:177-184
Ghadge GD, Slusher BS, Bodner A, Dal Canto M, Wozniak K, Thomas AG, Rojas C, Tsukamoto T, Majer P, Miller RJ, Monti AL, Roos RP. Glutamate carboxypeptidase II inihibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. PNAS 2003;100:9554-9559
49 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
NBQX
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class AMPA receptor antagonist
Manufacturer Novo Nordisk (?) Regulatory Approval Status Investigational
Mechanism of Prevents excitotoxic glutamate transmission Action
CASE FOR USE IN ALS Rationale There is evidence that disturbances in glutamate metabolism may contribute to the pathogenesis of ALS
Van Damme et al., 2003: NBQX has been shown to prevent excitotoxicity in several neuronal preparations.
Clinical Data None
Animal Data Van Damme et al., 2003: G93A transgenic mice were treated from day 70 until death by i.p.
50 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
injections of NBQX or saline. A dose of 8 mg/kg body weight was administered every week day. Treatment with NBQX improved the average time mice were able to stay on a rotating rod. The cumulative probablility of failure on this test showed a significant difference between NBQX and saline-treated mice (p=0.026). Using failure on Rotarod as a measure for disease onset, NBQX delayed the onset of clinical symptoms by 7 days. NBQX prolonged the average survival time from 129.9 +/- 3.6 to 143 +/- 2.8 days (p=0.002); this corresponds to a 10.3% increase of life span. The disease duration, defined as the time from failure on Rotarod until death, was 18.6 +/- 3.3 days in the control group and 24.9 +/- 3.4 days in the treatment group (p=0.19).
In Vitro Data None
HUMAN USE PROFILE Examined None Indications
Safety/Tolerability Inguersen SH, 1994 (abstract only): 16 normal volunteers received IV infusions of 0.0075 and 0.03 mg/kg over 30 minutes (6 subjects at each dose rate and 2 placebo at each tier). No adverse effects were reported.
PK/Drug Inguersen SH, 1994 (abstract only): In normal volunteers: t ½ = 0.75 h; Vd = 0.153 L/kg; renally Interactions secreted
- no information on BBB penetration - no information on drug interaction, but probably not hepatic
Comment: This compound has been in preclinical investigation for decades. Its usefulness clinically in limited by its extremely short t ½.
51 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development for ALS:
1. Human safety and BBB penetration. 2. Administration method to overcome extremely short t1/2.
REFERENCES
Ingwersen, SH, Ohrstrom JK, Petersen P, Drustrup J, et al. Human pharmacokinetics of the neuroprotective agent NBQX. Am J Ther. 1994. 1(4):296-303 (abstract only).
Van Damme P, Leyssen M, Callewaert G, Robberecht W, et al. The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett. 2003. 343:81-84.
52 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
NIMESULIDE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class (COX)-2 inhibitor
Manufacturer Regulatory Approval Status Mechanism of Bennett et al., 2000 (Abstract Only): preferential inhibition of prostaglandin synthesis via COX-2, and Action reductions in cytokine action/release, histamine release, the release of enzymes that degrade cartilage, and the release of superoxide anions and other toxic substances from neutrophils.
CASE FOR USE IN ALS Rationale Pompl et al., 2003: Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2 is elevated in the brain and spinal cord of ALS patients and ALS mouse model systems.
Clinical Data None
Animal Data Pompl et al., 2003: Mice expressing mutated human SOD1-G93A were treated with 1500 mg/kg via rodent diet. Dietary supplementation with nimesulide significantly delayed the onset of impairment in balance, coordination, and muscle strength, as assessed by Rotarod performance, and preserved motor functions through to 120 days of age. The nimesulide group also improved walking capacity through 124 days of age. Nimesulide did not alter the onset of end stage disease (bilateral hind limb paralysis) or the weight loss associated with the transgenic mice.
In Vitro Data None
HUMAN USE PROFILE Examined Drug Facts and Comparisons Online, 2004: Treatment of preterm labor
53 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Indications Aisen, et al., 2002: Clinical and laboratory experience with nimesulide suggests that it may be a good candidate for Alzheimer’s disease therapy.
Safety/Tolerability Aisen et al., 2002 (Abstract Only): Alzheimer disease patients were treated with 100 mg by mouth bid. Long-term therapy was well tolerated for periods exceeding 2 years.
Rainsford, 1999 (Abstract Only): Nimesulide is associated with a relatively low occurrence of adverse drug reactions especially in the gastrointestinal tract while those in the liver are within or below the general incidence with other NSAIDs.
Bennett et al., 2000 (Abstract Only): The novel therapeutic aspects include a relatively low toxicity to the gastrointestinal tract and kidneys, it can be given to most patients who experience respiratory problems with other NSAIDs, and the onset of analgesia is comparatively quick.
PK/Drug Rainsford, 1999 (Abstract Only): Nimesulide has a higher pKa (6.5) than conventional acidic NSAIDs. Interactions Bennett et al., 2000 (Abstract Only): Interactions with other drugs are few and of little or no clinical significance.
54 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Pompl et al., 2003: the relative potency of COX-2 inhibition by celecoxib and nimesulide is equivalent. Treatment with 1500 mg/kg in the diet for 3 months is well tolerated in B6C3 mice. Pharmacokinetics: nimesulide delivery to mice through the feed (2-3 months of treatment) reached ~30 micromolar concentration in the serum. Assessment of nimesulide in spinal cord revealed that ~10% of serum levels were detectable in spinal parenchyma.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Human BBB penetration. 2. Therapeutic concentration in animal model achievable in humans?
REFERENCES Aisen PS, Schmeidler J, Pasinetti GM. Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology. 2002 Apr;58(7):1050-1054 (Abstract Only).
Bennett A, Villa G. Nimesulide: an NSAID that preferentially inhibits COX-2, and has various unique pharmacological activities. Expert Opin Pharmacother. 2000 Jan;1(2):277-286 (Abstract Only).
Drug Facts and Comparisons Online. Nimesulide. www.efactsonline.com . 2004.
Pompl PN, Ho L, Bianchi M, McManus T, et al. A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2003 Feb;10.1096/fj.02-0876fje.
Rainsford KD. Relationship of nimesulide safety to its pharmacokinetics: assessment of adverse reactions. Rheumatol. 1999 May;38(1 Suppl):4-10 (Abstract Only).
55 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
NIMODIPINE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Voltage-gated calcium channel blocker
Manufacturer Bayer Regulatory Approval Status Approved for Subarachnoid Hemorrhage
Mechanism of Prevents Calcium-mediated neuronal damage Action
CASE FOR USE IN ALS Rationale Kriz J, 2003: The motor neuron death caused by mutant SOD1 is complex and probably involves multiple pathways, including alterations in calcium homeostasis.
Miller RG, 1996: Excessive glutamate triggers an influx of calcium intracellularly, causing cell death.
Clinical Data Miller RG, 1996: 87 ALS patients were enrolled in a randomized, placebo-controlled, double- blind crossover study. Patients received either 30 mg nimodipine three times daily or placebo and after 2 weeks, the dose was doubled and maintained for 3 months, if tolerated. There was a washout period of one month after the nimodipine treatment. 35 patients dropped out of the study (15 on nimodipine and 20 on placebo). No change in FVC slope of deterioration or other measures in the two groups.
56 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data Kriz J, 2003: A combination of riluzole, minocycline and nimodipine (doses of 30-40 mg/kg day of riluzole and nimodipine and 80-100 mg/kg of minocycline, in the diet) or control diet was administered to SOD1-G37R mice (n= 10 in each group), starting at 8-9 months of age. Treated animals life span increased by 6 weeks (54 vs 48 weeks; p<0.05), and the onset of muscle weakness was significantly delayed (48 vs. 43 weeks) as was the onset of paralysis (49 vs 45 weeks) (p<0.05). On histopathologic examination, there was reduced gliosis and neurodegeneration in the treated mice.
In Vitro Data None
HUMAN USE PROFILE Examined Indications Subarachnoid Hemorrhage; Ischemic Stroke
Safety/Tolerability MD Consult, 2004: Adverse experiences were reported by 92 of 823 patients with subarachnoid hemorrhage (11.2%) who were given nimodipine. The most frequently reported adverse experience was decreased blood pressure in 4.4% of these patients. Other adverse events included diarrhea, elevated liver function tests, etc. When patients with ischemic stroke were given 120 mg q4h, 50% developed hypotension.
Adverse experiences with an incidence rate of less than 1% in the 60 mg q4h dose group were: hepatitis; itching; gastrointestinal hemorrhage; thrombocytopenia; anemia; palpitations; vomiting; flushing; diaphoresis; wheezing; phenytoin toxicity; lightheadedness; dizziness; rebound vasospasm; jaundice; hypertension; hematoma.
57 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
PK/Drug Pharmacokinetics: Interactions MD Consult, 2004: In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/ml have been detected in the cerebrospinal fluid of nimodipine-treated subarachnoid hemorrhage (SAH) patients.
Nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within 1 hour. The terminal elimination half-life is approximately 8-9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1-2 hours; a consequence is the need for frequent (every 4 hours) dosing.
Drug Interactions
MD Consult, 2004: It is possible that the cardiovascular action of other calcium channel blockers could be enhanced by the addition of nimodipine.
Cimetidine has been shown to decrease the first pass effect, raising nimodipine concentrations.
58 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Animal model or in vitro evidence of activity in ALS (alone).
REFERENCES
Kriz J, Gowing G, Julien JP. Efficient three-drug cocktail for disease-induced by mutant superoxide dismutase. Ann Neurol 2003; 53:429-436
Miller RG, Shepherd R, Dao H, Khramstov A, Mendoza M, Graves J, Smith S. Controlled trial of nimodipine in amyotrophic lateral sclerosis. Neuromusc Disord 1996;6(2):101-104
59 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
ONO-2506
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Neuroprotectant (astrocyte modulator)
Manufacturer Ono Pharmaceutical Co Ltd Regulatory Approval Status Investigational (Proglia (IV) ; Cereact (po))
Mechanism of Action dePaulis T, 2003: Prevents reduction of GABA transporter expression and ameliorates the consequences of neurodegeneration.
CASE FOR USE IN ALS Rationale dePaulis T, 2003: The congener of the antiepileptic drug, valproic acid, ONO-2506 inhibits the formation of activated astrocytes after injury, restoring normal function of the astrocytes. This may decrease glutamate toxicity.
Clinical Data None – Phase II ongoing for ALS in Europe
Animal Data None
In Vitro Data
60 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
HUMAN USE PROFILE Examined Acute ischemic stroke, AD, PD, ALS Indications
Safety/Tolerability proprietary
PK/Drug Unknown Interactions
61 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA dePaulis T, 2003: ONO reduced infarct size in MCAO in rats by 40%; reduced DA loss in mouse MPTP model by 41%
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Animal model or in vitro evidence of activity in ALS. 2. Human safety and BBB penetration.
REFERENCES dePaulis T. ONO-2506. Curr Opin Invest Drugs 2003;4(7): ?
62 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
SODIUM PHENYLBUTYRATE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Aromatic short-chain fatty acid histone deactylase inhibitor; prodrug for sodium phenylacetate
Manufacturer Triple crown America, inc.: Provides triButyrateâ in tablets or powder form to sponsors of clinical investigators Ucyclid: Buphenylâ Regulatory Orphan drug for the treatment of urea cycle disorders. Approval Status Mechanism of Urea deacetylase inhibitor; induces cell differentiation; up-regulates lipid-metabolizing genes via Action peroxisome transcription factors.
CASE FOR USE IN ALS Rationale None
Clinical Data None
Animal Data None
In Vitro Data None
HUMAN USE PROFILE Examined Memorial Sloan Kettering Cancer Center: cancer treatment, cystic fibrosis, sickle cell disease, Indications thalassemia, and urea cycle disorders.
Safety/Tolerability Lexi-Drugs: More Frequent Adverse Effects: amenorrhea, menstrual dysfunction, anorexia, abnormal taste, offensive body odor
63 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Each 1 gram of drug contains 125 mg of sodium and, therefore, should be used cautiously, if at all, in patients who must maintain a low sodium intake.
Drug Facts and Comparisons Online, 2004: Less Frequent Adverse Effects (<2%): arrhythmia, depression, nausea, vomiting, constipation, rectal bleeding, renal tubular acidosis, rash, aplastic anemia, syncope.
PK/Drug PHARMACOKINETICS Interactions Miller et al., 1987: Sodium butyrate was administered i.v. at a dosage of 500 mg/kg/day as continuous infusions for 10 days in cancer patients. During infusion, plasma concentrations increased 6-fold over the endogenous butyrate level and reached 39-59 micromolar. After the end of the infusion, concentrations declined rapidly with a half-life of 6.1 +/- 1.4 min, and reached pretreatment levels within 1 hr. The total clearance rate was 83 +/- 12 ml/kg/min and the Vd was 738 +/- 245 ml/kg. Protein binding accounted for 9.1% of total sodium butyrate in plasma.
DRUG INTERACTIONS Drug Facts and Comparisons Online, 2004: Corticosteroids may decrease sodium phenylbutyrate and increase plasma ammonia concentrations; haloperidol/valproate may decrease sodium phenylbutyrate and cause hyperammonemia; probenecid may increase levels of sodium phenylbutyrate by affecting renal transport of the compound and its metabolites.
64 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
RATIONALE August 2004 Communicaton from Christine Brahe: Preliminary data suggest both SMN2 promoter activation and SMN2 RNA splicing.
ANIMAL MODEL Chang et al., 2001: SMA-like mice were treated with sodium butyrate at a concentration of 0.8 mg/ml or 8 mg/ml in distilled water beginning immediately after diagnosis. Both groups consumed ~5-10 ml/day/mouse (~4-80 mg/day). The sodium butyrate-treated mice survived 4-5 days longer than the untreated ones. After sodium butyrate treatment, the tails of types 2 and 3 SMA-like mice showed nearly normal muscle patterns. The tails of treated mice were slightly shorter than normal, and treated mice rarely developed chronic necrosis from the tip of the tail toward the root (2% for treated group vs. 50% for untreated group).
IN VITRO MODEL Chang et al., 2001: Epstein-Barr virus-transformed lymphoid cell lines from all three types of SMA patients were established. Sodium butyrate was able to change the expression pattern of the SMN2 gene. The amount of exon 7-containing SMN mRNAs increased in lymphoid cells cultured with 5 ng/ml to 500 mcg/ml of sodium butyrate. The maximal effect was found after 4 h of stimulation. Sodium butyrate-treated cells from all types of SMA patients showed an increased number of full- length SMN transcripts. Alternative splicing pattern of exons 3 and 5 was unchanged after sodium butyrate stimulation, but the alternative splicing pattern of exon 7 of the SMN2 gene changed to the SMN1 pattern. Western blot analysis indicated that butyrate also increased the intact SMN protein after 4 h stimulation with 0.5 ng/ml to 500 mcg/ml of sodium butyrate.
SAFETY/TOLERABILITY Chang et al., 2001: Mice were treated with 16 mg/day sodium butyrate solution and 40 mg/day. No definite toxicity at 16 mg/day was observed, whereas mice that received 40 mg/day sodium butyrate treatment died because of dehydration.
Egorin et al., 1999: A dose of 10 g/kg of sodium butyrate in mice was lethal to 2 of 2 mice within 1 min of drug delivery. Similar results were produced after a dose of 7.5 g/kg were given. All five mice given a dose of 5 g/kg were dead within 24 h of dosing. All five mice given a dose of 2.5 g/kg were without a righting reflex for 30 min after dosing, and all had necrotic tails by 24 h after dosing. All five mice given 1.25 g/kg were lethargic for 30 min after dosing but survived without obvious sequalae.
65 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
PHARMACOKINETICS Berg et al., 2001 (Abstract Only): Three animals received phenylbutyrate (130 mg/kg) as a 30-min infusion. After IV phenylbutyrate (PB) administration, the plasma AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the Cl was 7 +/- 1 ml/min/kg, and the AUCCSF:AUC plasma ratio was 41 +/- 47%.
Egorin et al., 1999: Mice were treated with IV bolus or oral gavage of sodium butyrate. IV doses were 0.31, 0.62, 0.94, and 1.25 g/kg. The oral dose was 5 g/kg. The four i.v. doses resulted in plasma concentration-time profiles that also indicated nonlinear PK and were well described by a one-compartment model with saturable elminiation. Values recorded for Km and Vmax ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min, respectively. Values for the volume of the central compartment (Vc) varied between 0.48 and 0.72 l/kg. At 1.25 g/kg, i.v. butyrate produced peak plasma concentrations of 10.5-17.7 mM, and plasma concentrations remained above 1 mM for 20-30 min. Sodium butyrate delivered orally to mice at 5 g/kg produced peak plasma concentrations of approximately 9 mM at 15 min after dosing and concentrations exceeding 1 mM for 90 min after dosing.
66 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Animal model or in vitro evidence of activity in ALS. 2. Human safety and BBB penetration at relevant doses.
REFERENCES
Berg S, Serabe B, Aleksic A, Bomgaars L, et al. Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. Cancer Chemother Pharmacol. 2001 May;47(5):385-90 (Abstract Only).
Chang JG, Hsieg-Li HM, Jong YJ, Wang NM, et al. Treatment of spinal muscular atrophy by sodium butyrate. PNAS. 2001 Aug; 98(17):9808-9813.
Drug Facts and Comparisons Online. Sodium Phenylbutyrate. www.efactsonline.com. 2004.
Egorin MJ, Yuan Zm, Sentz DL, Plaisance K, Eiseman J. Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats. Cancer Chemother Pharmacol. 1999;43:445-453.
Lexi-Drugs. Sodium phenylbutyrate. 2004.
Miller AA, Kurschel E, Osieka R, Schmidt CG. Clinical pharmacology of sodium butyrate in patients with acute leukemia. Eur J Cancer Clin Oncol. 1987;23(9):1283-1287.
67 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RILUZOLE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Benzothiazole
Manufacturer Rhone-Poulenc Rorer Regulatory Drug Facts and Comparisons Online, 2004: Amyotrophic lateral sclerosis (ALS): Treatment of patients Approval Status with ALS. Riluzole extends survival or time to tracheostomy.
Mechanism of Bryson et al., 1996 (Abstract Only): Riluzole affects neurons by 3 mechanisms: by inhibiting excitatory Action amino acid release, inhibiting events following stimulation of excitatory amino acid receptors, and stabilizing the inactivated state of voltage-dependent sodium channels.
Lexi-Drugs: Inhibitory effect on glutamate release, inactivation of voltage-dependent sodium channels; and ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.
CASE FOR USE IN ALS Rationale Snow et al., 2003: Currently riluzole is a standard of treatment for patients with ALS, since it has modest effects in prolonging survival in these patients.
Bryson et al., 1996 (Abstract Only): There is evidence in patients with ALS that riluzole can extend survival and/or time to tracheostomy.
Clinical Data Cochrane Database Syst Rev 2002;(2):CD001447 ; In a systematic review of 4 randomized trials, the reviewers concluded that riluzole 100 mg daily is reasonably safe in ALS patients and prolongs survival by about 2 months. In elderly individuals, and those with more severe ALS, the effects may be different (less).
Riluzole has been approved for ALS for a decade and is routinely used.
68 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data Kriz J, 2003: A combination of riluzole, minocycline and nimodipine (doses of 30-40 mg/kg day of riluzole and nimodipine and 80-100 mg/kg of minocycline, in the diet) or control diet was administered to SOD1- G37R mice (n= 10 in each group), starting at 8-9 months of age. Treated animals life span increased by 6 weeks (54 vs 48 weeks; p<0.05), and the onset of muscle weakness was significantly delayed (48 vs. 43 weeks) as was the onset of paralysis (49 vs 45 weeks) (p<0.05). On histopathologic examination, there was reduced gliosis and neurodegeneration in the treated mice.
Snow et al.,2003: G93A transgenic mice were given wither standard powdered murine chow, creatine (2% w/w) mixed in murine chow, or riluzole (100 mcg/ml) in drinking water ad libitum, or both creatine and riluzole. The onset of clinical symptoms were delayed by about 12 days in all three treatment groups compared with control. A significantly lower clinical symptom score was also observed when the mice ingesting Cr (Cr and Ril+Cr) were compared to those not ingesting Cr (Control and Ril). The number of medium, or large diameter neurons, as well as the total number of neurons in the ventral horns of the lumbar approximately L3 region of the spinal cord were not different between any of the treatment groups.
Gurney et al., 1996: G93A transgenic mice were administered either: Vitamin E, riluzole or gabapentin (po in either diet or water). Vit E was started at 30 days, other 2 agents started at 50 days. Vitamin E delayed disease onset by 12 to 15 days (14%), riluzole had no effect on disease onset and gabapentin unmasked symptoms earlier than controls (NS). Vitamin E also delayed progression (wheel running) but did not increase survival. Riluzole increased survival by 13 to 15 days (11%; p=0.039) and gabapentin increased survival by 8 days (NS).
In Vitro Data None
HUMAN USE PROFILE Examined None Indications Safety/Tolerability Drug Facts and Comparisons Online, 2004: The most commonly observed adverse reactions associated with the use of riluzole were: Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, circumoral paresthesia (dose-related); decreased lung function; abdominal pain; pneumonia; vomiting.
69 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Lexi-drugs, 2004: Less common adverse reactions: hypertension, tachycardia, postural hypotension, edema, headacye, pruritus, eczema, alopecia, dyspepsia, stomatitis, arthralgia, back pain, rhinitis, increased cough, aggravation reaction, exfoliative dermatitis, neutropenia, seizures
Siniscalchi A, 2004: The most frequent adverse effects related to riluzole treatment were: nausea, vomiting, anorexia, diarrhea, asthenia, somnolence, vertigo, circumoral paresthesia, abdominal pain, and dizziness. Some events tend to be related to the dose: vertigo, diarrhea, nausea, circumoral paresthesia and anorexia appear more frequently with 200 mg/day than with lower doses.
PK/Drug PHARMACOKINETICS Interactions Drug Facts and Comparisons Online, 2004: Absorption / Distribution: Riluzole is well absorbed (˜ 90%), with average absolute oral bioavailability of ˜ 50%. Pharmacokinetics are linear over a dose range of 25 to 100 mg every 12 hours. A high fat meal decreases absorption, reducing AUC ˜ 20% and peak blood levels by ˜45%. The mean elimination half-life of riluzole is 12 hours after repeated doses. With multiple dose administration, riluzole accumulates in plasma by about 2–fold, and steady-state is reached in < 5 days. Riluzole is 96% bound to plasma proteins, mainly to albumin and lipoproteins. Metabolism / Excretion: Riluzole is extensively metabolized to six major and a number of minor metabolites, not all of which have been identified. Some metabolites appear pharmacologically active in vitro. The metabolism is mostly hepatic and consists of cytochrome P450 dependent hydroxylation and glucuronidation. There is marked inter-individual variability in the clearance of riluzole, probably attributable to variability of CYP1A2 activity, the principal isozyme involved in N-hydroxylation. In vitro studies using liver microsomes show that hydroxylation of the primary amine group producing N-hydroxyriluzole is the main metabolic pathway. Cytochrome P450 1A2 is the principal isozyme involved in N-hydroxylation. Whereas direct glucuroconjugation of riluzole (involving the glucurotransferase isoform UGT-HP4) is very slow in human liver microsomes, N-hydroxyriluzoe is readily conjugated at the hydroxylamine group resulting in the formation of O- (> 90%) and N- glucuronides. Following a single 150 mg dose to six healthy males, 90% and 5% was recovered in the urine and feces, respectively, over 7 days. Glucuronides accounted for > 85% of the metabolites in urine. Only
70 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
2% was recovered in the urine as unchanged drug.
Bruno et al., 1997 (Abstract Only): 100 patients with ALS who were participating in a phase III dose- ranging trial of riluzole were sampled on 179 visits. In the basic one-compartment pharmacokinetic model, interindividual variability in plasma clearance (51.4%) was higher than intraindividual (visit-to- visit) variability (28%) indicating uniform pharmacokinetic bahavior during long-term therapy. Riluzole clearance was independent of dosage (25 to 100 mg twice daily), treatment duration (up to 10 months), age, and renal function. Typical value of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in women than in men and 36% lower in nonsmokers than in smokers.
DRUG INTERACTIONS Drug Facts and Comparisons Online, 2004: Effect of other drugs on riluzole metabolism: In vitro studies using human liver microsomal preparations suggest that CYP1A2 is the principal isozyme involved in the initial oxidative metabolism of riluzole and therefore potential interactions may occur when riluzole is given concurrently with agents that affect CYP1A2 activity. Potential inhibitors of CYP1A2 (eg, caffeine, theophylline, amitriptyline, quinolones) could decrease the rate of riluzole elimination, while inducers of CYP1A2 (eg, cigarette smoke, charcoal-broiled food, rifampin, omeprazole) could increase the rate of riluzole elimination. Drug / Food Interactions: A high fat meal decreases absorption of riluzole, reducing AUC by ˜ 20% and peak blood levels by ˜ 45%.
Lexi-drugs, 2004: Inhibitors of CYP1A2 that can increase levels of riluzole include: amiodarone, fluvoxamine, lomefloxacin, ofloxacin, ciprofloxacin, and ketoconazole Inducers of CYP1A2 that can decrease levels of riluzole include: carbamazepine, Phenobarbital, aminoglutethimide, rifampin Drug/Food Interactions: Avoid ethanol (can increase CNS depression); charbroiled foods may increase riluzole elimination.
71 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS REFERENCES Bruno R, Vivier N, Montay G, Le Liboux A, et al. Population pharmacokinetics of riluzole in patients with ALS. Clin Pharmacol Ther. 1997 Nov; 62(5):518-526 (Abstract Only).
Bryson HM, Fulton B, Benfield P. Riluzole. A review of its pharmacodynamic and pharmacokinetic properities and therapeutic potential in amyotrophic lateral sclerosis. Drugs. 1996 Oct; 52(4):549-563 (Abstract Only).
Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND). Cochrane Database Syst Rev 2002;(2): CD001447
Drug Facts and Comparisons Online. Riluzole. www.efactsonline.com. 2004.
Lexi-Drugs. Riluzole. 2004.
Snow RJ, Turnbull J, Da Silva S, Jiang F, et al. Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice. Neurosci. 2003; 119:661-667.
Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, Andrus PK, Hall ED. Benefit of Vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 1996;39:147-157
72 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
SCRIPTAID
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Histone Deacetylase Inhibitor (HDAC inhibitor)
Manufacturer Alexis Biochemicals Regulatory Approval Status Preclinical
Mechanism of Prevents protein aggregation Action
CASE FOR USE IN ALS Rationale Corcoran LJ, 2004: Mutant SOD1 forms aggresome-like structures in patients, tissue culture cells and animal models of ALS. A HDAC inhibitor may prevent this. However, it is not known whether these protein aggregates are toxic or beneficial.
Clinical Data None
Animal Data
In Vitro Data Corcoran LJ, 2004: In a screen of 20,000 compounds, Scriptaid was identified as an agent that
73 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
decreased the number of aggresomes from 77% in controls to 18% with Scriptaid. Further in vitro examination revealed that Scriptaid did not block microaggregation but prevents them from being formed into aggresomes.
HUMAN USE PROFILE Examined Indications None
Safety/Tolerability None
PK/Drug Interactions Unknown
74 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Animal model or in vitro evidence of activity in ALS. 2. Human safety and BBB penetration at relevant doses / concentrations.
REFERENCE
Corcoran LJ, Mitchison TJ, Liu Q. A novel action of histone deacetylase inhibitors in a protein aggresome disease model. Curr Biol 2004;14:488-492
75 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
TALAMPANEL
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class AMPA receptor antagonist / Antiepileptic
Manufacturer Eli Lilly and Co. Regulatory Approval Status Investigational
Mechanism of Prevents excitotoxic glutamate transmission Action
CASE FOR USE IN ALS Rationale There is evidence that disturbances in glutamate metabolism may contribute to the pathogenesis of ALS.
Clinical Data None – Phase II planned
Animal Data Unable to find Rothstein presentation – positive in mouse model?
76 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In Vitro Data None
HUMAN USE PROFILE Examined Indications Epilepsy
Safety/Tolerability Langan YM, 2003: In normal volunteers given 3-100 mg orally, no adverse consequences on HR, BP, ECG or laboratory values were demonstrated. However, doses > 50 mg were associated with ataxia and sedation. 60 mg q8h for 11 days was associated with dizziness, light-headedness and ataxia.
In patients with epilepsy, 35 mg q8h was associated with similar adverse effects.
PK/Drug Pharmacokinetics: Interactions Presumed BBB penetration – activity in epilepsy and side effects.
Langan YM, 2003: t ½ was, on average, 6.5 hours in normals over a range of doses 3-100 mg. However, in epilepsy patients (taking other AEDs), average t ½ was 3.3 h after a single dose and 5.6 h after multiple doses, suggesting nonlinearity.
77 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Drug Interactions:
Langan YM, 2003: Inhibits VPA metabolism
- is inhibited by VPA - is induced by CBZ, PHT and other AED inducers
Comment: since there are no known drug interactions with riluzole, it is difficult to predict whether an interaction with talampanel would occur. However, there may be additive adverse effects (similar mechanism) and one would need to study whether talampanel inhibited the metabolism of riluzole (it is possible).
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development in ALS:
1. Animal model or in vitro evidence of activity in ALS.
REFERENCE:
Langan YM, et al. Talampanel, a new antiepileptic drug: single- and multiple-dose pharmacokinetics and initial 1- week experience in patients with chronic, intractable epilepsy. Epilepsia 2003; 44(1):46-53
78 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
TAMOXIFEN
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Antiestrogen; Selective estrogen receptor modulator
Manufacturer Nolvadex Regulatory Approval Status Approved for breast carcinoma (1994)
Mechanism of Action In estrogen-receptor positive tumors, reduces the tumor size and growth.
CASE FOR USE IN ALS Rationale Protein kinase C inhibitor
Clinical Data None – Phase II on hold
Animal Data None
In Vitro Data None
79 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
HUMAN USE PROFILE Examined Breast cancer; breast cancer prevention in high risk women; other cancer Indications
Safety/Tolerability MD Consult, 2004: In patients treated with tamoxifen citrate for metastatic breast cancer, the most frequent adverse reaction to tamoxifen citrate is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.
PK/Drug Pharmacokinetics: Interactions MD Consult, 2004: Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/ml (range 35-45 ng/ml) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half- life of about 5-7 days.
Mickley KR, 2004: Tamoxifen doses of 12.5 to 500 mcg in ovariectomized mice reduced the neurotoxic effects of methamphetamine (improved DOPAC/DA ratios) and improved behavior. (This MAY be evidence of BBB penetration – unable to find any other evidence using PubMed)
Drug Interactions: MD Consult, 2004: When tamoxifen citrate is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
80 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial.
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen citrate.
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N- desmethyl tamoxifen plasma concentrationshave been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
81 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Animal model or in vitro evidence of activity in ALS. 2. Human BBB penetration.
REFERENCES
Tamoxifen. MD Consult. 2004. www.mdconsult.com.
Mickley KR, Dluzen DE. Dose-response effects of estrogen and tamoxifen upon methamphetamine-induced behavioral responses and neurotoxicity of the nigrostriatal dopaminergic system in female mice. Neuroendocrinology 2004;79(6):305-316
82 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
THALIDOMIDE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Immunomodulator
Manufacturer Celgene Regulatory Approval Status FDA approved for the treatment of Hansen’s Disease (Leprosy)
Mechanism of MD Consult, 2005: thalidomide may suppress excessive tumor necrosis factor-alpha (TNF-a) Action production and down modulate select cell surface adhesion molecules involved in leukocyte migration.
CASE FOR USE IN ALS Rationale Thalidomide may cause a decrease in TNFalpha and TNF alpha has been shown to be elevated in the CNS of both humans and mice with ALS.
Clinical Data None
Animal Data ALS TDF, 2005 (abstract only): ALSTDF tested thalidomide in 2001 at 7.5 mg/kg showed no effect, and in hindsight appeared to be far too low. Beal’s laboratory presented findings that thalidomide treatment reduced TNF-a, increased survival, and attenuated weight loss in SOD1 G93A mice. His doses were 50 and 100 mg/kg orally.
83 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
In Vitro Data None
HUMAN USE PROFILE Examined Hansen’s Disease Indications Although not FDA approved, thalidomide has been used to treat wasting associated with AIDS, multiple myeloma, aphthous stomatitis, rheumatoid arthritis, cutaneous lupus erythematosus, Behcet's syndrome, Crohn's disease, and graft versus host disease in bone marrow transplant patients.
Safety/Tolerability MD Consult, 2004: Black box warning re: birth defects; Associated with a high incidence of somnolence and peripheral neuropathy that can be permanent (check q 3 months). Also can cause dizziness and orthostatic hypotension.
Chintagumpala, 2004: Major toxicity in adults in reversible sedation. Additional serious adverse events include peripheral neuropathy (including constipation), thrombosis and rash. It has also been associated with thyroid dysfunction. In adult patients with Kaposi’s sarcoma, the maximum tolerated dose was 600 mg daily.
PK/Drug Pharmacokinetics Interactions MD Consult, 2004: The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen's disease, the mean time to peak plasma concentrations (Tmax) of thalidomide ranged from 2.9-5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract. The mean half-life of elimination ranges from
84 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
approximately 5-7 hours following a single dose and is not altered upon multiple dosing.
Drug Interactions
MD Consult, 2004: Has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Use with caution with agents known to cause peripheral neuropathy.
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Human BBB penetration.
REFERENCE
Thalidomide. ALS TDF. 2005. www.als.net/research/treatments/treatmentDetail.asp.
Chitagumpala M, Blaney SM, Bomgaars LR, Aleksic A, Kuttesch JF, Klenke RA, Berg SL. Phase I and pharmacokinetic study of thalidomide with carboplatin in children with cancer. J Clin Oncol 2004;22:4394-4400.
Thalidomide. MD Consult. 2005. www.mdconsult.com
85 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
TREHALOSE
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Artificial sweetener (food)
Manufacturer Cargill Regulatory Approval Status Generally regarded as safe (FDA)
Mechanism of www.caloriecontrol.org, 2004: Trehalose is a multi-functional sweetener found naturally, for Action example in honey, mushrooms, lobster, shrimp and foods produced using baker’s and brewer’s yeast. The commercial product is made from starch by an enzymatic process.
CASE FOR USE IN ALS Rationale Romisch K, 2004: Small molecules such as trehalose or glycerol are synthesized in high concentrations by single cell organisms when they are stressed, to prevent protein denaturation. Mutations that affect protein folding (as in ALS) may benefit from these osmolytes that can stabilize mutant secretory proteins. Trehalose may work as a therapeutic agent in protein trafficking diseases.
Clinical Data None
Couzin J, 2004: HD trial planned with combinations of supplements including blueberry extract, Co Q10, creatine, omega 2 fatty acids and cysteamine.
86 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Animal Data None
In Vitro Data None
HUMAN USE PROFILE Examined www.caloriecontrol.org, 2004: Trehalose has been shown to elicit a very low insulin response Indications and provide sustained energy. In addition, trehalose protects and preserves cell structure in foods and may aid in the freezing and thawing process of many food products by assisting in the maintenance of the desired texture of the food. It is also heat stable. Because trehalose is only half a sweet as sucrose it is more likely to be used for cell preservation than for sweetness.
Trehalose may be used in beverages, including fruit juices, purees and fillings, nutrition bars, surimi, dehydrated fruits and vegetables, and white chocolate for cookies or chips.
Safety/Tolerability Trehalose has a long history of human use. Numerous studies have been conducted to support its safety.
The US Food and Drug Administration has issued a letter of no objection to the Generally Recognized As Safe (GRAS) status for trehalose. Trehalose is approved in Japan, Taiwan and Korea. It may be used in the preservation of freeze-dried products in the United Kingdom.
For further information, please contact Cargill at (952) 742 6805 or visit our website at www.cargill.com/sfi.
87 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
PK/Drug Unknown Interactions
RELEVANT PRECLINICAL DATA
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Animal model or in vitro evidence of activity in ALS. 2. Human BBB penetration.
REFERENCE
Couzin J. Unorthodox clinical trials meld science and care. Science 2004: 304: 816-817
Romisch K. A cure for traffic jams: small molecule chaperones in the endoplasmic reticulum. Traffic 2004; 5(11): 815-820
88 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
VITAMIN E
PARAMETER REVELANT INFORMATION IDENTITY AND GENERAL INFORMATION Drug Class Antioxidant, fat-soluble vitamin
Manufacturer Various Regulatory Approval Status
Mechanism of Drug Facts and Comparisons Online, 2004: Vitamin E is a fat-soluble vitamin with actions related to its Action antioxidant properties. Vitamin E protects cellular constituents from oxidation and prevents the formation of toxic oxidation products; it preserves red blood cell (RBC) wall integrity and protects RBCs against hemolysis; it stimulates a cofactor in steroid metabolism; inhibits prostaglandin production; and suppresses platelet aggregation. In combination with selenium, vitamin E protects cell membranes from oxidative damage.
CASE FOR USE IN ALS Rationale Desnuelle et al., 2001 (Abstract Only): The antioxidant vitamin E has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS.
Kwiecinski et al., 2001 (Abstract Only): A role for oxidative stress in the etiology or progression of ALS and other neurodegenerative diseases has been recently proposed.
Gurney et al., 1996 (Abstract Only): Supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model of mice but does not prolong survival.
89 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Clinical Data Desnuelle, et al. 2004 (Abstract Only): Patients with ALS treated with riluzole, were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. After 12 months of treatment, alph- tocopherol had no effect on the rate of deterioration of function. Survival was not influenced by treatment. After 3 months of treatment analysis of oxidative stress markers showed an increase in glutathione peroxidase acid reactive species in the group of patients given alpha-tocopherol in combination with riluzole. Patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changed in biochemical markers of oxidative stress.
Kwiecinski et al., 2001 (Abstract Only): Patients with ALS were assigned to receive antioxidative therapy (vitamin E plus selegiline) or symptomatic treatment. At the end of the 18-month trial, 13 patients in the treatment group and 14 in the control group died or wre tracheostomized. A decline in functional disability was also similar in both groups.
Ascherio et al., 2004: Information on vitamin use was collected in 1982 and a follow up was conducted 10 years later. ALS mortality was 62% lower among long-term users of vitamin E than among nonusers. Compared with participants who used neither multivitamins nor vitamin E, participants who were regular users of mulivitamins but did not use vitamin E were not at reduced risk of ALS, whereas participants who were regular users of both multivitamins and vitamin E were at reduce d risk.
Graf et al., 2004: 160 patients with probable or definite ALS treated with riluzole were randomly assigned to either receive vitamin E (5x1000 mg/day) or placebo over a period of 18 months. Overall, the survival rate was similar in the two treatment groups at 18 months. Neither the primary or the secondary outcome measures of this trial could determine whether a megadose of vitamin E is effective in slowing disease progression in ALS.
Animal Data Gurney et al., 1996: Transgenic mice were fed a vitamin E supplemented diet containing 200 IU/kg vitamin E and 8 mg/kg selenium daily. Vitamin E significantly delayed the onset of clinical symptoms in the transgenic model. G1Hl+ mice normally show onset of clinical symptoms at a mean of 92-96 days of age; the mice treated with vitamin E delayed onset of clinical symptoms by 12 to 15 days of age (14%
90 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
improvement). Supplementation of vitamin E delayed the progression of disease in G1Hl+ mice by prolonging levels of wheel activity by 12 to 15 days; furthermore these mice maintained higher average levels of wheel activity at all ages than did age-matched controls. Greater wheel activity extended from 90 to 135 days of age, the period after the onset of clinical disease in untreated controls; there was a 60% improvement of total wheel activity with mice supplemented with vitamin E. Unfortunately, there was no effect on survival with the mice treated with vitamin E.
In Vitro Data None
HUMAN USE PROFILE Examined Drug Facts and Comparisons Online, 2004: Vitamin E has been used in certain premature infants to Indications reduce the toxic effects of oxygen therapy on the lung parenchyma (bronchopulmonary dysplasia) and the retina (retrolental fibroplasia). It has been investigated for the prevention of periventricular hemorrhage in premature infants. It has also been used in cancer, skin conditions, sexual dysfunction, to reduce the incidence of nonfatal MI, to lower the incidence of coronary artery disease, aging, fibrocystic breast disease (cystic mastitis), to treat dapsone-associated hemolysis, arthritis, and tardive dyskinesia. Use of vitamin E in combination with vitamin A has been reported in the treatment of keratosis follicularis (Darier disease), pityriasis rubra pilaris, ichthyosis, and acne. Use of vitamin E (400 IU) in combination with vitamin C (1 g/day) has resulted in significant risk reduction for preeclampsia during the second half of pregnancy.
Safety/Tolerability Drug Facts and Comparisons Online, 2004: Doses < 2000 IU are not likely to cause side effects. However, large doses (> 3000 IU) have been noted to produce symptoms of hypervitaminosis E, which include nausea, weakness, intestinal cramps, headache, flatulence, diarrhea, thrombophlebitis, pulmonary embolism, severe fatigue syndrome, gynecomastia, breast tumors, increased cholesterol and triglycerides, decrease in serum thyroid hormone, and altered immunity. Doses < 2000 IU are unlikely to cause side effects. Sepsis and necrotizing enterocolitis have been reported when vitamin E levels are maintained at 5 mg/dL in low-birth-weight infants.
Graf et al., 2004: 160 patients with probable or definite ALS treated with riluzole were randomly assigned to either receive vitamin E (5x1000 mg/day) or placebo. No differences between treatment groups could be detected as regards to vital signs, serious and other ADR reporting, concomitant medication, ECG’s and VEP’s. Also, standard laboratory tests did not indicate of toxic or otherwise
91 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
harmful effects caused by vitamin E. Vitamin plasma levels were significantly higher in the high dose vitamin E group than in the placebo group.
PK/Drug PHARMACOKINETICS Interactions Absorption / Distribution: Vitamin E is 20% to 50% absorbed by intestinal epithelial cells in the small intestine. Bile and pancreatic juice are needed for tocopherol absorption. Absorption is increased when administered with medium-chain triglycerides. Distribution to tissues via the lymphatic system occurs as a lipoprotein complex. High concentrations of vitamin E are found in the adrenals, pituitary, testes, and thrombocytes. Gurney et al., 1996: Vitamin E transport into the brain is limited, so vitamin E levels can only be replenished slowly after an oxidative insult.
Metabolism / Excretion: Vitamin E is stored unmodified in tissues (principally the liver and adipose tissue) and excreted via the feces. Excess vitamin E is converted to a lactone, esterified to glucuronic acid, and subsequently excreted in the urine.
DRUG INTERACTIONS Drug Facts and Comparisons Online, 2004: In high doses (>4000 IU), vitamin E may increase the hypoprothrombinemic effects of oral anticoagulants (e.g. warfarin) Vitamin E may impair the hematologic response to iron therapy in children with iron-deficiency anemia.
92 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
RELEVANT PRECLINICAL DATA
Reichman, 2004 (Abstract Only): Treatment with alpha-tocopherol has been shown to delay the progression of nursing home admission in patients with mild-to-moderate Alzheimer’s Disease.
MISCELLANEOUS SUMMARY:
Needed prior to development as a treatment in ALS:
1. Evidence of adequate BBB penetration in humans (at tolerable doses)?
REFERENCES
Ascherio A, Weisskopf M, O’Reilly E, et al. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann Neurol 2005; 57:104-110.
Desnuelle C, Garrel M, Favier A: A double-blind, placebo-controlled randomized clinical trial of alpha tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol study group. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001 Mar; 2(1):9-18 (Abstract Only).
Drug Facts and Comparisons Online. Vitamin E. www.efactsonline.com. 2004.
Graf M, Ecker R, Horowski B, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm. 2004 Oct 27 (Epub).
Gurney ME, Cutting FB, Zhai P, Doble A, et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996. 39:147-157.
Kwiecinski H, Janik P, Jamrozik Z, Opuchlik A. The effect of selegiline and vitamin E in the treatment of ALS: open randomized clinical trials. Neurol Neurochir Pol. 2001; 35 (1 Suppl):101-106.
93 Prepared by Susan Fagan, Pharm D Version 17 th May 2005 Detailed pharmacology review of neuroprotective agents for ALS Traynor BJ et al.
Reichman WE. Alzheimer’s disease: clinical treatment options. Am J Manag Care. 2000 Dec; 6(22 Suppl):S1125-1132 (Abstract Only).
94 Prepared by Susan Fagan, Pharm D Version 17 th May 2005