Drug Summaries
DRUG NAME: Caffeine MANUFACTURER: NA
Reviewer: Dr. M. Schwartschild last revised 4/29/02
AVAILABILE INFORMATION / CITATIONSCIENTIFIC RATIOINALE / A1 and A2A adenosine receptors are located in the striatum and are co-localized with D1 and D2 receptors (A1/D1 and A2A /D2).1-3 These adenosine receptors act functionally in an antagonistic fashion, opposing the actions of the dopamine receptors.4 Therefore, antagonism of these adenosine receptors results in the facilitation of dopaminergic post-synaptic transmission.
Caffeine, like other methylxanthines, are nonspecific antagonists at adenosine receptors (A1, A2).5-7 Caffeine has also been shown to modify dopamine release in various brain regions including the striatum.8-9 / 1. J Neurochem 1991;57:1062-7.
2. Mol Brain Res. 1992;14:186-95.
3. NeuroReport 1994; 6:73-6.
4. TINS 1997; 20:482-7.
5. Life Sci 1981;28:2083-97.
6. Acta Physiol Scan 1982; 115: 283-6.
7. Pharmacol. Tox. 1995;76;93-101.
8. J Pharm Pharmacol 1984;36:458-60.
9. Neurosci Lett 1996;212:53-56.
ANIMAL MODEL DATA / RODENT: Although caffeine is a nonspecific antagonist, its affects on A2A receptors seem to be more important in mediating its anti-PD effects. This belief comes from the fact that rats with unilateral nigrostriatal 6-hydroxydopamine-induced lesions or those undergoing unilateral dopaminergic denervation have their impaired motor symptoms reversed with administration of caffeine.1-4 Symptom relief is comparable to that observed with administration of dopamine agonists alone.3,4 However, selective D2 antagonism will block the beneficial effect. In contrast co-administration of a selective D1 antagonist will have little detrimental effect on the lesioned rats rotational behaviors. 3,4 One limitation found with caffeine’s effects in PD is tolerance with repeated administration. 5-8 For example, caffeine’s effects on contralateral rotational behavior in 6-hydroxydopamine denervated rats decreases with repeated administration.5,6
This effect can be relatively rapid (within 1- week). Interestingly, tolerance with caffeine can be reversed with co-administration of the D2 receptor agonist, bromocriptine, however the D1 agonist, SKF38393, cannot does not reverse tolerance.9,10
There is also some evidence to suggest that caffeine may improve memory deficits observed in PD.11 In a rat model of PD-induced amnesia, (rats undergoing intra-nigral MPTP administration), animals pretreated with caffeine had significantly higher avoidance scores. This effect was independent of locomotor ability. However, caffeine’s ability to improve memory and learning in this model was limited, in that the caffeine-MPTP treated animals scores never reached those of control animals.
In a murine MPTP model, caffeine pretreatment (5-20 mg/kg, 10 minutes before each MPTP injection) was able to decrease dopamine depletion (surrogate marker of striatal function) to 40% of that observed with controls.12 In addition loss of DAT binding sites (marker of dopaminergic function) was attenuated even after one week following caffeine administration. In this model doses of 5-20 mg/kg were safe and effective in preventing MPTP induced neurotoxicity, however higher doses were toxic and often lethal. Caffeine’s protective effects could be mimicked by specific A2A antagonism (KW-6002) and by genetic inactivation (A2A knockout mice) of the A2 receptor. Recently, the role of A2A receptors in PD neuroprotection has been reaffirmed, by the observation that KW-6002, an A2A receptor antagonist, prevents DA neuronal loss in both 6-OHDA and MPTP treated rodents.13 These findings support the fact that caffeine’s neuroprotective effects are mediated by its actions on the A2A receptor. / 1. Psychopharmacology 1988;94:38-45.
2. Neuropharmacology 1989;28:407-409.
3. J Pharmacology Exp Ther 1995;274;207-14.
4. Neuroscience. 1992;51;501-12.
5. J Pharmacol Exp Ther. 1991;256:62-68.
6. Acta Physiol Scand. 1982;283-286.
7. J Pharmacol Exp Ther. 1993;266:1563-72.
8. Eur J Pharmacol. 1982;79:125-8.
9. European Neuropsychopharmacology. 1999;9:515-521.
10. Eur J Pharmacol. 2000;396:93-9.
11. Brain Res Bull. 2001;55:101-6.
12. J Neurosci. 2001; 21:RC143.
13. J Neurochem. 2002;262-70.
PHARMACOKINETICS
(INCLUDING BBB PENETRATION) / In healthy patients
clearance= 1.5 ml/kg/min, half life= 4.8 hours
elimination slows with hepatic disease. In rat microdiaysis studies a 30 mg/dose results in a free brain caffeine concentration of 120 µM.1 This suggests adequate CNS penetration. / 1. Life Sci. 1991;49:1843-52.
SAFETY/TOLERABILTY IN HUMANS / Well tolerated in common doses, may cause dose-related agitation, jitteriness insomnia or blood pressure, heart rate increases
DRUG INTERACTION POTENTIAL / Caffeine is not highly protein bound, however it is metabolized by CYP1A2 and is prone to hepatic enyzme inducing/inhibiting medications (including fluoxamine, clozapine, theophylline).1 / 1. Clin Pharmacokinet.
2000;39:127-53.
AVAILABILE DOSAGE FORMS / Caffeine is found ubiquitously in the diet. There is 137 mg/cup of coffee, 47 mg/cup of tea, 46 mg/can of cola soda, and 7 mg per serving of chocolate candy.
RECOMMENDED RESEARCH PHASE IN PD / Phase II
Information needed / Dosing and Safety/ Tolerability in PD
CLINICAL TRIAL/EPIDEMIOLOGICAL EVIDENCE IN HUMAN PD
Included below are the larger studies evaluating caffeine and the risk of PD. The available studies evaluating caffeine and PD prevention are overall positive, however they are limited, in that they are primarily retrospection/case-control in nature, or they do not assess caffeine intake in a well controlled manner. Typically, caffeine or coffee intake is assessed as a categorical variable (1-2 cups/day of coffee), hence there is also no definite dose or dose-range that has been evaluated.
Benedetti and colleagues reviewed medical records from the Rochester Epidemiology Project from 1976-1995 to identify patients who had developed PD (n=196).1 Incident cases were matched with respect to age and sex to a general control population in an attempt to identify risk factors (smoking/other tobacco use, coffee consumption or alcohol intake) associated for the development or prevention of PD. Of the PD cases 62% were men and 38% were women with median age of PD onset of 71 years (41-97). Coffee consumption was significantly more common in control subjects than in PD cases (OR =0.35, 95% CI= 0.16-0.78). There was also a significant trend of decreasing risk with the number of cups of coffee consumed (1-3 cups OR=0.56, ≥ 4, OR=0.18). Coffee’s effects remained significant even after covariates were considered. Coffee was also associated with a significant delay in the onset of PD (median onset PD no coffee 72 (42-97) years, with coffee consumption 64 (41-80) years, p=0.0002). Among other variables considered, cigarette smoking was less common in PD cases than control subjects however, statistical significance was not reached (OR=0.69, 95% CI=0.45-1.08). Cigarette smoking was not associated with a later onset of PD in those who did and did not smoke. The incidence of pipe and cigar smoking was also comparable in case and control patients. In contrast, tobacco chewing or snuff use was significantly more common in control subjects than in PD cases (OR=0.18, 95% CI=0.04-0.82). In regards to alcohol use, control subjects were also more likely to be diagnosed with alcoholism than PD cases (OR=0.41, 95% CI= 0.19-0.89).
The association of caffeine, particularly coffee intake and PD was also evaluated as of a part of a 30-year follow-up study of 8004 Japanese American men (45-68 years) participating in the Honolulu Heart Program.2 Data were collected through records obtained through hospital records and death certificates (retrospective) and prospectively through office visits occurring after 1991. Caffeine intake was assessed through dietary notes obtained at visits. As part of the study, subjects were asked about their dietary consumption of caffeinated products within the previous 24-hour diary period. This value was extrapolated to the entire week. Information regarding smoking history was also assessed and used as a covariant in the analysis. Median age at enrollment was 53 years (45-68) with a median follow-up of 27 years (0.8-30). Among all the patients 102, (1.3%) developed PD with onset occurring at a median age of 73.6 years (54-89 years). The median time between baseline examination and PD diagnosis was 16.6 years (2-30 years). Those who consumed caffeine had a significantly lower incidence of PD than those who did not (p <0.001). For example, the adjusted incidence of PD decreased from 10.4:10,000 person-years in those who did not consume coffee to 1.9:10,000 person years for those who consumed at least 28 ounces/day. This effect was dose-related with increased caffeine consumption inversely correlated with the risk of developing PD (p<0.01). Caffeine’s statistical associations were consistent in smokers and nonsmokers and when data were analyzed for coffee and non-coffee intake caffeine sources.
Ascherio and colleagues evaluated the incidence of PD in 47,351 men and 88,565 women who were involved health care professionals. Subjects were followed prospectively through a series of life style questionnaires containing among other things the quantity of caffeine-containing products consumed and development of PD. Questionnaires were administered at baseline and every 2-4 years and any self-report of PD or PD-like symptoms was evaluated by a physician to confirm the diagnosis of PD. Median follow-up in the study was 10 years in men and 16 years in women. In this time, 157 (0.3%) men and 131 (0.1%) women developed PD. After adjusting for age and smoking, there was a significant inverse relationship in coffee intake and the development of PD (p<0.004). The relative risk (95% CI) compared to coffee nonconsumers was <1 cup/day-0.8 (0.5-1.2), 1-3 cups/day-0.6 (0.4-0.9), 4-5 cups/day 0.5 (0.2-1.2) and 0.6 (0.2-2.6). In women a U-shaped relationship between coffee intake and the development of PD was found. The lowest incidence for the development of PD in women was in the 1-3 cups/day of coffee group. The relative risk (95% CI) compared to coffee nonconsumers in women was <1 cup/day-1.1 (0.6-2.2), 1-3 cups/day-0.6 (0.4-0.9), 4-5 cups/day 1 (0.6-1.7) and 0.6 (0.5-2.2). Among both groups when the total amount of daily caffeine was estimated and results were reanalyzed results remained similar to that observed when only coffee was considered. (Note that association between a decreased risk of PD and decaffeinated coffee was not observed). Interestingly, in this study any association between caffeine and PD risk was less apparent in women.
1. Neurology 2000;55:1350-7.
2. JAMA 2000;283:2674-9.
3. Ann Neurol. 2001;50:56-63.
DRUG NAME: Amantadine MANUFACTURER:
Reviewer: Dr. C Adler last revised 5/2/02
AVAILABILITY / CITATIONSCIENTIFIC RATIONALE / Uncompetitive, low affinity, NMDA receptor antagonist
Antagonizes the effects of pathologic glutamate concentrations, not physiologic- therefore fewer AEs than with MK801 / Kornhuber, Eur J Pharmac Molec Pharmac Sect 1991;206:297-300
Chen, J Neurosci 1992; 12:4427-4436
ANIMAL MODEL DATA / RODENT: Gerbils received 40 mg/kg MPTP for 4 days. On the fifth day, animals were treated with 15 mg/kg of either deprenyl, amantadine or the combination and were sacrificed either 1,2, or 5 hours later. Brain concentrations of serotonin and dopamine metabolites were analyzed using HPLC. Whereas animals who received only MPTP experienced a 25-31% reduction in both dopaminergic and serotonergic metabolites, both deprenyl and amantadine caused accumulation of DA and 5-HT. There was some evidence of synergy of the two compounds.
PRIMATE: only studied for symptomatic effects
OTHER: / Rausch, J Neural Trans. Suppl 1990; 32: 269-75
(abstract only reviewed)
PHARMACOKINETICS
(INCLUDING BBB PENETRATION) / Amantadine transverses the BBB after oral administration. In a study of post-mortem brain tissue from 21 patients who had received amantadine, brain concentrations were found to range from 48.2 – 386 mcM whereas CSF concentrations were much lower (<17 mcM). This suggests an accumulation in the tissue.
The drug is well absorbed after oral administration, and is primarily eliminated renally. It has a plasma t ½ of 16 hours in patients with normal renal function. In older individuals, the t ½ can increase to 45 h. The dose must be adjusted in renal dysfunction. / Kornhuber, Neuropharmacol 1995;34:713-721
Aoki, Clin Pharmacokin 1988;14:35-51
SAFETY/TOLERABILTY IN HUMANS / Amantadine is well-tolerated in patients with PD and has been used for over 30 years. The most frequent adverse effects reported are (5-10% of patients) nausea, dizziness and insomnia. Amantadine can also cause anticholinergic side effects such as dry mouth, urinary retention and blurred vision, and confusion. Orthostasis and peripheral edema can also occur. Livedo reticularis is a common side effect and occurs more in men than in women / MD consult, 2002
DRUG INTERACTION POTENTIAL / No known pharmacokinetic drug interactions of clinical importance
May have synergistic effect with deprenyl / Aoki, Clin Pharmacokin 1988;14:35-51
CLINICAL TRIAL/EPIDEMIOLOGICAL EVIDENCE IN HUMAN PD / Amatadine has short term symptomatic benefits in PD. It is commonly used at doses of 200mg to 300mg day divided b.i.d or t.i.d respectively. Withdrawl symptoms are common
Survival was studied in 836 PD patients who had been treated by a single center over a 23 year period. Five independent predictors of improved survival were identified by multivariate analysis: high 10 y survival, amantadine use, absence of dementia, PD vs other causes of parkinsonism and low H&Y at presentation. The mean duration of tx with amantadine was 37 months. The improved survival may be due to symptomatic effects (the difference was about 4 months) but may be evidence of neuroprotection. / Timberlake. Ann Neuro 1978; 3: 119-128.
Uitti RJ, Neurology 1996; 46: 1551-1556
AVAILABLE DOSAGE FORMS / 100 mg tablets; 100 mg capsules; 50 mg/5 mL syrup
RECOMMENDED RESEARCH PHASE IN PD / III
DRUG NAME: Co-Q 10 MANUFACTURER: Various
Reviewer: Dr. C. Shults last revised 10/02
AVAILABILITY / CITATIONSCIENTIFIC RATIONALE / Complex 1 mitochondrial activity is reduced in Substantia Nigra in post-mortem studies in PD and in the platelets of early, untreated PD patients
Complex 1 is susceptible to oxidative damage.
CoQ 10 is an essential component of Complex 1 and II in humans. It serves as an electron acceptor and anitoxidant that can potentially limit oxidative damage to complex I
CoQ 10 levels were reduced in platelet mitochondria in early untreated PD patients. / Schapira, J Neurochem 1990; 54:823-827
Haas et al. Ann Neurol. 1995;37:714-722
Jha, J Biol Chem 2000;275:26096-26101
Schulz, Exp Neurol 1995; 132: 279-283
Shults et al. Ann Neurol. 1997;42:261-264.
ANIMAL MODEL DATA / RODENT:
Mice: chronic intoxication with MPTP with 400 mg/kg CoQ x 10 days before MPTP tx. CoQ + nicotinamide completely prevented DA depletion (not CoQ alone)
Aged Mice: CoQ10 (oral) 200 mg/kg/day x 5 wks attenuated the decrease in striatal DA concentrations caused by MPTP
PRIMATE: None
OTHER: / Schulz, Exp Neurol 1995; 132: 279-283
Beal, Brain Res 1998;783:109-114
PHARMACOKINETICS
(INCLUDING BBB PENETRATION) / In animals, oral administration resulted in a significant effect on striatal DA, and therefore likely crosses the BBB.
Oral supplemental with CoQ increased brain mitochondrial levels / Schulz, Exp Neurol 1995; 132: 279-283
Matthews et al. PNAS 1998;95:8892-8897.
SAFETY/TOLERABILTY IN HUMANS / In an open label, pilot study of 10 PD patients, CoQ 10 at 200 mg/day for 3 months was admin. There were no changes in UPDRS and no side effects were reported.
15 PD patients were given one of 3 oral doses of Co Q10 in a Vit E vehicle (400, 600 or 800 mg/day) x one month. All doses were associated with significantly increased CoQ10 levels in plasma and there were no side effects and it was well tolerated. At 800 mg/day, there were increased casts in urine in 2/5 patients. No change in UPDRS, but patients were on PD meds. / Strijks, Molec Aspects Med, 1997;18(suppl): S237-S240
Shults, Neurology 1998; 50:793-795
DRUG INTERACTION POTENTIAL / Patients in the Shults ’98 study (above) were all receiving PD meds, no interactions were detected.
CLINICAL TRIAL/EPIDEMIOLOGICAL EVIDENCE IN HUMAN PD / In The CARE HD trial, patients with HD tolerated 600mg/day of CoQ-10 well and showed a trend in functional improvement that was not statistically significant
QE2 study: 80 de novo PD subjects on placebo, 300, 600, 1200mg day of CoQ followed until need for sympt therapy, up to 16 months. UPDRS change was primary outcome measure. Test for linear trend between groups on UPDRS( primary analysis) negative but difference in rate of change between 1200mg group (7pts) and placebo (12pts) significant / HSG, Neurology 2001 57: 397-404
Shults, Arch Neurol. 2002 Oct;59(10):1541-1550.
AVAILABLE DOSAGE FORMS / Various
RECOMMENDED RESEARCH PHASE IN PD / II-III
Information needed / Further dose finding
Preliminary efficacy/lack futility
DRUG NAME: NIL – A (GPI 1485) MANUFACTURER: Guilford
Reviewer: Dr. L. Sudarsky last modified 5/7/02