Treatment of periodic limb movement syndrome

The present invention is directed to a method for treating patients afflicted with periodic limb movement syndrome (PLMS) which includes administering to said patient prior to sleep a combination of: carbidopa and levodopa in 25 and 100 mg quantities, respectively, and carbidopa and levodopa in 25 and 200 mg quantities, respectively, in sustained release form. The sustained-release carbidopa and levodopa preferably is supplied in a tablet contained 50 mg of carbidopa and 200 mg of levodopa. Caffeine may be administered to the patients following sleep.

CROSS-REFERENCE TO RELATED APPLICATIONS 
None 
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 
Not applicable. 
BACKGROUND OF THE INVENTION 
Restless Legs Syndrome (RLS) is best described as irresistible leg 
movements often accompanied by a creeping sensation deep in the limbs. Its 
is reported to be the fourth leading cause of insomnia after psychiatric 
disorders, drug abuse, and sleep apneas. Brodeur, et al., "Treatment of 
restless legs syndrome and periodic movements during sleep with L-dopa: A 
double-blind, controlled study", Neurology, 38, 1845 (December 1988). 
Bedtime is a major problem for these patients since rest, particularly 
lying down in bed, is associated with increased dysesthesia and 
irresistible leg movements, which interfere with sleep onset. Most 
frequently, the patients move their legs vigorously, flexing, stretching, 
and crossing them one over the other. The intensity of muscular jerks can 
vary greatly from one case to another. Often, patients have to get out of 
bed several times a night. 
Nearly all patients with RLS also experience stereotyped, repetitive 
movements once asleep, a condition known as periodic movements during 
sleep or periodic limb movement syndrome (PLMS). Periodic movements during 
sleep represent a distinct nosological entity from RLS. Independent PLMS 
occurs along with a wide range of sleep-wake complaints, including early 
sleep onset difficulty, nocturnal awakenings, and daytime sleepiness. See 
Kryger, et al., "Principles and Practice of Sleep Medicine", 1989, 
Saunders Company, Chapter 43; Culpepper, et al., "Time of Night Patterns 
in PLMS Activity", Sleep, 15(4):306-311; .Shahal, et al., "Cyclic Leg EMG 
Activity During NREM-REM Sleep in Patients with Period Leg Movements in 
Sleep", Sleep Research???; Valencia, et al., "Incidence of Sleep Apnea and 
Nocturnal Myoclonus Among Elderly Females in a Mexican Population", Sleep 
Research, 1990, 19:303; Becker, et al., "Reliability of Bedpartner's 
Reports for Symptoms of Sleep Apnea and Periodic Leg Movements", Sleep 
Research, 1990:19:188; Sandyk, et al., "Serotonin in Involuntary Movement 
Disorders", Int. J. Neuroscience, 1988; 42-43; Kotagal, et al., 
"Relationship of EEG Changes to Periodic Leg Movements", Sleep Research, 
1990; 19:244; Shafor, et al., "Lumbo-Sacral Spine Abnormalities and 
Periodic Leg Movements in Sleep", Sleep Research, 1990:19:292; Shahal, et 
al., "Cyclic Leg EMG Activity During NREM-REM Sleep", Sleep Research, 
1990:19:130 
Treatment of RLS and PLMS has varied and includes clonazepam and other 
benzodiazepines, propoxyphene and other opiates, and L-dopa and other 
dopoaminergic drugs, for example. See Montplaisir, et al., "The Treatment 
of Restless Leg Syndrome With or without Periodic Leg Movements in Sleep", 
Sleep, 15(5):391-395 (1992) and Kryger, et al., supra; Bonnet, et al., 
"The Use of Triazolam in Older Patients With Periodic Leg Movements, 
Fragmented Sleep, and Daytime Sleepiness", Journal of Gerontology: Medical 
Sciences, 1990, Vol. 45, No. 4, M139-144; Scrima, et al., 
"Gamma-Hydroxybutyrate Effect on Nocturnal Myoclonus: A Double-Blind 
Study", Sleep Research, 1990; 19:289; Bamford, et al., "Letter Failure of 
Clonidine to Ameliorate the Symptoms of Restless Legs Syndrome", Sleep, 
10(4):398-399 (1987); Guilleminault, et al., "Periodic leg movement, sleep 
fragmentation and central sleep apnea in two cases: reduction with 
Clonazepam", Dur. Respir. J., 1988, 1, 762-765. Further on the use of 
L-dopa can be found in the following publications: Brodeur, et al., supra; 
Guilleminault, et al., "Periodic Leg Movement, L-Dopa, 
5-Hydroxytryptophan, and L-Tryptophan", Sleep, 10(4):393-397 (1987). 
While L-dopa has been used somewhat successfully in the treatment of PLMS, 
often-repeated dosages over the course of the night are required. Dosages 
effective in the treatment of PLMS also can lead to daytime drowsiness in 
some patients. The sustained-release form of carbidopa-levodopa was 
thought to be the answer to repeated nighttime dosages; however, this has 
not been borne out in clinical studies. Thus, a new regimen is needed in 
order to deal effectively with patients afflicted with PLMS. 
BRIEF SUMMARY OF THE INVENTION 
The present invention is directed to a method for treating patients 
afflicted with periodic limb movement syndrome (PLMS) which includes 
administering to said patient prior to sleep a combination of: carbidopa 
and levodopa in 25 and 100 mg quantities, respectively, and carbidopa and 
levodopa in 25 and 100 mg quantities, respectively, in sustained release 
form. The sustained-release carbidopa and levodopa preferably is supplied 
in a tablet contained 50 mg of carbidopa and 200 mg of levodopa. Caffeine 
may be administered to patients following sleep as it has been observed 
clinically that caffeine can serve to mitigate some of the spillover 
effects of carbidopa and levodopa. 
DETAILED DESCRIPTION OF THE INVENTION 
Sinemet.RTM. CR (Merck & Co., Inc.) is a sustained-release tablet 
containing a 1:4 weight ratio of carbidopa and levodopa (Sinemet.RTM. CR 
50-200 contains 50 mg of carbidopa and 200 mg of levodopa; Sinemet.RTM. CR 
25-100 contains 25 mg of carbidopa and 100 mg of levodopa). Other 
ingredients in Sinemet.RTM. CR 50-200 are D&C Yellow 10, magnesium 
stearate, iron oxide, and a drug delivery system that controls the release 
of carbidopa and levodopa as it slowly erodes (about 4-6 hours). 
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a 
white, crystalline compound, slightly soluble in water, with a molecular 
weight of 244.3. It is designated chemically as 
(-)-L-.alpha.-hydrazino-.alpha.-methyl-.beta.-(3,4-dihydroxybenzene) 
propanoic acid monohydrate. Its empirical formula is Co.sub.10 H.sub.14 
N.sub.2 O.sub.4 .multidot.H.sub.2 0. Levodopa, an aromatic amino acid, is 
a white, crystalline compound, slightly soluble in water, with a molecular 
weight of 197.2. It is designated chemically as 
(-)-L-.beta.-amino-.beta.-(3,4-dihydroxybenzene) propanoic acid. Its 
empirical formula is C.sub.9 H.sub.11 NO.sub.4. The non-sustained-released 
form of Sinemet.RTM. (often called the "fast acting" form) is supplied in 
three strengths: 25-100, 10-100, 25-250, carbidopa-levodopa, respectively 
(mg). Its inert ingredients are reported to include cellulose, magnesium 
stearate, and starch. Colorants also are added to the tablets in order to 
be able to distinguish between the three strengths of the drug. 
Heretofore, this drug combination is prescribed to relieve symptoms of 
Parkinson's disease. 
Use of standard (fast-acting) carbidopa-levodopa to treat PLMS does 
moderate PLMS in patients that are administered the drug combination prior 
to sleep. However, studies have revealed that multiple doses over the 
course of the night often are needed in order for the drug's affect to be 
sustained. The sustained-release form of carbidopa-levodopa was thought to 
alleviate the need for subsequent night administrations; however, the 
drug's effectiveness still leaves a lot to be desired. 
Unexpectedly, it has been discovered that a combination of 
carbidopa-levodopa and sustained-released carbidopa-levodopa dramatically 
improves the drug's effectiveness in treating PLMS while obviating the 
need for subsequent doses of the drug during the night. The reason for 
such improvement in the drug's effectiveness is not totally understood. 
Yet, when a simple combination of the drugs is administered, say 
carbidopa-levodopa (25 mg-100 mg, respectively) and sustained-release 
carbidopa-levodopa (25 mg-100 mg, respectively), dramatic improvements in 
PLMS is seen. As the data will demonstrate, the novel dosage regimen of 
carbidopa-levodopa resulted in an almost three-fold improvement in PLMS 
compared to conventional carbidopa-levodopa and a two and one-quarter-fold 
improvement in PLMS compared to sustained-release carbidopa-levodopa. 
There are spillover effects from the administration of carbidopa and 
levodopa in the treatment of RLS/PLMS. It has been observed clinically 
that caffeine may be administered in small doses (e.g., 50-100 mg) to 
patients following sleep to mitigate some of the spill over effects of 
carbidopa and levodopa. 
The following example shows how the present invention has been practiced. 
It should not be construed as limiting the present invention. In this 
application, all citations are expressly incorporated herein be reference.

EXAMPLE 
A study of the effect of three different techniques for using 
carbidopa-levodopa combination (Sinemet.RTM. tablets) to reduce PLMS was 
undertaken. Detailed scoring of two consecutive night polysomnaographic 
sleep studies were employed for each patient. The patient received no 
medication for the first night and one of the three different drug 
regimens for the second night. The OSMI Standard Method of scoring the 
"Total Number of Movements" from continuous polysomnographic records of a 
full night's sleep was employed to evaluate the drug regimens evaluated. 
This method is based on Richard Coleman's "Periodic Movements in Sleep 
(Nocturnal Myoclonus) and Restless Leg Syndrome" published in Sleep and 
Waking Disorders: Indications and Techniques, C. Guilleminault, Editor, 
Butterworths Publishing Co., Boston, Mass., pp. 265-295 (1982), the 
disclosure of which is expressly incorporated herein by reference. The 
criteria in the OSMI Method are: 
1. The person must be asleep. 
2. A movement is scored when it occurs as part of a series of 4 consecutive 
movements that are separated by at least 4, but not more than, 90 seconds. 
In most instances, however, the movements should be separated by about 
20-40 seconds. 
3. The duration of the movements should be between 0.5 and 5 seconds. 
4. The amplitude of the movements should be at east one-half the pen 
deflection of the leg EMG recorded in the pre-sleep testing period 
(patient calibration). 
5. Scoring for the total number of movements--Isolated (i.e., 
non-successive) movements are not counted. Movements occurring 
synchronously in both legs (with 4 seconds) are counted as one movement). 
The three groups of patients were drawn from historical OSMI recordings of 
patients that had: 
1. polysomnaographic sleep studies recorded for two successive nights. 
2. been given Sinemet.RTM. the second night and had not been given other 
medications or used a C-PAP machine. 
The 3 groups of patients received the following drug regimen (Night 2): 
Group A: 7 patients who received standard Sinemet.RTM. 25-100. 
Group B: 6 patients who received sustained-release Sinemet.RTM. 50-200. 
Group C: 6 patients who received a combination of Sinemet.RTM. 25-100 and 
one-half dose of sustained-release Sinemet.RTM. 50-200. 
The following data were recorded: 
TABLE 1 
______________________________________ 
Number of Periodic Limb Movements 
______________________________________ 
Group A FAST ACTING Group 
Patient No. 
A1 A2 A3 A4 A5 A6 A7 Average 
______________________________________ 
Night 1 34 43 80 110 154 197 211 118.4 
Night 2 43 24 59 100 82 121 184 87.6 
Absolute 
-9 19 21 10 72 76 27 30.9 
Change 
% Change 
26.5 -44.2 -26.3 
-9.1 -46.8 
-38.6 
-12.8 
-26.1 
______________________________________ 
Group B SUSTAINED RELEASE Group 
Patient No. 
B1 B2 B3 B4 B5 B6 Average 
______________________________________ 
Night 1 221 153 230 31 320 396 225.2 
Night 2 77 81 112 0 206 408 147.3 
Absolute 
144 72 118 31 114 -12 77.8 
Change 
% Change 
-65.2 -47.1 51.3 -100.0 
-35.6 
3.0 -34.6 
______________________________________ 
Group C INVENTIVE FORMULATION Group 
Patient No. 
C1 C2 C3 C4 C5 C6 Average 
______________________________________ 
Night 1 23 46 103 137 208 287 134.0 
Night 2 17 0 13 52 46 51 29.8 
Absolute 
6 46 90 85 162 236 104.2 
Change 
% Change 
-26.1 -100.0 -87.4 
-62.0 -77.9 
-82.2 -77.7 
______________________________________ 
In summary, the fast-acting Sinemet.RTM. test group revealed a 26.1% 
decrease in PLMS; the sustained-release Sinemet.RTM. test group revealed a 
34.6% decrease in PLMS; and the inventive test group revealed a 77.7% 
decrease in PLMS. Thus, the inventive method was about 3 times more 
effective than standard Sinemet.RTM. and more than twice as effective as 
sustained-release Sinemet.RTM.. This data amply demonstrates the efficacy 
of the present invention and the unexpected results achieved by the 
present invention.