Ranbaxy Ex. 1011
`IPR Petition - USP 9,050,302
`
`

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`286
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`M. MAMELAK ETAL.
`
`in one
`shortening the REM sleep latency and prolonging the first REM sleep period.
`subject, REM sleep occurred at sleep onset; in the morning the subject reported being
`unable to move for a short period before falling asleep. GHB had induced sleep paralysis.
`This finding led Broughton and Mamelak to examine the effects of GHB in narcoleptics
`(7). It was postulated that narcolepsy stemmed from a failure to consolidate sleep at night
`and that GHB given repeatedly during the night would help reintegrate sleep because of
`its unique facilitating actions on both NREM and REM sleep. It was hoped that this would
`alleviate the diurnal symptoms of the disease and, in the first trial of the compound, such
`alleviation occurred. More extensive clinical and sleep laboratory trials have since confirmed
`this observation.
`
`CLINICAL AND SLEEP LABORATORY FINDINGS
`
`This article summarizes the published clinical and sleep laboratory data on the use of
`GHB in narcolepsy and presents new clinical data on 48 patients who have been treated
`with GHB for as long as 9 years. In all the studies reviewed here. the diagnosis of narcolepsy
`was established on the basis of a medical history of daytime sleepiness and cataplexy and
`was confirmed by sleep laboratory data which demonstrated a sleep onset REM period at
`night or during at least one sleep latency test during the day. The patients in these studies
`all received --2.'25~3 g of GHB two or three times during the night. In all, they received
`S—7 g of GHB every night. Broughton and Mamelak have reported two trials of GHB, the
`first a preliminary trial on four patients (7), and the second a more elaborate trial in which
`Continuous 48-h recordings were made on l4 narcoleptic patients before and after 7-10
`days of treatment with GHB (8,9). In these trials, patients were off all medication for at
`least 2 weeks before starting GHB. Scharf et al. (10) recently reported on the effects of
`GHB on 30 narcoleptic patients. These investigators conducted sleep laboratory studies on
`their patients before and after 4 Weeks of treatment with this agent. During this interval.
`the patients who were using tricyclics were withdrawn from these drugs. Overall stimulant
`consumption in this patient group was also reduced. Twelve of the patients were again
`studied in the laboratory after 6 months.
`
`Clinical findings
`All studies agree that over the first few nights of treatment, GHB virtually eliminates
`nightmares and hallucinations. Sleep paralysis may be intensified on the first or second
`night but then disappears also. Dreaming persists, but loses its frightening quality. In the
`morning, most patients report having slept sounder and feeling more rested. Daytime attacks
`of sleep and cataplexy are slower to disappear, but nevertheless are significantly reduced
`in number after 1 week of treatment (10). Residual attacks of cataplexy are milder, shorter
`in duration. and easier to control, tending to occur late in the day when the patient is tired.
`The most refractory symptoms are daytime drowsiness and the need for sleep. Even with
`stimulants, these symptoms are not fully alleviated in some cases. Nevertheless, it is im-
`portant to emphasize that in spite of the sleep latency data to be reviewed below, GHB
`does effect an improvement in daytime alertness. For example, Montplaisir and Barbe-
`zieux (1 1) treated five nonapneic patients who had excessive daytime drowsiness with
`GHB. None of their patients were given stimulants. Within weeks, all patients reported
`feeling more alert during the day. However. GHB must be used in repeated doses during
`The night. and symptoms usually recur the following day when treatment is stopped 01'
`when only one dose is used.
`
`Sleep. Vol. 9, No. 1, I986
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`NARCOLEPS1’ AND GHB
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`2'87
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`Sleep laboratory findings
`The most constant effect observed in patients after GHB is administered is an increase
`in SW8 and a decrease in the REM sleep latency. GHB characteristically induces a sleep-
`onset REM period followed by a period of SWS, after which the patient often spontaneously
`awakcs. This sequence takes -2 to 3 h. Decreased REM latency is a persistent effect of
`the drug and may be observed even after 6 months of treatment ([0). Total nocturna_l REM
`sleep duration may be increased but usually is unchanged. The number of REM sleep
`periods is unchanged, but the REM density is decreased. Total sleep time at night may be
`increased or unchanged. Patients develop no tolerance to the hypnotic actions of GHB over
`a 6-month period. GHB improves sleep continuity at night and significantly decreases the
`duration of REM sleep and SWS during the day. Daytime sleep periods > 45 min in
`duration decrease in frequency, but drowsy stage 1 sleep may even be increased in duration
`(9). No change occurs in the average sleep latency during the day after 4 weeks or even
`after 6 months on GHB (10). REM latency during the day. however,
`is significantly de
`creased. It should be noted that the sleep and REM latency tests during the day were
`conducted with some patients taking stimulants. Although the average sleep latency did
`not change, patients required less stimulant medication when taking GHB.
`
`LONG-TERM USE OF GHB
`
`The cases of 48 patients who have been taking GHB for 6 months to 9 years are now
`being followed in Toronto. The cases of other patients who were started on this treatment
`in Toronto are being followed by their physicians in other parts of Canada and the United
`States. These patients, 21 men and 27 women, range in age from 17 to 71 years. All combine
`stimulants during the day with GHB at night. The commonest schedule is GHB about 30
`mg/kg or 2.25—3 g twice each night and a single long—acting I5 mg dexedrine dospan in
`the morning. Patients are encouraged to nap late in the afternoon when the dexedrine is
`wearing off to produce a more alert evening, but many do not do so regularly. The use of
`GHB in this patient series ranges from 4.5 to 9 gfnight. The use of dexedrine ranges from
`10 to 30 mg daily. Some patients prefer methylphenidate, but none uses more than 30 mg
`daily. As part of their treatment regimen, patients are advised to refrain from heavy meals
`and excessive quantities of carbohydrate—rich foods. Once the treatment regimen has been
`adjusted to achieve optimal levels of sleep at night and wakefulness during the day, little
`change is required. The development of drug tolerance has not been observed.
`Thirty—six patients, 13 men and 23 women, are virtually sytnptom—fnee. They are able
`to function satisfactorily at work or school and are not embarrassed by their illness. The
`remainder are symptomatic to varying degrees. As in the earlier studies, daytime drowsiness
`and the need for sleep are the most common residual symptoms. Cataplexy is rarely a
`serious concern. Poor nocturnal sleep of patients who are taking GHB appears to he one
`factor that predicts a poor response. Patients who relate the development of their illness to
`irregular work hours or to a head injury also tend to respond less well. This largely accounts
`for the disparity in the response observed between the men and women. Nevertheless, it
`should he noted that some patients who have had these predisposing factors have responded
`well. Cataplexy can be difficult to control in patients who have been withdrawn from high
`doses of tricyclics. At present only 1 patient remains on 10 mg chlorimjpramine daily after
`nearly 3 years on GHB. Symptoms can intensify in all patients, even those who have
`responded well, during periods of stress. Similarly, drowsiness can prevail during long
`periods of monotonous activity.
`
`Sleep, Vol. 9, Na. 1. F956
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`288
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`M. MAMELAK ET AL.
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`Few adverse effects have been observed. All patients have been followed with serial
`liver, renal and blood studies, periodic chest x—rays. and electrocardiograms‘, no abnor-
`malities have been noted. On the first few nights of treatment with GHB, two patients had
`enuresis. Scharf et al. (10) reported one such incident in their series. Patients who resist
`the sleep-inducing properties of the drug may become confused and emotionally labile.
`When treatment with GHB is first started, patients may experience sleep paralysis or
`discover that they are cataplectic if they try to walk after taking this agent. Price et al.
`([2) reported cataplexy and confusion in narcoleptic patients given GHB intravenously
`during the day. Nevertheless, three patients in the Toronto series have reported intermittent
`sleepwalking while on GHB. This is a more persistent adverse effect which may appear
`after a period of treatment with GHB. It has been satisfactorily controlled with 5-10 mg
`of methtritneprazine at bedtime. Weight loss has been an unexpected benefit for a number
`of obese patients. GHB is also being used without adverse effects in one narcoleptic patient
`with central sleep apnea (13).
`Five patients have discontinued treatment with GHB. One did so because he found the
`treatment regimen inconvenient. A young woman planned to become pregnant and feared
`the potential teratogenic effects of GHB. The other 3 patients did not feel that they were
`being helped.
`
`Mechanism of action
`
`The effectiveness of GHB can be attributed to its capacity to induce the major symptoms
`of narcolepsy, that is, sleep and the motor inhibitory phenomena associated with REM
`sleep, and to contain them at night. Thus, the reliable induction of REM and NREM sleep
`at night, coupled with the prevention of daytime sleep by stimulants, gradually recruits and
`consolidates sleep at night, and eliminates it during the day. Sleep paralysis and nocturnal
`hallucinations disappear with this recruitment. The treatment. however,
`is palliative. Short-
`latency nocturnal REM sleep periods and daytime REM sleep betray the persistent dis-
`sociation of sleep.
`Could an abnormality in endogenous GHB metabolism be a factor in the development
`of narcolepsy? Early REM sleep periods occur with some consistency in two conditions,
`narcolepsy and depression. In both of these conditions, the early REM sleep periods are
`thought to reflect a metabolic shift towards increased cholinergic and decreased catecho-
`laminergic neurotransmission (14). In narcoleptic dogs, for example, increased numbers of
`muscarinic cholinergic receptors have been described in the pontine region (15). Dopamine
`utilization is decreased in the brains of these animals, although dopamine levels are increased
`(16). GHB produces a comparable metabolic shift. It increases brain dopamine levels but
`inhibits dopamine release (17), and it enhances acetylcholine release, at least in the striatal
`region where this has been measured (18). GI-IB can induce early REM sleep periods in
`cats (4), but it does not do so reliably in humans except in depression and narcolepsy. The
`nervous system in these conditions appears particularly sensitive to the actions of GHB
`which, in such states, can provoke not only sleep onset REM periods, but dissociated
`episodes of motor inhibition in the form of sleep paralysis and cataplexy. GHB receptors
`are found in highest concentrations in nerve ending fractions rich in acetylcholine (2), a
`neurotransmitter closely implicated in the induction of REM sleep (14). It would be in-
`teresting to know if there are any changes in the sensitivity of these receptors in narcolepsy.
`
`1. Snead OC, Morley BJ. Ontogeny of gammahydroxybutyric acid. 1. Regional concentration in developing
`rat, monkey and human brain. Brain Res 1981;227:579-89.
`
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`Sleep, Vol. 9. No. I. 3986
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`NARCOLEPSY AND GHB
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`Sleep. Vol‘. 9, No. I. 1936