Use of adenosine, adenosine analogs or nucleoside uptake blockers, e.g. dipyridamole, as drug treatments for obstructive sleep apnea and snoring

Infusion of adenosine, adenoside analogs and nucleoside uptake blockers, e.g. dipyridamole, will decrease the number of apneas and associated oxyhemoglobin desaturation during sleep in patients with obstructuve sleep apnea.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention generally relates to the medical treatment of obstructive 
sleep apnea and its associated symptom of snoring, and specifically to the 
use of adenosine, adenosine analogs, or nucleoside uptake blockers, e.g. 
dipyridamole as drug treatments for obstructive sleep apnea and snoring. 
2. Prior Art 
Obstructive sleep apnea is a common disorder which has no effective drug 
treatment. Since sleep apnea may be due in part to decreased ventilatory 
drive, ventilatory stimulants may provide effective treatment and decrease 
the number of apneas during sleep in patents with sleep apnea. 
In the past, protriptyline, medroxyprogesterone, almitrine and doxapram 
were studied for their effects on sleep apnea. Protriptyline had slight 
effect on reducing apnea/hypopnea frequency and arousal frequency. 
However, this drug did not effect the mean apnea duration, and has no 
significant effect on apnea time as a portion of sleep stage time. This 
drug did improve the average oxygenation during sleep. Medroxyprogesterone 
acetate was found to have beneficial effects on several variables measured 
in the awake state in obesity-hypoventilation patients. Almitrine, a 
carotid body stimulating agent, was found to have no effect on apnea 
frequency in REM or NREM sleep. There was a slight reduction in NREM apnea 
duration. This study concluded that almitrine was probably not useful for 
obstructive sleep apnea. Doxapram, a known ventilatory stimulant, failed 
to decrease apneas during sleep. It does cause termination of disordered 
breathing events at higher levels of oxyhemoglobin saturation. 
SUMMARY OF THE INVENTION 
Infusion of adenosine, adenosine analogs or nucleoside uptake blockers, 
e.g. dipyridamole will decrease the number of apneas and associated 
oxyhemoglobin desaturation during sleep in patients with obstructive sleep 
apnea. 
These and other and further objects and features of the invention are 
apparent in the disclosure, which includes the above and ongoing 
specification, with the claims, and the drawings.

DETAILED DESCRIPTION OF THE INVENTION 
Nucleoside adenosine (ADO) has been shown to stimulate breathing by 
increasing awake ventilatory drive in normal subjects. Infusion of 
nucleoside uptake blockers such as dipyridamole (DPM) into peripheral 
blood also stimulates ventilation in humans. Nucleoside uptake blockers' 
major physiological action is to increase plasma adenosine. Human and 
animal studies suggest that adenosine stimulates ventilation through an 
action on the carotid bodies or other arterial chemoreceptors. 
EXAMPLE 1 
1. Adenosine Infusion 
After sleeping for one hour, between 50 .mu.g/kg/min to 75 .mu.g/kg/min of 
adenosine is infused into an upper limb vein of the patient. This infusion 
will run for 3 to 5 minutes and then stop for 5 minutes. 
2. Dipyridamole Infusion 
After sleeping for one hour, 0.4 mg/kg of intravenous dipyridamole was 
infused over 15 minutes during stages 1 and 2 of sleep. In addition, 
dipyridamole may be given orally in a 100 mg dosage. 
3. Results 
As compared to baseline, each patient's apneas which received the 
dipyridamole infusion were significantly shorter and associated with less 
oxyhemoglobin desaturation. 
______________________________________ 
Patient 1 Patient 2 
______________________________________ 
1. Apnea Length (sec) 
17 + 7* vs 11 + 3 
25 + 5 vs 17 + 5 
Baseline vs Drug 
P &lt; 0.02 P &lt; 0.01 
2. 02 Saturation (%) 
89 + 2 vs 92 + 2 
75 + 7 vs 84 + 5 
at Apnea Nadir 
P &lt; 0.01 P &lt; 0.01 
Baseline vs Drug 
______________________________________ 
EXAMPLE 2 
1. Adenosine Infusion 
During sleep, between 50 .mu.g/kg/min to 75 .mu.g/kg/min of adenosine is 
intravenously administered over 5 minutes. 
2. Dipyridamole Infusion 
During sleep, 80 .mu.g/kg/min of dipyridamole (DPM) is intravenously 
administered over 5 minutes. 
Three patients given DPM were subsequently given three mg/kg of the 
adenosine antagonist, aminophylline (AM). 
3. Results 
______________________________________ 
Apnea Time (Sec.)/5 Minutes of Sleep 
______________________________________ 
Control 98 .+-. 23 Control 113 .+-. 36 
Mean .+-. SE 
ADO *49 .+-. 21 
DPM *57 .+-. 44 
*P &lt; 0.05 
Post Drug 
96 .+-. 30 AM 89 .+-. 37 
______________________________________ 
The mean oxyhemoglobin saturation significantly increased during both 
adenosine and dipyridamole infusions, and the number of apneas/5 min. was 
significantly lower during adenosine infusion. 
As can be seen in FIGS. 1-3, the apnea length and oxyhemoglobin 
desaturation were significantly less during adenosine infusion. 
While the invention has been described with reference to specific 
embodiments, modifications and variations of the invention may be 
constructed without departing from the scope of the invention, which is 
described in the following claims.