Patent Application: US-28051702-A

Abstract:
the invention relates to a method of treating diverse human disorders that may arise , in part , out of sleep hypoxia and oxygen deprivation occurring in the context of sleep apnea / hypopnea disturbances . the disorders that may be treated by the invention comprise gastroesophageal reflux disease , asthma - associated gastroesophageal reflux , ger - associated asthma , asthma , cardiomyopathy , cardioarrhythmia , congestive heart failure , sudden infant death syndrome , and diverse neurologic conditions . the mode of treatment uses somatostatin receptor ligands , particularly somatostatin - receptor agonists . the invention concerns the method of treatment utilizing , and compositions comprising sstrls and somatostatin receptor agonists , including agonists of the somatostatin receptor types 2 and 5 , particularly , the type 2a receptor , including octreotide and lanreotide .

Description:
as discussed above , gerd is associated with an abnormally low basal lower esophageal sphincter pressure ( lesp ), and the degree to which the lower esophageal sphincter pressure departs from the normal range correlates with the severity of gerd and associated conditions , such as barrett &# 39 ; s esophagus ( coenraad et al ., 1998 ; lidums and holloway , 1997 ; loughney et al ., 1998 ; oberg et al ., 1999 ; singh et al ., 1994 ). while the effects of somatostatin and somatostatin analogues , such as octreotide and related compounds on esophageal pressure has been explored , there has been no recognition of the use of these compounds in the treatment of gerd and related conditions , prior to applicant &# 39 ; s invention . ( barrioz et al ., 1998 ; gunshefki et al , 1992 ). similarly , while others have explored the use of somatostatin and somatostatin analogues in cases of upper gastrointestinal hemorrhage and in surgical conditions of the pancreas , there has been no recognition of the utility of these compounds in the treatment of gerd and related conditions . ( scarpignato et al ., 2001 ; scarpignato et al ., 1999 ). others , while confirming the published effects of somatostatin in normal humans on esophageal body pressure and post - prandial lesp , found no effect of somatostatin upon on basal esophageal lesp or on the frequency of post - prandial tlesp relaxation events ( straathof et al ., 2000 ). these findings are consistent with the idea that somatostatin receptor agonists primary activity is to decrease excessive neuronal tone that has been mediated through g protein - linked mechanisms . the concept of the instant invention is that gerd is associated with a chronic increase in nanc inhibitory neuronal control , mediated in part by pacap and vip stimulated increase in nitric oxide release . under basal conditions in normal individuals the esophageal lesp is not influenced by an excess of inhibitory neuronal stimuli . the invention therefore is directed to a treatment utilizing agonists of the somatostatin receptors , which increases lower esophageal sphincter pressure that has been lowered by a chronic upregulation of nanc inhibitory tone . since gerd is associated with dysmotility within the esophageal body , particularly in the advanced stages and in patients with barrett &# 39 ; s esophagus ( coenraad et al ., 1998 ; demeester and demeester , 1999 ; lidums and holloway , 1997 ; mason and bremner , 1993 ), the invention provides a treatment which increases intraesophageal body pressure and motility . esophageal injury from gerd is dependent upon the presence of gastric acid , which is secreted in the stomach and subsequently refluxed into the esophagus . therefore , in one embodiment , the invention provides a treatment utilizing agonists of the somatostatin receptors , which reduce the esophageal exposure to acid . the inhibition of secretion of gastric acid , by the administration of histamine - 2 receptor antagonists , or proton - pump inhibitors , provides the basis for current therapy of gerd . however , those treatments are associated with elevations of serum gastrin levels and atrophy of the gastric mucosa . it is widely known that somatostatin plays a physiologic role in the normal homeostatic control of acid secretion ; its intragastric secretion is triggered by lumenal acid exposure of antral d cells , and circulating gastrin exposure of fundal d cells , and inhibited by alkalinity . through effects on sstr - 2a receptors , somatostatin inhibits the secretion of both gastrin and histamine , the principal triggers for acid secretion by the gastric parietal cells . however , because the acid secretion inhibitory effects of exogenously administered somatostatin analogues are not as profound or as persistent as those attainable by either proton - pump inhibitors or histamine - 2 receptor antagonists , they were not considered to be effective for treating duodenal ulcers , and have not been considered candidates for the treatment of gerd . acute and chronic therapy with somatostatin receptor agonists , e . g ., sstr - 2a agonists , inhibits gastric acid secretion without producing elevations in circulating levels of gastrin ( bauer et al ., 1989 ; karnes et al ., 1989 , wyatt et al ., 1996 ). although this effect may not be competitive with proton pump inhibitors in magnitude and convenience for the treatment of gastric and duodenal ulcers , when these effects are coupled with the promotility and increased lesp effects of sstr - 2a agonists on the esophagus , sstr - 2a agonists effectively reduce the esophageal exposure to acid . esophageal injury from gerd is dependent upon the presence within the refluxed gastric contents of the proteolytic enzyme pepsin , which is secreted as pepsinogen by the gastric chief cells in the stomach under stimulation by acetylcholine , gastrin , and cholecystokinin . the present invention therefore , in another embodiment , inhibits pepsinogen secretion and its activation to pepsin . the repeated reflux of duodenal contents and especially , of bile acids into the esophagus in the course of duodenogastroesophageal reflux is particularly damaging to the esophageal mucosa and that extensive exposure to bile contents is characteristic of advanced gerd complicated by barrett &# 39 ; s esophagus and early adenocarcinoma occurring in barrett &# 39 ; s esophagus ( stein et al ., 1998 ; vaezi and richter , 1995 ). the invention therefore provides a treatment with somatostatin receptor agonists which decreases the rate of entry of bile , bile salts and proteolytic enzymes into the duodenum , thereby decreasing the quantity of bile acids and proteolytic enzymes present within the duodenal contents , thereby decreasing the severity of injury to esophageal mucosa that would arise in the course of duodenogastroesophageal reflux events in gerd . while the effect of somatostatin and octreotide on bile flow has been explored , there has been no recognition of their relevance to the pathophysiology of gerd ( gyr and meier , 1993 ; velosy et al ., 1999 ). patients with gerd experience an increased frequency of transient lower esophageal sphincter relaxation ( tlesr ) events following ingestion of a meal . ( dent , 1997 ; dent et al ., 1988 ) it is known that endogenous cholecystokinin ( cck ) triggers an increase in tlesrs following a meal , and the work of boulant indicates that this cck effect is mediated through local release of nitric oxide ( boeckxstaens et al ., 1998 ; boulant et al ., 1994 ; clave et al ., 1998 ; zerbib et al ., 1998 ). while octreotide and related compounds have been recognized as having an impact on circulating lebels of cholecystokinin , there has been no recognition of their utility in the treatment of gerd and related conditions . ( ewins et al ., 1992 ); shiratori et al ., 1991 ; stolk et al ., 1993 ; van berge henegouwen et al ., 1997 ). therefore , yet another embodiment of the invention provides a treatment which utilizes somatostatin receptor agonists to decrease the rate of secretion of cholecystokinin following a meal , and to block the peripheral actions of cholecystokinin . gerd is associated with an excess of non - adrenergic , non - cholinergic ( nanc ) inhibitory signals , which produce the observed low basal lower esophageal sphincter pressure ; therefore , impaired esophageal motility and increased frequency of transient lower esophageal sphincter relaxation events . it is known that the interactive signaling molecules vasoactive intestinal peptide ( vip ), pituitary adenylate synthase activating peptide ( pacap ) and nitric oxide are major nanc inhibitory neurotransmitter substances , which relax smooth muscle within the gastrointestinal tract . of these substances , the data are strongest for continued participation of nitric oxide in all of the motility events within the esophagus ( boulant et al ., 1994 ; konturek et al ., 1997 ; luiking et al ., 1998 ; murray et al ., 1995 ; singaram et al ., 1994 ). the work of aggestrup , singaram , and others , teaches that vasoactive intestinal peptide ( vip ) and nitric oxide are present in significant quantities in the esophagus , and can contribute to gastroesophageal reflux ( aggestrup et al ., 1985 ; konturek et al ., 1997 ; luiking et al ., 1998 ; murray et al ., 1995 ; ny et al ., 1995 ; singaram et al ., 1994 ; uddman et al ., 1991 ). the high levels of nitric oxide in gerd patients may come from two pathways . the work of murthy and others teaches that pacap and vip produce gastrointestinal smooth muscle relaxation by actions at two separate sites . in studies on rodent stomach and intestine , and intestinal myenteric ganglia , preganglionic release of nitric oxide ( from neuronal nitric oxide synthase , nnos ) enhances the release of vip from post - ganglionic peptidergic neurons ( grider et al ., 1992 and 1993 ). although comparable studies have not been performed within the esophagus , within stomach and intestinal smooth muscle cells pacap and vip activate adenylate cyclase through pac - 1 and vip - 2 receptors , and , by activating the natriuretic peptide clearance receptor , pacap and vip trigger ca ++ influx via nifedipine - sensitive calcium channels ; the increased intracellular ca ++ activates membrane - bound endothelial nitric oxide synthase ( enos ), increased nitric oxide activates soluble guanylate cyclase , and cgmp - mediated muscle relaxation ( murthy and makhlouf , 1994 ; murthy et al ., 1998 ). there is a similar myogenic nitric oxide synthase in canine lower esophageal sphincer smooth muscle cells , activated by enteric nerve stimulus or by exogenous no ( salapatek et al ., 1998 and 1998 ). the les myogenic nos activation mechanism is known to involve l - type calcium current and k + channel interactions ; however , the specific nos species has not been identified . in addition , the intestinalized epithelium in patients with barrett &# 39 ; s esophagus shows high levels of inducible nitric oxide synthase ( wilson et al ., 1998 ). nitric oxide generated within that epithelium could supplement vip - induced nitric oxide in producing relaxant effects upon esophageal smooth muscle . in asthma patients with ger , the inhibitory effects of pacap and vip can be supplemented by disease - associated nocturnal peripheral release of tnf - alpha and il - 1 beta which can increase expression of inducible nitric oxide synthase in the esophagus . while others have explored the activity of ssr - 2a agonists on vip and pacap ( katz and erstad , 1989 ; zindel , 1989 ; zeng et al ., 1999 ; athmann et al , 2000 ) and their effect on the production of inducible nitric oxide ( chao et al ., 1997 ; chao et al ., 1999 ), there has been no recognition of their effect on gerd or related conditions . a further embodiment of the invention therefore provides a treatment with somatostatin receptor agonists which decreases inhibitory signals to the gut by decreasing the rate of secretion of pacap and vip both from peptidergic neurons and from post - ganglionic pacap and vip neurons that have been activated by a pre - ganglionic nitrergic stimulus produced by release of no . from neuronal nos ( nos ). these effects are complemented by blocking the peripheral actions of pacap and vip , through inhibition of adenylate cyclase activation , and by inhibiting calcium influx via calcium channels in the interstitial cells of cajal which serve an intermediary function within the esophageal musclulature . furthermore , somatostatin receptor agonists inhibit the production of inducible nitric oxide through inhibition of the cellular release and peripheral actions of interferon - gamma , tnf - alpha and il - 1 beta . this treatment concept of inhibition of les relaxation by inhibiting the sequence of nnos → myogenic nos activation is consistent with the observation that nnos deleted ( nnos −/−) mice have an hypertensive ( achalasic ) lower esophageal sphincter ( kim et al ., 1999 and sivarao et al ., 2001 ). there is a striking parallel between the effects of cholecystokinin ( cck ) on the lower esophageal sphincter ( les ) and the sphincter of oddi , which controls the rate of entry of bile into the dudenum . cck produces repeated episodes of sphincteric relaxation in both the les and the sphincter of oddi ( boeckxstaens et al ., 1998 ; boulant et al ., 1994 ; clave et al ., 1998 ; middelfart et al ., 1999 ; richards et al ., 1993 ; shima et al ., 1998 ; shima et al ., 2000 ; tokunaga et al ., 1993 ; zerbib et al ., 1998 ). the effects of cck on both the les and the sphincter of oddi are mediated by release of nitric oxide , presumably from nitrergic neurons ( boulant et al ., 1994 ; shaffer , 2000 ; shima et al ., 2000 ). while the impact of sstr - 2a agonists on the les and the sphincter of oddi has been explored , there has been no recognition of their utility in the the treatment of gerd and related conditions ( barrioz et al ., 1998 ; binmoeller et al ., 1992 ; difrancesco et al , 1996 ; gunshefski et al ., 1992 ; velosy et al ., 1999 ). in yet another embodiment , the invention provides a treatment which utilizes somatostatin receptor agonists to produce parallel constrictive effects on the les and the sphincter of oddi . applicant &# 39 ; s treatment with somatostatin receptor agonists addresses the core pathophysiologic basis for the esophageal dysmotility and slack lower esophagel sphincter characteristically present in gerd patients , which exists because of high rates of secretion of pacap and vip , leading to increased levels of nitric oxide within the diseased esophageal tissues . the neurotransmitters reinforce each other &# 39 ; s production and biologic effect . therapy with somatostatin receptor agonists decreases inhibitory signals to the gut by decreasing the rates of secretion of pacap and vip , by blocking the peripheral actions of pacap and vip , through down - regulation of adenylate cyclase , and by inhibiting calcium influx via calcium channels that is the basis of the activation of enos within the gastrointestinal smooth muscle ( glassmeier et al ., 1998 ). furthermore , by reason of their inhibitory effects on the cellular release and peripheral actions of interferon - gamma , tnf - alpha , and il - 1 beta , delivered to the esophagus either by neuronal secretion or as part of the inflammatory response to refluxed gastric content , somatostatin receptor agonists inhibit the production of inducible nitric oxide . the total effect of therapy is to improve cephalocaudal esophageal motility , provide a tighter lower esophageal sphincter , and a tighter spinchter of oddi , reducing the entry of bile into the duodenum . within this context , the inhibitory effects of somatostatin receptor agonists in reducing the secretion of acid , pepsinogen , histamine , and bile salts , have an increased biologic impact . in yet another embodiment , the invention provides a treatment with somatostatin receptor agonists which enhances the utility and decreases the toxicity of serotonin agonists and other prokinetic agents in patients with gerd . although these agents have useful effects in at least a proportion of gerd patients , the utility of the treatment approach as a whole has been limited by the requirement to use high drug dosages which produce toxicity in a proportion of individuals . since , as disclosed in the present invention , gerd is a disorder characterized by high levels of inhibitory tone , high doses of the prokinetic agents were needed . with the removal of the inhibitory tone by treatment with somatostatin agonists , the effects of the prokinetic agents , including serotonin agonists , is greatly improved . confirmation of this concept has recently been published with regard to the effects erythromycin on gastric emptying when combined with octreotide in healthy subjects ( athanasakis , et al ., 2002 ). somatostatin 2a receptor agonist therapy as a single treatment program , or in pharmacologically coherent combinations also ameliorates the symptoms of asthma - associated ger , and ger - associated asthma by reducing the frequency and severity of ger episodes in asthmatics , thereby reducing the frequency and severity of : 1 ) esophageal acid induced bronchoconstriction by way of a vagal - esophageal - bronchial reflex , 2 ) heightened bronchial reactivity , 3 ) microaspiration into the upper airway of refluxed esophageal contents . moreover , by effects detailed herein , treatment with somatostatin receptor agonists , produces therapeutic effects upon asthmatic conditions , that are independent of these agents effects upon ger . as discussed above , asthma is associated with a hyper - reactive airway , and among the characteristics of a hyper - reactive airway is the increased expression of inducible nitric oxide synthase ( nos ). untreated asthmatics have an increased content of nitric oxide in their exhaled air . it is known that the expression of inducible nitric oxide synthase ( nos ) can be increased in airway epithelial cells by the pro - inflammatory cytokines tumor necrosis factor alpha ( tnf - alpha ) and interleukin - 1 beta ( il - 1 beta ), and by interferon gamma ( ifn - gamma ) ( asano et al ., 1994 ; guo et al ., 1997 ). although originally perceived as a deliterious part of the inflammatory response in airway cells , inducible nitric oxide synthase , and the nitric oxide it produces are now believed to be a part of the tissue defense mechansims to detoxify reactive oxygen species ( ros ), notably superoxide , produced by inflammatory cells ( dweik et al ., 2001 ). in asthmatic patients the inflammatory process to respiratory allergens or other physicochemical stimuli becomes sufficiently severe that the process itself damages lung tissue . inflammation , with associated ros release , is amplified in considerable measure by cytokines such as tnf - alpha and il - 1 beta produced locally by lymphocytes and macrophages , and possibly delivered through tnf and il - 1 containing nerves . in one embodiment , therefore , the invention provides a treatment using somatostatin receptor agonists to inhibit the synthesis and release and block the peripheral actions of tnf - alpha , il - 1 beta , and inf - gamma by monocytes and t - cell lymphocytes , cell varieties are characteristically increased in the hyperactive bronchi of asthmatic patients , as well as within the central nervous system and peripheral nerves . eosinophilic infiltration is characteristically present in the hypersensitive airway tissues of asthmatic patients . it is known that that the normal function of the nuclear transcription factors nf - kappab and c - fos / ap - 1 is necessary for the control of il - 5 and eotaxin genes that are essential for the differentiation , maturation and trafficking of eosinophils , and similarly that the presence and function of the p50 subunit of nf - kappab is essential to the eosinophilic response to a regional allergic stimulus ( hein et al ., 1997 ; yang et al ., 1998 ). the invention utilizes somatostatin receptor agonists to inhibit the activation of nf - kappab and c - fos / ap - 1 nuclear transcription factors . applicant believes that at least in part , this effect may be due the inhibitory actions of sstr - 2a agonists upon synthesis and release of the inflammatory cytokine stimulants for nf - kappab and c - fos / ap - 1 , as well as the the ability of sstr2a agonists to activate phosphotyrosine protein phosphatases , counterbalancing the initial stimulatory effects of cytokine - activated protein tyrosine kinases ( see todisco et al ., 1994 ; todisco et al ., 1995 ; yamashita et al ., 1999 ). the inventive treatment utilizing somatostatin receptor agonists in the treatment of asthma , provides effects which are part of a broad immunomodulatory action of the somatostatin agonists , which is described in the instant application in detail . applicant &# 39 ; s invention thus provides broad anti - inflammatory activity , by inhibiting activation of the nuclear transcription factors nf - kappab and c - fos / ap - 1 , within monocytes and lymphocytes , thereby inhibiting gene transcription for tnf - alpha , il - 1b , ifn - gamma , and inos , and blocking the peripheral effects of et - 1 and substance p . the inhibitory effect of somatostatin agonist therapy on the activation of nf - kappab and c - fos / ap - 1 and the binding of ap - 1 resembles a similar inhibitory effect produced by glucocorticoid hormones , which are widely used in the treatment of asthma and other inflammatory disorders . as discussed herein within the section entitled “ pathophysiologic context of the invention ”, gerd , ger - associated asthma , asthma - associated ger , and asthma are disorders with a decided diurnal pattern , wherein the symptoms are commonly more severe at night . within that context , the applicant has discovered that the increased nocturnal severity of symptoms is produced by the diurnal pattern of secretion , within the brain and the peripheral tissues , of particular neuropeptides that have both a somnolent effect and peripheral effects . in gerd patients without asthma , pacap and vip would be plausible effector agents , in symptomatic asthma patients tnf - alpha and il - 1 beta would be plausible additional neuropeptides producing the observed effects . because these patients commonly have disordered sleep , with multiple arousals , they are commonly drowsy during the day as well , plausibly , maintaining elevated neuropeptide secretion ( s ). applicant &# 39 ; s invention thus provides broad relief of the hostile diurnal disease pattern by using somatostatin receptor 2a agonists to inhibit excessive secretion of somnolence producing neuropeptides pacap , vip , tnf - alpha and il - 1 beta ; and by blocking their cellular reactions . because this therapy relieves symptoms of sleep apnea , it also ameliorates the extent to which apnea - associated hypoxia exacerbates the symptoms of the several disorders . while others have explored the activity of ssr - 2a agonists on sleep function ( reviewed in barkan , 1997 and krueger et al ), prior to the instant invention , there has been no recognition of their effect on gerd , asthma or related conditions . since sleep apnea , including obstructive sleep apnea ( osa ) and the accompanying hypoxia is widely associated with gastroesophageal reflux in both adults and in infants and young children , including those with a history of apparent life - threatening events ( altes ), the present invention , therefore , in yet another embodiment , proposes that sstr - 2a agonists can be used for the prevention and management of a broad range of osa - associated illnesses , not limited to these drug &# 39 ; s present use in the management of acromegaly - associated osa . these uses include , but are not limited to , the prevention and management of osa - associatd ger , osa - associated cardiomyopathy , osa - associated cardioarrhythmia , osa - associated median nerve compression neuropathy ( carpal tunnel syndrome ), and sleep apnea - associated altes ,. the sleep apnea / hypopnea syndrome , including obstructive sleep apnea , central sleep apnea , with cheyne - stokes respiration , and mixed sleep apneas also have major deliterious effects on individuals experiencing them ; the data indicate that it is the chronic and recurrent hypoxic periods that produce the injury rather than the particular cause or pattern of apnea ( blackshear et al ., 1995 ; engleman et al ., 2000 ; erkinjuntti et al ., 1987 ; hayakawa et al , 1996 ; kimura et al ., 1999 ; kleopa et al ., 1999 ; malone et al ., 1991 ; peled , 1998 ; ponikowski et al ., 1999 ; rosenow , 1994 ; stepansky et al ., 1997 ). since sstr - 2a agonists have a broad capacity to inhibit secretion of somnolence - producing neuropeptides , the present invention , in yet another embodiment , proposes that sstr - 2a agonists can be applied to the prevention and management of a broad range of sleep apnea - and sleep - hypoventilation - associated illnesses and conditions . these applications include , but are not limited to , the prevention and management of sleep - apnea or sleep - hypoventilation - associated : gastroesophageal reflux , cardiomyopathy , cardioarrhythmia , median nerve compression neuropathy ( carpal tunnel syndrome ), congestive heart failure , pulmonary hypertension , systemic hypertension , and cognitive impairment . the illnesses or conditions further include apnea or hypoventilation occurring in the context of a present or past cerebrovascular occlusion or hemorrhage , ischemia - reperfusion injury , neuroimmune , neurodegenerative and neuroinflammatory disorders , including amyotrophic lateral sclerosis ( als ), myasthenia gravis , dementia , and alcoholism . since tissue injuries , including hypoxic and ischemic injury , are commonly associated with the activation of the calcium - dependent protease calpain and calpain inhibitors lessen the extent of tissue injury ( badalamente et al ., 1989 ; blomgren , et al ., 1999 and 2001 ; du , et al ., 1999 ; edelstein , et al ., 1996 and 1999 ; harriman , et al ., 2000 ; lizuka , et al ., 1991 ; iwamoto , et al ., 1999 ; li , et al ., 1996 ; shields , et al ., 2000 ; wang , et al ., 2000 ), and since calpain activation can be inhibited by sstr - 2a agonists ( bellocq , et al ., 1999 ), in yet another embodiment , the present invention encompasses the use of sstr - 2a agonists to limit damage and amelorate dysfunction in disorders of calpain activation , where the injured cell population expresses somatostatin receptors , these would include but not be limited to injuries produced by ischemia / reperfusion , and other hypoxia , neurodegenerative and neuroinflammatory disorders , dementia , and alcoholism and accidental injury to the central nervous system , heart , liver , kidney , and gastrointestinal tract . development of the present invention was stimulated by an event in applicant &# 39 ; s clinical practice of oncology . octretotide was added to the treatment program of a patient with terminal cancer because the patient &# 39 ; s cancer concentrated radiolabelled octreotide on a nuclear medicine scan . treatment was initiated with subcutaneous octreotide at a dose of 150 microgram twice daily , then three times daily , and then finally the patient was shifted to a longer - acting depot formulation of octreotide ( sandostatin lar ) that was given intramuscularly on a monthly basis . following the initiation of octreotide administration , the patient reported rapid and complete disappearance of gerd symptoms that had been present for many years . control of gerd symptomatology was maintained for several months until the patient expired of a common complication of the cancerous condition , unrelated to the therapy . it is envisioned that therapy with injectable peptidic somatostatin receptor ( sstr ) agonists can begin with subcutaneous administration on a three times daily basis , and then , when acceptable tolerance of the drug is demonstrated , proceed to an intramuscular depot preparation of the peptidic sstr agonist . therapy with orally bioavailable sstr agonists and for non - peptidic sstr agonists would be based upon their intrinsic molecular potency , the extent of absorption and the rapidity of degradation and or excretion . in the general case it can be assumed that the active dosage range for intravenous administration would range from 0 . 001 to 5 mg / kg / day , and that the active dosage range for oral administration would range from 0 . 1 to 50 mg / kg / day . the precise determination of initial and maintenance dosing would be determined by clinical assessment . the precise determination of what would be considered an effective dose may be based on factors individual to each patient , including their size , age , severity of the condition being treated , and the like . one skilled in the art , specifically a physician , would be able to determine a sufficient amount of active ingredient which would constititute an effective dose without being subjected to undue experimentation . the following invention shall be further described by the following non - limiting examples are indicative of the treatment approach with formulations that have undergone extensive clinical assessment . for treatment of gerd , a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutanteously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance and the demonstration of symptomatic benefit , and with objective demonstration of the reduction in reflux events . a rough parallelism is predicted between the dose of octreotide that produces an increase in esophageal motility and esophageal sphincter pressure , and the dose that produces gall bladder distension due to tightening of the sphincter of oddi . once control of gerd symptoms is achieved , the dosage can be adjusted to the patient &# 39 ; s tolerance , balancing relief of gerd symptoms against the symptoms of loose stools and abdominal discomfort which can be caused by the reduction of bile salts in the intestinal content . historically , this dosage range can be about 300 mcg / day . for treatment of gerd , a therapeutically effective amount of octreotide acetate for injectable suspension ( depot formulation ) sandostatin lar ® depot would be from 10 to 30 mg octreotide base equivalent by intra - muscular ( im ) injection administered every 4 weeks ( 28 days ). a rough parallelism is predicted between the dose of octreotide that produces an increase in esophageal motility and esophageal sphincter pressure , and the dose that produces gall bladder distension due to tightening of the sphincter of oddi . once control of gerd symptoms is achieved , the dosage can be adjusted to the patient &# 39 ; s tolerance , balancing relief of gerd symptoms against the symptoms of loose stools and abdominal discomfort which may be caused by the reduction of bile salts in the intestinal content . extrapolating from the historical experience with octreotide for injection , this dosage range can be about 10 mg / month . for treatment of gerd , a therapeutically effective amount of lanreotide ( somatuline la ) would be 30 mg administered by im injection at from 7 to 14 day intervals . a rough parallelism is predicted between the dose of octreotide that produces an increase in esophageal motility and esophageal sphincter pressure , and the dose that produces gall bladder distension due to tightening of the sphincter of oddi . once control of gerd symptoms is achieved , the dosage can be adjusted to the patient &# 39 ; s tolerance , balancing relief of gerd symptoms against the symptoms of loose stools and abdominal discomfort which may be caused by the reduction of bile salts in the intestinal content . extrapolating from the historical experience with long - acting lanreotide ( somatuline - la ), this dosage range can be about 30 mg every 14 days . for treatment of asthma - associated gastroesophageal reflux ( ger ), a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutanteously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance and the demonstration of symptomatic benefit , and with objective demonstration of the reduction in reflux events . for the ger symptoms a rough parallelism is predicted between the dose of octreotide that produces an increase in esophageal motility and esophageal sphincter pressure , and the dose that produces gall bladder distension due to tightening of the sphincter of oddi . once control of ger symptoms is achieved , the dosage can be adjusted to the patient &# 39 ; s tolerance , balancing relief of ger symptoms against the symptoms of loose stools and abdominal discomfort which may be caused by the reduction of bile salts in the intestinal content . historically , this dosage range can be about 300 mcg / day . in those patients where the ger symptoms have arisen in the course of allergic or atopic asthma , that is characterized by diffusely inflamed membranes and a hyperactive airway , stabilization of the airway inflammation by inhaled steroids is indicated before cautiously initiating octreotide therapy at a low dosage of 100 mcg bid , with careful escalation thereafter observing both the ger symptoms and the asthmatic symptoms . when tolerance is assured , a shift to the ( depot formulation ) sandostatin lard ® depot would be appropriate at a low monthly dosage of 10 mg . for treatment of ger - associated asthma where the asthma symptoms appear to by induced primarily by the ger events , and there is a low suspicion of allergic or atopic asthma , that is characterized by diffusely inflamed membranes and a hyperactive airway , nevertheless , stabilization of the airway inflammation by inhaled steroids is indicated before cautiously initiating octreotide therapy at a low dosage of 100 mcg bid , with careful escalation thereafter observing both the ger symptoms and the asthmatic symptoms . when tolerance is assured , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at a low monthly dosage of 10 mg . if after several months the ger symptoms persist at this dosage level , and asthmatic symptoms are under control , further cautious escalation to 20 mg / month can be explored . for treatment of asthma the goal of sstr - 2a agonist therapy is to reduce the extent and severity of diffuse membrane inflammation and airway hyperactivity , through decreasing the release of the cytokines tnf - alpha , il - 1 beta and interferon gamma , and to block the peripheral effects of these cytokines . these actions complement the anti - inflammatory effects of inhaled glucocorticoids , as does the calpain - inhibitory effect of sstr - 2a agonists , which increases glucocorticoid binding and signaling in macrophages ( bellocq , et al ., 1999 ). however , because sstr - 2a agonists also reduce neuronal vip and pacap release , thereby possibly decreasing airway muscle relaxation , stabilization of the airway inflammation by inhaled steroids is indicated before cautiously initiating octreotide therapy at a low dosage of 100 mcg bid , with careful escalation thereafter with close attention to the acute status of the asthmatic symptoms . when tolerance is assured , a shift to the ( depot formulation ) sandostatin lark ® depot would be appropriate at a low monthly dosage of 10 mg . for treatment of obstructive sleep apnea ( osa ), a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea events and that which produces gastrointestinal effects on esophageal motility , and pressure changes in the lower esophageal sphincter and the sphincter of oddi ; this can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of sleep apnea / hypopnea - associated ger , a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea - associated ger and the dose that which produces gall bladder distension through an increase in pressure in the sphincter of oddi ; this range may be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . improvement in the ger symptoms may occur more rapidly than a demonstrable change in sleep apnea events , which may occur over a period of months . for treatment of sleep apnea - associated asthma there are two goals of sstr - 2a agonist therapy ; 1 ) to reduce the extent and severity of diffuse membrane inflammation and airway hyperactivity , and 2 ) to reduce the severity and frequency of sleep apnea events . both of these goals are obtained through decreasing the synthesis and release of the cytokines tnf - alpha , il - 1 beta and interferon gamma , and through blocking the peripheral effects of these cytokines . with regard to the airway membranes these actions complement the anti - inflammatory effects of inhaled glucocorticoids , as does the calpain - inhibitory effect of sstr - 2a agonists which increases glucocorticoid binding and signaling in macrophages ( bellocq , et al ., 1999 ). however , because sstr - 2a agonists also reduce neuronal vip and pacap release , thereby possibly decreasing airway muscle relaxation , stabilization of the airway inflammation by inhaled steroids is indicated before cautiously initiating octreotide therapy at a low dosage of 100 mcg bid , with careful escalation thereafter with close attention to the acute status of the asthmatic symptoms . when tolerance is assured , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at a low monthly dosage of 10 mg . for treatment of sleep apnea - associated cardiomyopathy the goal of sstr - 2a agonist therapy is to reduce the severity and frequency of the sleep apnea / hypopnea events , which produce repeated hypoxic occurrences with resulting cardiac damage . a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea events and that which produces gastrointestinal effects on esophageal motility , and pressure changes in the lower esophageal sphincter and the sphincter of oddi ; this range can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of sleep apnea - associated cardioarrhythmia the goal of sstr - 2a agonist therapy is to reduce the severity and frequency of the sleep apnea / hypopnea events , which produce repeated hypoxic occurrences with resulting cardiac damage and cardioarrhythmia . a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea events and that which produces gastrointestinal effects on esophageal motility , and pressure changes in the lower esophageal sphincter and the sphincter of oddi ; this range may be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of sleep apnea / hypopnea that occurs in the context of congestive heart failure the goal of sstr - 2a agonist therapy is to reduce the severity and frequency of the sleep apnea / hypopnea events , which produce repeated hypoxic occurrences with resulting cardiac damage . a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea events and that which produces gastrointestinal effects on esophageal motility , and pressure changes in the lower esophageal sphincter and the sphincter of oddi ; this range may be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of sleep apnea / hypopnea that occurs in the context of cognitive impairment and contributes thereto in a variety of geriatric conditions , the goal of sstr - 2a agonist therapy is to reduce the severity and frequency of the sleep apnea / hypopnea events , which produce repeated hypoxic occurrences with resulting central nervous system damage . a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the likely dose required can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of sleep apnea in infants with a history of apparent life - threatening events ( alte ), referred to as a “ near - miss ” for sudden infant death syndrome ( sids ) the goal of sstr - 2a agonist therapy is to reduce the severity and frequency of the sleep apnea / hypopnea events , which produce repeated hypoxic occurrences which may be life - threatening . a therapeutically effective amount of octreotide acetate would be from 2 to 6 micg / kg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . a rough parallelism is predicted between the dose of octreotide that produces a decrease in sleep apnea events and that which produces gastrointestinal effects on small bowel motility ( di lorenzo , et al . 1998 ). for treatment of central sleep apnea ( csa ) a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of mixed pattern sleep apnea a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of cerebrovascular occlusion - associated sleep apnea a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of dementia - associated sleep apnea a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of amyotrophic lateral sclerosis - associated sleep apnea a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of alcoholism - associated sleep apnea a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 to 20 mg / month . for treatment of disorders tissue injury with excess calpain activation a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lard ® depot would be appropriate at 10 to 20 mg / month . for the combined use of octreotide and a prokinetic agent in patients with gerd , a therapeutically effective amount of octreotide acetate would be from 100 to 600 mcg / day subcutaneously ( sc ) in two or three divided doses , with the dosage adjusted to patient tolerance . the expected daily dose can be about 300 mcg / day . when patient tolerance is established , a shift to the ( depot formulation ) sandostatin lar ® depot would be appropriate at 10 mg / month . when stability of the sandostatin lar ® depot dosage is established , the prokinetic agent should then be initiated at approximately a quarter of the usual daily dose . the prokinetic agent dosage can then be escalated to meet the symptom goals for the individual patient . having thus described in detail preferred embodiments of the present invention , it is to be understood that the invention defined by the appended claims is not to be limited to particular details set forth in the above description , as many apparent variations thereof are possible without departing from the spirit or scope of the present invention . aggestrup , s ., uddman , r ., jensen , s . l ., sundler , f ., schaffalitzky de muckadell , o ., holst , j . j ., hakanson , r ., ekman , r ., and sorensen , h . r . : regulatory peptides in the lower esophageal sphincter of man . regul pept 10 ( 2 - 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