Patent Abstract:
a non - invasive method of determining the presence of inflammation in a region of the gastrointestinal tract of an organism comprises introducing an arterial dilating agent into the circulatory system that provides blood flow to that region , then introducing a blood flow marking medium into the circulation providing blood flow to that region . the amount of blood flow marking medium present in that region is then monitored as an indication of the extent of inflammation present in that region . the capability of inflamed gastrointestinal tract tissue to take up increased amounts of the blood flow marking medium provides an indication of the presence of an abnormal pathologic process in that region of the gastrointestinal tract . in the preferred embodiment of the method , the arterial dilator is dipyridamole . the blood flow marking medium is thallium - 201 , and its accumulation in the region of the gastrointestinal tract is monitored by measuring the radioactive emissions by thallium - 201 scintigraphy . the method permits the non - invasive determination of the presence of inflammation in the gastrointestinal tract of an organism .

Detailed Description:
the present invention is a method of determining the presence of inflammation in a region of the gastrointestinal tract of an organism . inflammation is a biological response to mucosal or mural injury , and includes such biological responses as reactive hyperemia and infiltration of inflammatory cells such as polymorphonuclear leukocytes and lymphocytes . inflammation will be seen in conditions such as esophagitis , gastritis , gastric ulcer , duodenitis , duodenal ulcer , enteritis , ulcerative colitis , crohn &# 39 ; s disease , proctitis , and other conditions known to one skilled in this field . the method is performed by introducing an artery dilating medication into the circulatory system that supplies blood flow to a region of the gastrointestinal tract being studied . then a blood flow marking medium is introduced into the circulatory system that supplies blood flow to the same region . if the entire gastrointestinal tract is to be imaged , or if specificity of distribution to particular organs is not desired , intravenous administration can be employed . for example , these substances can be injected into an antecubital vein in the conventional manner . these substances will be distributed widely throughout the gastrointestinal tract by the systemic circulation , and will affect the entire gastrointestinal tract , including the blood supply of the region being studied . alternatively , these substances can be anatomically selectively introduced into arteries that supply specific anatomic regions of the tract . for example , a cannula can be introduced into the gastric artery to introduce the artery dilating medication and blood flow marking medium directly into the blood supply to the stomach . in this situation , the stomach or other specific region can be primarily visualized . it is anticipated , however , that in the preferred embodiment general systemic intravenous administration will be used to supply the dilating medication and blood flow marker to the region of the gastrointestinal tract being studied . the amount of blood flow marking medium to appear in the region is then monitored , which provides an indication of the presence or absence of inflammation in that region of the gastrointestinal tract . monitoring refers to observing the quantity of the medium concentrated in the tissue of interest , for example the stomach or esophagus in cases of suspected gastritis or esophagitis . the preferred embodiments will use a gamma camera to perform scintillation photography , which will produce a photographic image that correlates intensity of tissue uptake with darkness of the image . hence in fig1 blood flow is great in the heart , liver , and kidney , which have corresponding dark images on the photograph . the stomach does not have significant uptake , and has a correspondingly light image . however in fig2 which shows a patient with gastritis , blood flow to the inflamed stomach is greater , and this increased uptake is seen as a darker image on the photograph . in a particularly preferred embodiment of the method , dipyridamole is the arterial dilating agent that allows the increase in delivery of a blood flow marking medium or tracer such as thallium - 201 to a region of the gastrointestinal tract which is inflamed by some disease process . these disease processes include but are not limited to gastritis , ulcers , esophagitis , enteritis , and colitis from a number of pathologic conditions including , but not limited to peptic ulcer disease , hiatus hernias , helicobacter pylori infection , regional enteritis ( crohn &# 39 ; s disease ), ulcerative colitis , and diverticulitis . this increased uptake of the blood flow tracer can then be imaged using a gamma camera , and the identification of the increased tracer uptake can be used clinically to diagnose the presence of gastrointestinal tract inflammation . the salutary effect of dipyridamole in determining the existence of inflamed tissue in the gastrointestinal tract was confirmed in a prospective study . the study population consisted of 39 consecutive patients experiencing chest pain syndromes who underwent a routine dipyridamole thallium - 201 pharmacologic stress test . patients were fasting from the night before the test and did not take their morning medications . the test was performed according to a standard protocol ( gould , leppo ). a dose of 0 . 56 mg / kg of dipyridamole was infused intravenously ( for example into an antecubital vein ) over four minutes to the supine patient . serial blood pressures and 12 lead electrocardiograms were monitored . one to two minutes after cessation of the dipyridamole infusion , 3 mci of thallium - 201 was injected intravenously . image acquisition was begun three to five minutes after the thallium - 201 injection . using a large field of view gamma camera with a low energy , all purpose collimator , an anterior planar image was first obtained over five minutes . next , a 180 degree tomographic imaging set was obtained consisting of 32 images , each of 30 seconds duration , starting at 45 degrees right anterior oblique and proceeding in 6 degree increments around the patient , ending at 45 degrees left posterior oblique . delayed imaging was performed four hours after a second intravenous injection of thallium - 201 ( 1 mci ). both sets of raw image data underwent tomographic reconstruction for routine cardiac readings . however , for the purpose of assessing gastroesophageal thallium - 201 uptake , both the initial 32 post - dipyridamole raw images as well as the four hour delayed images were displayed on a computer screen as cine loops . without knowledge of the clinical history of the patient , these cine images were then interpreted by an experienced observer . the intensity of the thallium - 201 uptake by the stomach and esophagus was graded in a semi - quantitative manner , using the liver as a consistently visualized internal standard , such that : patients &# 39 ; symptoms and histories were obtained and recorded prospectively prior to the dipyridamole thallium - 201 test from a direct interview with the patients and review of their medical record . specifically , patients were questioned as to the presence or absence of current active symptoms of heartburn , dysphagia , epigastric discomfort related to meals and position , nausea , vomiting , or acid reflux ( richter , spiro , weinstein ). patients were also questioned as to the medications which they were taking , including prescription as well as over - the - counter medications . past medical history concerning gastroesophageal diagnosis ( hiatus hernia , peptic ulcer disease , etc .) and procedures ( e . g ., gastric surgery ) were also obtained from the patients and their medical records ( table 1 ). table 1______________________________________characteristics of the patient populationn = 39category n______________________________________age ( years ) 68 ± 2sex ( m / f ) 14 / 25nsaid 3asa 8prednisone 5b - blocker 13ca antagonist 18nitrate 5digoxin 6diuretic 8ace inhibitoranti - gastritis medications 20antacid 5h2 - blocker 14sucralfate 0omeprazole 3misoprostol 1hx hh 10hx pud 20hx gastric surgery 5nsaid = non - steroidal anti - inflammatory medicationsasa = aspirinb - blocker = beta adrenergic blockadeca antagonist = calcium channel antagonistace inhibitor = angiotensin converting enzyme inhibitoranti - gastritis = antacid , h2 - blocker , omeprazole , meds sucralfate , misoprostolh2 - blocker = ranitidine , cimetidine , pepcidhx = history ofhh = hiatus herniapud = peptic ulcer disease______________________________________ statistical analysis : differences between groups were assessed by an unpaired t - test . to determine which variables had independent predictive value for gastric thallium - 201 uptake by multivariate logistic regression analysis , the grading of the gastric uptake was dichotomized such that grades 0 and 1 were considered &# 34 ; no significant thallium - 201 uptake ,&# 34 ; and grades 2 and 3 were considered &# 34 ; significant thallium - 201 uptake .&# 34 ; a p value of & lt ; 0 . 05 was considered statistically significant . all data are expressed as mean ± standard error of the mean . in this study , 17 patients had active symptoms referable to gastritis , while 22 did not . using the four point scoring system , patients with active symptoms of gastroesophageal discomfort were found to have a thallium - 201 stomach uptake score on the initial post - dipyridamole images of 1 . 76 ± 0 . 24 . conversely , patients without active symptoms had a score of 0 . 64 ± 0 . 18 , p = 0 . 0001 . in addition , patients previously identified by their physicians as requiring one or more anti - gastritis / anti - ulcer medications ( n = 20 ), showed significantly higher thallium - 201 stomach uptake scores on their initial post - dipyridamole images , as compared to patients not receiving such medication ( n = 19 ), ( 1 . 55 ± 0 . 27 vs . 0 . 68 ± 0 . 15 , respectively , p = 0 . 009 ). on the four hour delayed images , patients with and without active symptoms of gastric inflammation had thallium - 201 scores of 1 . 53 ± 0 . 27 and 0 . 45 ± 0 . 16 , respectively , p = 0 . 0001 . patients who were and were not taking medications for symptoms of gastric inflammation had gastric thallium - 201 scores of 1 . 25 ± 0 . 27 and 0 . 58 ± 0 . 18 , respectively , p = 0 . 05 . there were no significant differences in stomach thallium - 201 uptake between patients on or off cardiac medications ( i . e ., beta blockers , calcium antagonists , nitrates , digoxin , diuretics , and angiotensin converting enzyme inhibitors ). in addition , there were no statistically significant differences in gastric thallium - 201 uptake in patients on or off other medications which have been associated with gastric irritation ( e . g ., prednisone , and non - steroidal anti - inflammatory drugs ). however , the number of patients on these medications was low . of the eight patients on aspirin , three were on low - dose enteric coated aspirin ( 325 mg / day ) and none of the three had significant gastric thallium - 201 uptake , whereas the one patient on high dose non - enteric coated aspirin ( 3000 mg / day ) had 3 + uptake localized to the distal stomach . this patient had undergone upper endoscopy four months earlier , which had also shown inflammation in the distal part of the stomach . to determine which factor or factors had independent predictive value of thallium - 201 uptake on initial post - dipyridamole images , a stepwise logistic regression analysis was performed , using a dichotomous categorization of thallium - 201 gastric uptake scores as either &# 34 ; significant &# 34 ; ( 2 or 3 ) or &# 34 ; not significant ( 0 or 1 ). independent variables included in the analysis were active symptoms , anti - gastritis medications , age , a change in heart rate in response to dipyridamole , and a change in systolic blood pressure in response to dipyridamole . only two of these variables had significant positive predictive value : the presence of active gastritis symptoms ( p = 0 . 0008 ) and the use the anti - gastritis medications ( p = 0 . 0008 ). moreover , all of the patients with &# 34 ; significant &# 34 ; thallium - 201 uptake ( n = 14 ) had active symptoms and / or were taking anti - gastritis medications . although dipyridamole is a potent dilator of arteries , other arterial dilators may be used in the alternative . these include adenosine and adenosine receptor agonists ( e . g . cyclohexyladenosine , n - ethyl adneosine - 5 &# 39 ;- uroamide ), nitroglycerine - type compounds ( isosorbide dinitrate , isosorbide mononitrate ), nitroprusside , forskolin hydralazine , and angiotensin converting enzyme inhibitors ( e . g . lisinopril , captopril , enalapril , enalaprilat ). also , other blood flow marking mediums or tracers may be used as alternatives to thallium - 201 . these include but are not limited to technetium - 99m labelled sestamibi ( in a dose of 5 - 20 mci ) and teboroxime ( 5 - 20 mci ), rubidium - 81 ( 1 - 5 mci ), rubidium - 82 ( 15 mci ), potassium - 43 ( 1 - 5 mci ), oxygen - 15 labeled water ( about 20 mci ), and copper - 67 ( 5 - 15 mci ). the artery dilating medication is introduced into the subject in a sufficient amount to dilate the arteries and increase the blood supply to the region of the gastrointestinal tract that is being scanned . for example , a dose of 0 . 56 mg / kg dipyridamole would be sufficient when administered intravenously to the subject . doses of other arterial dilators that are known to produce generalized arterial dilation include 0 . 4 mg of nitroglycerin sublingually , 40 mg orally of isosorbide dinitrate , 20 mg of isosorbide mononitrate , and 60 to 120 mg orally of the calcium channel blocker diltiazem , or 30 to 60 mg orally of nifedipine . adenosine is commercially available as adenocard , which can be given in 6 or 12 mg doses . an example of an angiotensin converting enzyme inhibitor that can be used with the present invention is lisinopril , in a dose of 10 - 40 mg orally , or enalaprilat 1 . 25 mg iv . the blood flow marking medium is a material , such as a radioactive tracer , that concentrates in areas of increased blood flow . it is infused in a dosage that is sufficient to show an increased uptake in areas of increased blood flow . in particular embodiments , it is an amount that is sufficient to show uptake equal to or greater than the liver uptake , in regions of the gastrointestinal tract ( such as the stomach , esophagus or intestines ) that are inflamed . for example , a dose of 3 mci of thallium - 201 would be sufficient to achieve this effect . gamma camera , or other flow tracer measurements , can begin as soon as the cardiovascular system has sufficient time to distribute the flow tracer to the gastrointestinal tract . measurements may begin , for example , in 3 to 5 minutes after initial injection into the systemic vascular tree . less time will be needed if injection is made directly into a branch artery supplying the region of interest , such as the gastric or superior celiac artery . measurements can be made for several hours after injection , for example , 2 - 4 hours . as used herein , a &# 34 ; region &# 34 ; of the gastrointestinal tract refers to a subdivision or subdivisions of interest . such subdivisions include the esophagus , stomach , small intestine ( and subdivisions thereof including the duodenum , jejunum , or ileum ), large intestine ( including subdivisions thereof , such as the ascending colon , transverse colon and descending colon ), and the rectum . the liver is not considered a part of or a region of the gastrointestinal tract for purposes of this disclosure . the term &# 34 ; nitroglycerin or nitroglycerin - like compound &# 34 ; means nitroglycerin , nitroprusside , or other cognate drugs which are administered to humans in medical practice , and which dilate arteries . having illustrated and described the principles of the invention in a preferred embodiment , it should be apparent to those skilled in the art that the invention can be modified in arrangement and detail without departing from such principles . therefore , the illustrated embodiment should be considered only as a preferred example of the invention and not as a limitation on the scope of the claims . i therefore claim as my invention all modifications and equivalents to the illustrated embodiment coming within the scope and spirit of following claims . 1 . richter j . e . heartburn , dysphagia , odynophagia , and other esophageal symptoms . in : sleisenger m . h . and fordtran j . s ., eds . gastrointestinal disease : pathophysiology , diagnosis , and management . 5th edition . philadelphia : w . b . saunders co . ; 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