Patent Application: US-201514965912-A

Abstract:
this invention aims to capture and teach the high - level concept of combining doses of medications in unconventionally substandard amounts , for the treatment of medical pathologies . by combining multiple medications , each of which is aimed at treating the same disease process and each in a given substandard dosage , it should allow for greater comprehensive efficacy while simultaneously bypassing conventional side - effects , clinically significant medication interactions , and other potentially unforeseen deleterious effects , all because the dosage is small enough and collaborative chemical diversity manifests favorable kinetic dynamics , thereby mitigating unwanted drug effects while enhancing the targeted indication .

Description:
areas of the greatest concentration of medical resources , such as hypertension , diabetes mellitus , hyperlipidemia and symptomatic treatment of depression can help to best illustrate implementation of the cooperative combination system method , from the extensive available research and development in these treatment areas . it would seem the most common diseases of greatest significance in the general population elude even the greatest attempts at controlling their pathologic progression . with this in mind , quite often multiple drug regimens are eventually required to lessen illness , but still consequent comorbidities and even direct mortality evade the best conventional attempts with the current treatment approach method . consider the numerous chemical agents available to treat hypertension , including various dosage forms . there are slightly more than a half - dozen distinct physiologic mechanisms of action in this pharmacopoeia . interestingly , there are nearly one hundred available hypertension medications ( see list 1a ). there are even combination medications , combining various mechanisms . these combinations provide doses that are therapeutic , individually , and are in one tablet / capsule , for advanced hypertension , much like the polypills mentioned earlier . these combinations too are studied and approved to be effective minimally at a given dose . it is crucial to note , whether it is a combination seen on the list provided or the polypill concept , these are not the same as taking six unique , via mechanism of action , medications and decreasing the low dose proportionally , by about ⅙ , to a substandard degree , for newly diagnosed uncomplicated hypertension . the combination of 6 chemical mechanisms , contoured to roughly ⅙ of a general low dose is thought to reinvent the current treatment standard . in other words , the doses detailed in this teaching have previously not been considered for use in the medical community , nor , more importantly , has it been postulated for them to be available in combination for commercial use . however , it is well understood that many diseases , especially chronic ones , benefit from or eventually require more than one agent to adequately mitigate the malady . m r law and n j wald , et . al . orchestrated a meta - analysis of 354 randomized trials to appreciate the value of low dose combinations on blood pressure lowering . this low dose corresponds to the fda designated minimally effective doses . the low dose is less than the dose needed to obtain a typical target blood pressure in a typical hypertensive patient . this analysis was published by the british medical journal in 2003 . the authors state no trial has studied the effect of three hypertension drugs in combination , but it is suggested the effects would likewise be additive . the authors even report they have a patent application for a formula regarding a combination pill to reduce 4 cardiovascular risk factors . it is assumed the novel concept in the cooperative medication patent application has never occurred to the authors . if such a notion did , then the authors would not limit such a formula to 4 cardiovascular risk factors , certainly not to one given formula . nothing of the published meta - analysis suggests the authors uncovered the beyond low dose or substandard combination therapy for which no entity has been known to postulate . the clinical allhat trial illustrates only about one - third of hypertensive patients were treated effectively with a single medication agent . the seventh report of the joint national committee on prevention , detection , evaluation , and treatment of high blood pressure ( jnc 7 ) states advanced hypertension requires combination therapy . there is much indecision regarding how to standardize the titration of combination therapy and what agents best serve the general population of hypertensive patients . this may well be related to the great concentration of single mechanism medications , used in high concentration , sought to mitigate complex pathologies , especially with the backdrop of significant malpractice litigation when decisions are made with excess ambiguity . carvedilol is a hypertension medication that blocks alpha - 1 adrenergic receptors , and blocks both beta - 1 and beta - 2 adrenergic receptors . lisinopril prevents angiotensin converting enzyme from converting angiotensin 1 to angiotensin 2 to lessen blood pressure . chlorthalidone prevents reabsorption of sodium and chloride in the kidney , creating a diuretic effect . amlodipine prevents calcium ion passage into vascular smooth muscle and the myocardium . clonidine works in the central nervous system to block alpha - 2 adrenergic receptors . hydralazine dilates peripheral vessels directly . potassium and magnesium are electrolytes lost when using chlorthalidone . pyridoxine is a vitamin involved in the mechanism of hydralazine . coenzyme q10 is found in most cells in the body and its deficiency is associated with many maladies , including hypertension . under the landmark combination idea , one may take carvedilol 1 mg ( low dose = 6 . 25 mg ), lisinopril 2 mg ( low dose = 10 mg ), chlorthalidone 4 mg ( low dose = 25 mg ), amlodipine 0 . 8 mg ( low dose = 2 . 5 mg ), clonidine 0 . 02 mg ( low dose = 0 . 2 mg ), hydralazine 5 mg ( low dose = 40 mg ), potassium 1 meq , pyridoxine 20 mg , magnesium 10 mg and coenzyme q10 , and combine the substandard doses in a single tablet . this tablet could provide more thorough treatment of the chronic hypertension process ( see fig1 ), and do it in a way that side - effects are mitigated ( see fig2 ). the idea of allowing the longer half - life medications , such as lisinopril and amlodipine to dissolve in an immediate release exterior of the tablet while providing a center matrix for slow - delivery of the remaining anti - hypertensives is a detail beyond the embodiment of this unique idea ( see fig3 ). either way , the concept lends itself to easier titration and tapering , thereby further lessening side - effects via the various half lives of the various medications . however , a biphasic tablet , possibly scored for further enhanced titration / tapering efforts , or the need to offer twice daily dosing , will need consideration . also , determining the practical stability of such a combination of medications is beyond the teaching intent of this novel treatment practice . further details , such as proportioning this prototype combination from a series of low starting doses or a consensus standard effective treatment dose is left for those with more theoretical medical actuary information , be it for initially treating a disease state of uncomplicated hypertension or any illness sought with this new model . likewise , type 2 diabetes mellitus ( formerly “ non - insulin dependent ” or “ adult onset ” diabetes ) is such a wide - scale malady that many medications exist , including various dosage forms , with fewer unique mechanisms . however , a cooperative combination using roughly ¼ the low dose or a consensus standard effective treatment dose could stand to allow the treatment to be effective longer , with greater tolerability , etc . the parts of this potential combination include : metformin , sitagliptin , glyburide and pioglitazone . metformin decreases glucose production in the liver . it decreases the absorption of glucose in the small intestine and it increases tissue sensitivity to insulin . sitagliptin increases insulin synthesis and decreases levels of glucagon . glyburide stimulates insulin release from the pancreas . pioglitazone increases insulin sensitivity in the tissues . levocarnitine is associated with improved glucose utilization . psylium husk slows the absorption of glucose and aids in the prevention of diabetic gastropathy . resveratrol is a dietary antioxidant that has been associated with the prevention of heart disease , a pathology associated with diabetes . a metformin 200 mg ( low dose = 1000 mg ), sitagliptin 12 . 5 mg ( low dose = 25 mg ), glyburide 0 . 3 mg ( low dose = 2 . 5 mg ), pioglitazone 4 mg ( low dose = 15 mg ), levocarnitine 200 mg ( low dose = 990 mg ), with psylium husk and resveratrol collaboration could be a revolution in diabetes treatment ( see fig1 & amp ; 2 ). the idea of allowing the longer half - life medications to dissolve in an immediate release exterior of the tablet and providing a center matrix for slow - delivery of the metformin is a detail beyond the intent of this unique idea ( see fig3 ). either way , the concept lends itself to easier titration and tapering , thereby further lessening side - effects via the various half lives of the various medications . however , a biphasic tablet , possibly scored for further enhanced titration / tapering efforts , or the need to offer twice daily dosing , will need consideration . the proportions may differ when clinical actuary or trial data is further developed , but the general concept is rational , unique , and untried . diabetes mellitus , like hypertension , is well understood to need combination therapy ( see examples in list 2a ). it is common consumer knowledge . consumer report &# 39 ; s best buy drugs , updated december 2012 , focused on oral diabetes medications , clearly stating , on the recommendation page , that taking more than one diabetes drug is often necessary , but taking more than one diabetes drug raises the risk of adverse effects and increases costs . similarly , treating hyperlipidemia could be best accomplished , initially , with a cooperative combination of medications . list 3a includes commercially available combinations that even include medications for different indications , such as hyperlipidemia and hypertension , or hyperlipidemia and clot prevention . as noted , the polypills mentioned previously combine various hypertension medications with an anti - clot mechanism , a hyperlipidemia treatment , some even containing potassium . simvastatin reduces 3 - hydroxy - 3 - methylglutaryl - coenzyme a reductase in such a way that it eliminates much of the fatty substances associated with cholesterol disease . fenofibrate works in a fashion not fully understood , but inhibits the formation of triglycerides and increases the breakdown of certain triglyceride lipoproteins . ezetimibe prevents the absorption of cholesterol in the small intestine . niacin works to decrease bad cholesterol made by the liver , inhibits fat tissue lipolysis , decreases liver esterification , and increases lipoprotein lipase activity . coenzyme q10 is found in most cells in the body and its deficiency is associated with many maladies . the use of a “ statin ” medication such as simvastatin reduces coenzyme q10 . omega - 3 - acid ethyl esters are part of the general population &# 39 ; s dietary deficiency and when supplemented are associated with reduced liver triglyceride synthesis . resveratrol is a dietary antioxidant that has been associated with the prevention of heart disease . the suggestion of combining simvastatin 4 mg ( low dose = 5 mg ), fenofibrate 5 mg ( low dose = 54 mg ), ezetimibe 0 . 5 mg ( only dose = 10 mg ) with niacin , coenzyme q10 , omega - 3 - acid ethyl esters , and resveratrol is consistent with the landmark concept of this application . the idea of allowing all but the simvastatin to be released immediately while providing a center matrix for evening delivery of simvastatin is a detail beyond the teaching embodiment of this unique idea ( see fig3 ). another readily obvious cooperative combination use may even be applied to psychological symptoms . it is often seen in clinical practice , that like the abovementioned combinations , the use of one available prescription medication is too often inadequate to appropriately control a given indication . often times , this may be related to many complicated confounding factors , but in the case of treating psychological maladies , the placebo effect is much greater . it may be anticipated that a reinvention of the current model can amplify such an effect , but if the chemicals used to symptomatically treat such psychological manifestations offer relief individually , then again the combination would be rational to hold more promise . again , this indication offers commercially available combinations ( see list 4a ). the combinations offered are for comorbitities of depression , and are done so with doses therapeutic for such comorbidity individually , such as anxiety , bipolar symptoms , or psychosis . likewise , the anti - depressant dose in the commercial combination is also a therapeutic dose . these combinations are not the cooperative substandard doses combined with at least three mechanisms used for the symptoms of depression treatment . sertraline works by selectively inhibiting the reuptake of serotonin , a chemical process associated with positive feelings . venlafaxine inhibits the reuptake of norepinephrine , serotonin , and dopamine , multiple chemicals associated with positive feelings . mirtazipine effects have not been fully elucidated , but have been associated with antagonizing alpha - 2 adrenergic and serotonin 5 - ht2 receptors . similarly , trazodone effects have not been fully elucidated , but have been associated with antagonizing alpha - 1 adrenergic and serotonin 5 - ht2a and 5 - ht2c receptors instead , while also inhibiting the reuptake of serotonin . likewise , amitriptyline effects are not fully understood , but are associated with the inhibition of the reuptake of norepinephrine and serotonin . the full effects of methylphenidate are not fully known , but it is a central nervous stimulant that affects dopamine transport systems . ariprazole is also a medication with effects not fully understood , but it is known to partially agonize dopamine and serotonin 5 - ht1a receptors while antagonizing serotonin 5 - ht2a receptors . the effects of ergocalciferol are extensive but the association of positive feeling and the general dietary deficiency of the city - dwelling population are the aim of its addition . also , tryptophan is a dietary precursor to serotonin , a key chemical for feelings of pleasure . similarly folic acid deficiency is associated with feelings of depression . sertraline 4 mg ( low dose = 25 mg ), venlafaxine 15 mg ( low dose = 75 mg ), mirtazipine 2 mg ( low dose = 15 mg ), trazodone 4 mg ( low dose = 25 mg ), amitriptyline 4 mg ( low dose = 25 mg ), methylphenidate 0 . 25 mg ( low dose = 2 . 5 mg ), aripiprazole 0 . 25 mg ( low dose = 2 . 5 mg ), with ergocalcipherol , tryptophan , and folic acid would be as comprehensive a chemical treatment there has ever been for the symptoms of depression , and consequently have the potential to be the safest and most effective at alleviating symptoms ( see fig1 & amp ; 2 ). the idea of allowing the likely stimulating medications , such as sertraline , methylphenidate , and aripiprazole to dissolve in an immediate release exterior of a tablet , yet contain a center matrix for slow - delivery of the remaining likely sedatives , such as mirtazipine , trazodone and amitriptyline is a detail beyond the intent of teaching this unique idea ( see fig3 ). either way , the concept lends itself to easier titration and tapering , thereby further lessening side - effects via the various half lives of the various medications . however , a biphasic tablet , possibly scored for further enhanced titration / tapering efforts , or the need to offer twice daily dosing albeit with a non - uniform morning versus evening tablet , will need consideration . the applications are many , but the abovementioned are just pedagogical examples of this new art applied to help make the abstract art tangible . the prototype tablet proportions have been contoured to not be exact proportions , via the author &# 39 ; s experiential knowledge from over a decade of intense study in the given areas of disease treatment . as the potential to better mimic the reverse of a given pathology and consequently lessen side - effects that characterize a given mechanism , the medication interactions should likewise be lessened . interactions will still be an issue , and in a greater quantity , as they are of clinical concern with the standard single potent active chemical agent model , but the clinical significance may actually be lessened when multiple mechanisms are represented in the way this art describes . the choice of which medication to prescribe for a particular indication , given hundreds of choices , will be mitigated through the radical simplification offered by cooperative combination therapy . initiating , increasing , or decreasing a given therapeutic regimen will be so rudimentary that it would likely significantly lessen medication errors , namely the institute of medicine reported most common errors . in so doing , the comparative effects will be better understood with a larger population being treated similarly . the clinical inertia , such as which single choice is better or which to add to a failing regimen , is drastically reduced & amp ; clinical goals may be reached to a tremendous degree . kubinyi , h . drug research : myths , hype and reality . nature rev , drug discov . 2 , 665 - 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