Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. Introduction Brazil. DF, Brasilia Author: Corresponding 3 2 1 o´ isnRibas Jos´e Wilson and safely treatment. intake, consensus food Keywords: a to inadequate establish contributing and to loss, factors trials mass important clinical fat-free randomized three loss, increase reduce GH to significantly imperative secretion. can is reduced sequelae. it MK-677 is However, which its with heart effectively. no sarcopenia, and supplementation congestive were of with GH There that development individuals sensitivity. of shown in the insulin profile have decreased levels. safety studies in unfavorable supra-therapeutic an bias but prevent had a promotes MK-677 may is However, MK-677 there and that however, failure. MK-677. showing feedback tolerated, to humans, A negative well attributable in intake. effects is to (MK-677) adverse food MK-677 secretagogue subject inadequate that GH and oral is indicate loss, the studies that and Available mass of reviews release fat-free efficacy secretion, and systematic GH safety GH of pulsatile the present reduced reporting at The is (Transparent looked which study. study duplications PRISMA sarcopenia, this recent of in review- and development discussed systematic title the and of to exclusion included contributing were visceral rules existing articles the abdominal the 5 http://www.prisma-statement.org/). to decrease process, held this meta-analysis- according and was After elaborated FFM it work. was Initially, of this study in decline efficacy. described the and ghrelin interest safety, prevent the active following factor-1, levels, orally growth IGF-I first tolerability. insulin-like and the acceptable decline sarcopenia, as GH the with (MK-677) increase elderly. with elderly (AVF) secretagogue would correlates the the GH mass fat elderly in in fat-free Thus, healthy in disability secretion secretion. decline in physical GH the (GH) and MK-677 pulsatile sense, hormone independence this increase growth of In may of loss patients. mimetic age frailty, ill of the critically development in with survival the associated lower for with factor associated is risk and important an is sarcopenia Introduction: Abstract 2020 26, May Ph.D MSc, 1 Filho, Zotarelli Jose Idiberto Dr. REVIEW SYSTEMATIC (MK-677) OF USE THE APPROACHES MAJOR ffiito o available not Affiliation eta cec masdr Brazil. Brazil. Ambassador, Preto/SP, Science S˜aoRio Bentham Jos´e Work, do Scientific Brazil. Zotarelli-Filho DF, the Brasilia of Medicine, Doctor Integrative for Center Advanced Clinic, Reviv Conclusion: K67 btmrn Hsceaou.Sroei.Elderly. Sarcopenia. secretagogue. GH Ibutamoren. MK-677. h ubro iaiiisdet g sepce odul y26.I hsseai,tedvlpetof development the scenario, this In 2060. by double to expected is age to due disabilities of number The O UCEMS ANI LEL:ABRIEF A ELDERLY: IN GAIN MASS MUSCLE FOR h otcnre acpnatetetmtosaentiinloefeigadrssac training, resistance and overfeeding nutritional are methods treatment sarcopenia confirmed most The 1 rsil alsRbioTeotonio Ribeiro Carlos Priscilla , o´ isnRbs ei lnc dacdCne o nertv Medicine, Integrative for Center Advanced Clinic, Reviv Ribas, Jos´e Wilson Methods: Results: oa f1 rilswr on novn K67 Hsecretagogue, GH MK-677, involving found were articles 18 of total A Objective: 1 1 naciia td,M-7 etaie he motn factors important three neutralized MK-677 study, clinical a In 1 h anojcie eet eemn hte oral whether determine to were objectives main The dbroJseZtrliFilho Jos´e Zotarelli Idiberto , HSECRETAGOGUE GH 2,3 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. ftesuc ffiacn n1suis ute,2suisddntdsls h nomto ntecnitof conflict the on information the disclose absence not the did Also, studies participants. 1. of of 2 Figure risk Further, number high studies. limited a a 1 with studies had in statement. 4 studies financing interest in Five of resulted risk. source evaluation uncertain overall the with the of studies bias, 2 of risk and for bias English tool Cochrane and conflicting the Portuguese some Considering in decided reported was investigator studies bias extraction Only third of articles. data A Risk the The 2. choose selection. reviewer to by decision The study evaluated. final reviewed and were the fully research made and and performed 1 points 2) reviewer and by (1 study performed each reviewers in independent bias the Two meta-analyses- to of by and risk according validated reviews and elaborated and systematic selection study was verified of Study study this later reporting (Transparent present in and PRISMA Medicine).The discussed tool review- of and http://www.prisma-statement.org/). DeCS systematic Initial- Library of the included in- searched. National rules searching were were the (US the by following databases articles System LIBRARY determined duplications Terms 14 COCHRANE were and MeSH process, AND descriptors title this OVID exclusion the After EMBASE, ly, existing PUBMED, work. the factor- 1). this held growth (Figure insulin-like was in sarcopenia, it secretagogue, described Initially, GH terest efficacy. MK-677, involving and found safety, were articles 1, 24 of total A strategy search and sources abdominal Data decrease and mass, muscle of GH decline Methods increase tolerability. the would [5]. acceptable prevent elderly elderly with healthy levels, the (AVF) in (IGF-I) in fat MK-677 I secretion visceral oral factor GH whether growth pulsatile determine with insulin-like increase to (Ibutamoren correlates and may aimed secretagogue study mimetic mass GH present ghrelin fat-free Thus, the active secretion. in Therefore, orally (GH) decline first hormone the growth the intracellular of sense, as in diseases, age MK-677) this disability the neurodegenerative - sarcopenia In physical with intake, of im- others. and associated caloric pathophysiology is decline and The independence reduced sarcopenia the mass disorders, patients. by of of ill hormonal Muscle influenced loss critically development stress, 2060. be frailty, in oxidative the by may survival of lower scenario, and double development with multifactorial this to the associated is In expected is for and [4]. is factor elderly regulation age risk kg the metabolic to 3.8 important and and due an 7 disabilities fitness is about physical of lose number for can women the portant with and context, [3]. men associated important this fat decade, is is intra-abdominal In 8th and mass increased the elderly for with Muscle In the factor respectively, [1]. in [2]. risk mass, disability patients life important muscle physical ill an of of and critically is decade independence in sarcopenia third survival of of shorter the loss development frailty, The in of regulation. peak development fitness the its metabolic after and decreases physical for mass muscle humans, In lwCato h ril eeto process. selection article the of Chart Flow ohaeinstrument Cochrane a dpe oass h ult fteicue studies. included the of quality the assess to adopted was 2 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. otreyas Haoede o nraesrnt nhatyedry nfc,srnt a mrvdin improved has strength fact, relationship In the two Finally, elderly. weeks. for 26 healthy for injections in testosterone GH with strength combination daily in increase alone following not GH take patients does who men alone hypopituitary older GH healthy elderly years, in normal three in improved GH to its on has effect because unobserved strength perhaps the and Although AVF, months, affect 12 at not although levels Finally, did LDL GH. [9]. reduced MK-677 increased (29), it elderly of AVF, women levels, effects reduce GH lipolytic postmenopausal not the did increased adults, neutralized MK-677 potentially effects Despite obese but adipogenic and and elderly. small orexigenic GH-deficient normal combined detect in in to (AVF) [9]. not designed fat use we not but visceral area method was cross-sectional abdominal CT study the reduces slice fat Surprisingly, the GH single lean although inaccurate placebo. groups, increase, the both with not with in than differences increased did MK-677 mass important muscle found with fat was thigh more Bodyweight total the GH. increased Although lipolytic of mass unlike placebo. stores, lean the fat limb than increases MK-677 a and ghrelin study, which after elderly, this anorexia, the more In physiological in increase counteract loss increase. to can weight GH that of to effect reflects cause attributable new which a not a is water, are appetite, that intracellular increased effects transiently in has [9]. life mimetic increase also average ghrelin FFM but concomitant increased the secretion A for GH perspective, stimulates mechanism kg. provide in- Ghrelin likely To 5.5 MK-677 the ~ placebo. is IGF-I. is mass, to from lifespan cell compared feedback average body kg adult’s with [7,8]. 1.6 adults an MK-677, by young in by (FFM) in loss activation observed Mass Fat-Free receptor levels the to ghrelin creased secretion sustained was a pulsatile mechanism experienced IGF-I an likely mimetic and is ghrelin The treatment GH MK-677 (GH) the of hormone took amplitude growth who the of subjects in safety elderly increase long-term Healthy the debate. production, much of GH area of scenario stimulating the In eeomn n Discussion and Development 3 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. sntkonwehrciial infiateet npyia ucinhv enahee.Measurement achieved. been it have IGF-I, function these serum physical four independently, on increased the live effects MK-677 of to significant with three clinically ability treatment in whether and Although known placebo domain significant. not over physical statistically is improvement performance, not greater functional were showed limb differences and MK-677 lower MK-677 patients between of [13]. differences although measures scores significant study, SIP-NH no overall were this compared therapy. or There 63-107) of In measures placebo. = end performance in (CI) the daily functional 8-28) interval after improving of = confidence months in CI months (95% 6 (95% placebo 6 84% further increase by to a 17% levels assignment for a IGF-I Random followed with serum were extremity. increased Patients involved treatment the placebo. MK-677 or at if MK-677 replacement congestive excluded with hip hypertension, were uncontrolled treatment total Patients after cancer, fracture or mellitus, days [13]. diabetes hip and failure trauma, 18 older competent (161) heart severe and mentally most or years sixty-one fractures and 65 at multiple and aged fractures had consent hundred or they with postoperative One postoperatively, patients the stable fracture days and hip clinically centers. included 14 outpatient rehabilitation Canada, criteria Entry in and and Switzerland, recovery included. 3 hospitals were Belgium, functional patients between care double-blind Denmark, fracture acute recruited randomized, Sweden, hip in were placebo-controlled, on England, fracture, Patients a MK-677 in to States. of conducted centers compared effects it United medical ng/mL the Thus, Thirteen 51.4 evaluate individuals. by to study study. [12]. elderly necessary the increased failure was mobile during patients heart congestive it falls previously treated with fewer context, individuals stairs in in this experienced climbing levels profile group In of speed safety IGF-1 unfavorable gait MK-677 power an increased average Also, the had as the MK-677 Also, well However, weeks, receive as placebo. averages. placebo. 24 placebo, to the in After to assigned to compared difference 61). considerably patients point compared = increased 0.7 fracture group (n a MK-677 hip placebo the with or elderly in 62) W 123 12.5 = These at at (n looked MK-677 <0.001). placebo. of study (p with 25mg/day compared double-blind MK-677 [11]. MK-677 after randomized, MK-677 with to treated higher Another attributable subjects times effects in 0.001). 1.76 adverse IGF-1 (p> on in no was placebo increase were placebo after IGF-1 greater There higher versus mean 65% times MK-677 a 1.07 the demonstrate of was MK-0677, data IGF-1 effect average receiving the The a patients evaluated patients. is In study hemodialysis there 22 crossover however, in tolerated, double-blind levels well randomized IGF-1 is a supra-therapeutic MK-677 prevent addition, that may In indicate [11]. and MK- sensitivity recent studies feedback that Available insulin A negative showing decreased humans, sequelae. to [10]. in in its subject intake bias (MK-677) and is secretagogue food GH that GH inadequate of oral release and levels the GH loss of pulsatile mass efficacy promotes and fat-free number safety 677 secretion, large the GH development at a the looked reduced of to contributing study is studies factors which important require three would sarcopenia, neutralized MK-677 result of study, clinical this one be but in would addition, bone, fracture In on [8]. of MK-677 risk years months The many of 12 GH. over effects with at individuals the as decreased of of remodeling, 18 density measure bone least mineral increased at best bone with for the neck consistent required in Femoral is is increase which treatment density. small MK-677, and [11] bone decreases with the did increased glucose. initially that which density demonstrate fasting mineral stated MK-677, to in bone months with increase be GH, the studies with cannot treated underlie short-term it patients glucose may of cortisol, In study fasting results serum our in the in in increases the on found increase and Small Based cortisol significant GH in [11]. serum statistically Both months. mortality elderly a intake. 12 the increased find food at in not with inadequate found glucose and were associated the blood FFM, HbA1c to and is contributing of and resistance factors loss and important insulin secretion, three frailty increase GH neutralized MK-677 reduced of MK-677 adults, characteristic sarcopenia: older of healthy a development of [10]. study is our adults In sarcopenia healthy elderly. in sense, not this but found adults, In been fragile has in capacity physical performance Increasing improve nonlinear. substantially is to performance strength physical and strength between 4 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. hs nig otatwt iia,rnoie,dul-ln,paeocnrle td yBc ta.[13] al. et Bach by part study in placebo-controlled due double-blind, been randomized, have [15]. similar, may heart group a group with this congestive contrast ibutamoren developed in findings the of (1.7%) These high in group rate CHF pressures. placebo the of blood the rate elderly increase in basal higher one lower 123 could the and to in although ibutamoren (6.5%) study, recovery group the that study fracture ibutamoren during placebo-controlled the concerns hip CHF in double-blind, to in patients ibutamoren randomized, Four ibutamoren due with only (CHF). studies of the early failure are term was role discontinued data Long and the was safety treatment studies. examined However, of that most studies [12] weeks ibutamoren. of few 24 of sizes al. during with use small et patients safe, the and Adunsky lengths with be overall events available. to short adverse are appear the serious to secretagogues at due hormone looking limited growth review literature, this in current cited of limits determine [15]. functional the to in anabolism How- the Within needed results increasing Although or are and stay group. studies improvement. hospital breakdown further of significant ibutamoren protein fracture length anabolism, a mortality, reducing the on hip affects improvements, considered in ibutamoren catabolism in not ibutamoren of speed down were impact placebo slowing gait they positive whether all to second that a and in A compared suggests small power group work so (p=0.036). ibutamoren climbing above ibutamoren were fracture assessing stair the increases hip design in in these before improvement ever, life similar independent independent were an a improved who more found with measures those a recovery, performance (n=123), of towards extremity 70% tendency study signif- lower in a a smaller four particular also show of in not was out and did There three patients, group although ibutamoren group. placebo life, the this to of outcomes, compared in quality functional group on assessing ibutamoren the In impact in dose icant respectively). observed daily 17%, were in a levels elevations vs. IGF-1 conclusion, on (84% in In based increases elderly p<0.01). significant [14]. the more 0.37; formation in Thus, = and turnover correlated resorption (r bone osteocalcin group stimulates bone mean serum secretagogue, MK-677 of basal and GH markers in the placebo) n active change biochemical in vs. and orally The IGF-I <0.001 677 an serum placebo). (p MK-677, MK-677). for for basal vs. 10.4% of in groups) daily in <0.05 by 63 MK-677 change MK-677 (p BSAP combined = the 22.6% of and (all (n at with mg 29.4% weeks MK-677 NTX by with 7 25 of Treatment osteocalcin next or excretion therapy). the serum 10 urinary of for mean 5, weeks daily increased or 9 MK-677 weeks weeks completed of 9 placebo 9 mg in 25 for for impairment. 28 by doses functional daily followed = for placebo weeks, mg criteria oral 2 50 objective initial by receive met who followed the to biolog- people weeks, the randomized elderly Subsequently, 2 105 were [14]. for in (55-94%). Subjects placebo) studied levels daily were IGF-I 30) vs. MK-677 serum of = <0.05 increased received effects significantly (n (p ical people 2 MK-677 MK-677 8% studies, elderly for of by both healthy mg osteocalcin placebo in urinary 50 Thus, 25 serum average or addition, or mean increased In MK-677 weeks increased weeks mg 4 placebo). MK-677 2 for 25 for weeks. vs. 20) or MK-677 2 <0.05 = initially mg mg (p (n were 25 respectively 10 placebo data and 17%, of a mg Dose-response and doses 10 10% levels. with oral by Treatment post-treatment received NTXs 10-12/group). and who (BSAP) = Pre phosphatase subjects (n and - alkaline weeks elderly marker, IGF. bone-specific healthy resorption and and in formation bone osteocalcin obtained bone a serum of cross-links, of markers (NTXs) determination (65 as for N-telopeptide weeks. chronic elderly collected of 2-9 187 of was determination trials. in effect blood for clinical markers the placebo-controlled collected turnover determined double-blind, was bone bone randomized, We Urine and on three IGF-I. IGF-I GH in produced serum of enrolled stim- on over) locally effect and and MK-677 large or turnover years secretagogue a circulating bone GH Probably increases of of individuals. and stimulation administration elderly vitro by to in mediated administered osteoblasts is when stimulates activity (GH) osteoblast hormone may ulates stimulation growth GH sense, sufficiently alternatively, this studies; be [13]. intervention In not improvement small may functional of significant measures objective in performance primary result high functional the measures, not outcome Current as validated use of evaluation. lack for the initial to responsive of due difficult lack is patients and fracture variability hip in trials clinic 5 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. References nothing. declare and authors loss The interest mass of fat-free trials conflicts clinical , randomized of factors increase Declaration secretion. to important imperative treatment. GH is three consensus reduced it a However, reduce are establish effectively. significantly which to and safely can sarcopenia, but intake, training, of MK-677 food resistance development inadequate with and the overfeeding supplementation to nutritional that are contributing shown sarcopenia treating have of studies methods confirmed most regular well The with as followed ibutamoren, ibutamoren, be with treatment for should during recommended patients Conclusion [10]. levels is These monitoring IGF-1 daily HbA1c trials. and treatment orally and controlled composition waste mg glycemia randomized body include 25 as in in of ibutamoren changes studied dose of for dose initial use examinations the An the is deficiency. for this GH indications as as for current well treatment also as literature, as should conditions, scenario. the and work of recovery on variety Future and a based exercise GH. under studies Therefore, catabolic exogenous outcomes safety the patient with larger in on ibutamoren However, ibutamoren composition of of body use. effects safety on ibutamoren the ibutamoren the of determining to compare context on attributable the accurately focus directly in should to hyperglycemia effects that of needed adverse risk parameters are other increased the an few supports with the sleep, [8]. literature use, in current data and the changes safety sense, MLG, long-term adiposity this large turnover, or In and parameters bone program muscle exercise individuals, functional an studies recovery, obese effects available of hospital positive context in Although include stimulation, investigated appetite and parameters. children, further loss important in be velocity other of growth or on states data into ibutamoren composition Available insight of on body objective effect little [8]. on beneficial provide currently support treatments a drugs but are support treatment, ibutamoren these studies There ibutamoren of of with existing outcomes. levels effects durations IGF-1 patient although the prolonged and impacting GH ibutamoren, for and in cohorts levels of increases support GH large effects elevating evaluating in the studies observe drugs examining few these not studies for did roles few patients beneficial elderly currently study group healthy placebo-controlled are ibutamoren 32 double-blind, There the in randomized, administration in a ibutamoren fracture. effect [15]. Nevertheless, hip of effects adverse from adverse effects clinical (p<0.05). recovering 4-week patients a group the elderly to placebo 161 evaluating due in the months treatment in 6 discontinued than for patients ibutamoren of more use However, the examined also who HgisJ re .Ccrn adokfrSseai eiw fItretos eso .. [up- 5.1.0 Version Interventions. of Reviews Systematic for Handbook Cochrane S. Growth Green J, al. et Higgins TE, 6. Stevens J, Busby-Whitehead MF, Bellantoni Schwartz T, Munoz, Munzer C, JD, McKeever Sorkin S, MR, Korenman Blackman D, 5. Kiel F, Kaiser M, Gelato Recombinant M, of Farmer review J, safety Ng 2008. Ongoing D, Plotkin UpToDate. Professionals: implica- Healthcare 4. editor. clinical for and Podcast BD, activation Safety of Rose Drug mechanism FDA FDA. receptor: In: hormone 3. growth The UpToDate. MJ. Waters AJ, hormone. Brooks growth 2. of Physiology S. Melmed 1. ae ac 01.TeCcrn olbrto;2011. controlled Collaboration; randomized Cochrane a The 2011]. men: March and dated women aged healthy in 2002;288:2282–92. subjects. administration JAMA elderly steroid trial. frail sex in secretagogue and GH hormone oral an MK-677, of Use 1997;4(SupplA):35–36. MA. Bach Metab G, Endocrinol Gormley D, death. Krupa of R, risk increased possible and (somatropin) Hormone Growth Human 2010;6(9):515–25. Endocrinology. reviews Nature tions. MA. Waltham, 6 Posted on Authorea 26 May 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.159050681.10910720 | This a preprint and has not been peer reviewed. Data may be preliminary. CamnI,Bc A a atrE amrM rp ,Tyo M ta.Siuaino the of Stimulation al. et AM, Taylor D, Krupa M, Farmer E, Cauter Van MA, Bach adminis- Oral IM, BJ. Chapman Gertz 15. K, Cerchio D, Krupa J, Ng J, Bolognese D, Plotkin MA, Bach MG, Murphy 14. Rizzoli JS, Christiansen JP, H´ebert Devogelaer G, R, Thamsborg C, MK- Zetterberg K, DA. Rockwood Papanicolaou MA, Bach N, Liu 13. Y, Berd BB, Scott J, Lutkiewicz N, Heyden MK- J, agonist Chandler receptor A, ghrelin Med Adunsky Oral Sex WK. 12. Bolton Secretagogues. MO, Thorner Hormone BD, Growth Gaylinn of JT, Patrie Efficacy GA, and Campbell Safety 11. The AW. Pastuszak JT, Sigalos 10. Ns ,PzoiS,OieiM,e l ffcso noa hei iei nbd opsto and composition body on mimetic ghrelin oral an of Effects al. et MC, Oliveri SS, Pezzoli treatment and R, prevention Nass in 9. hormone activity Growth physical al. and et Protein Posturzy´nska LA, A. M, Barbour Tur˙za´nska Drelich JW, 8. K, Leitner CE, McCurdy BD, Gaylinn K, Iida JP, Rincon Del 7. oou M-7)i elh lel ujcs h ora fciia nornlg n metabo- and endocrinology secre- clinical GH of a of Journal administration The oral subjects. daily elderly by 1996;81(12):4249–57. healthy axis lism. in I (MK-677) factor growth togogue (GH)-insulin-like hormone growth Jul;14(7):1182- 1999 Res. and Miner healthy Bone in J turnover Group. bone Study of 8. MK-677 markers The increases adults. elderly MK-677 impaired secretagogue functionally hormone growth patients the 0677 in Apr;52(4):516-23. of MK secretagogue, tration 2004 V; hormone Fuh Soc. growth J, Geriatr Ng oral Am AM, an Taylor J MK-0677, J, fracture. of Farrington hip effects T, Schwab with The L, Group. Yu Study O, Fracture Gluck Hip N, Beisaw JL, Ochsner R, multicenter, a doi: 9. Sep-Oct;53(2):183-9. fracture: Nov 2011 hip 2010 Geriatr. from Gerontol Epub recovering Arch 10.1016/j.archger.2010.10.004. patients study. IIb of phase treatment placebo-controlled the randomized, for mesylate) (ibutamoren 10.1093/ndt/gfw474. study.0677 blinded doi: randomized a 1;33(3):523-530. Mar patients: hemodialysis 2018 Transplant. in 1 Dial factor Nephrol growth insulin-like 8. serum increases Apr 0677 2017 Epub 10.1016/j.sxmr.2017.02.004. doi: Jan;6(1):45-53. 2018 Rev. trial. randomized a adults: older doi:10.7326/0003-4819-149-9-200811040-00003. healthy in outcomes clinical 1):1660-1666. cz 2019;72(9 Lek. Wiad sarcopenia. of mechanism 2007;56:1638–46. tissue: Diabetes adipose resistance. in activity insulin 3-kinase hormone-mediated phosphoinositide growth and for expression alpha p85 of regulation 7 n nenMed Intern Ann 2008;149(9):601–611. .