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Potential for use of stem cells in breast resconstructive surgery

Breast cancer is the mostcommon cancer experiencedby women worldwide. TheAmerican Cancer Societyestimates that over 214,000new cases of breast cancer willbe diagnosed in 2006 anddata from the AmericanSociety of Plastic Surgeonsshow that more than 80,000breast reconstruction surgeriesare performed every year.

The discomfort and psy-chosocial stresses caused bymastectomy of one or bothbreasts should not beignored. Current surgicaloptions for breast recon-struction are quite invasiveand involve either implantsor transplantation andreshaping of fat fromanother part of the body.Adipose- or fat-derived stemcells may be able to providea better, alternative sourceof durable replacementsoft tissue.

‘Adipose- or fat-derived stem cells may be able

to provide a better, alternative source of durable replacement

soft tissue.’

Stem cells have been her-alded by many as a potentialcure for a wide variety of dis-eases, ranging from the neu-rological, such as Parkinson’sdisease, to autoimmune dis-orders, such as diabetes.Their potential for use in tis-sue diseases also originatesfrom their ability to develop

into specific cell types. Fat-derived stem cells have dem-onstrated, when subject todiffering laboratory condi-tions, differentiation intocells characteristic of bone,cartilage, fat, nerve, muscleand blood vessels.

Teams from the Universi-ties of California in LosAngeles (CA, USA) and theUniversity of Pittsburgh firstreported the isolation ofstem cells from fat in 2001.This has led to researchinvestigating their potentialwith regards to the treat-ment of heart attack, strokeor bone injury, amongothers.

It is estimated that removalof 1 lb of fat in a proceduresuch as a tummy tuck canyield up to 200 million stemcells. When cultured in a lab-oratory, these can be multi-plied up to ten times over a2-week period. Therefore, itis hoped that surgeons will beable to obtain the requiredstem cells from a patient’sstores of abdominal fat.

The current focus at theUniversity of Pittsburghinvolves a combination offat-derived stem cells with anextracellular matrix of micro-scopic beads that hasregenerative properties.

Results from preliminaryanimal studies are promis-ing. The stem cells appear toattach to the beads easilyand can be induced into dif-ferentiating into mature fatcells. When injected

subcutaneously into rats, thecellular combination formedwhat the researchers describeas ‘a mound’ of tissue.

‘It is estimated that removal of 1 lb of fat in a procedure such as

a tummy tuck can yield up to 200 million

stem cells.’

Fat from breast cancerpatients is currently beingused as the stem cell sourcein order to ascertain if thesebehave in the same way asthose derived from healthywomen. In addition, studiesare also being conducted intowhether or not these stemcells have any impact on can-cer cells. “A major question iswhether or not they will insome way promote thegrowth of cancer cells. Wecertainly hope this will notbe the case,” commentedJ Peter Rubin, leader of theresearch group and AssistantProfessor of Plastic andReconstructive Surgery at theUniversity of Pittsburgh.

If successful, this methodhas the potential for regener-ating new breast tissue, agoal that will certainly beappreciated by the manywomen who are affected bybreast cancer and mastec-tomy every year. In fact,according to the AmericanCancer Society, over 214,000new cases of invasive breastcancer will be diagnosed bythe end of this year.

Researchers from the University of Pittsburgh (PA, USA) are investigating whether fat-derived stem cells might provide a new and improved method of breast

reconstruction following surgery.

Heart attack patients to

receive therapy with their own

stem cellsA total of 50 patients across two hospitals in London (UK) are due to have stem cells removed from their own bone marrow and injected into their heart as part of a groundbreaking new attempt to repair the damage caused to the heart tissue as a result of heart attack.

It is hoped that the stem cells will develop into healthy heart tissue and repair the damage caused by acute heart attack, in order to delay or prevent the progression to heart failure. The trial, which is to receive funding from the UK Stem Cell Foundation, will take place at the London Chest Hospital and Heart Hospital and will be the first to examine the effects of using stem cells within the 5-h time window following an acute heart attack.

The project follows on from previous studies in Europe that showed success in animal models. Speaking of the project, Dr Anthony Mathur, Consultant Cardiologist at the London Chest hospital, commented “If we can demonstrate improvement in the quality of life of patients, then this will be a significant step forward in the treatment of heart disease.” He added that “because the stem cells are taken from the patient themselves, there are minimal ethical issues surrounding this procedure. There is also less likelihood of rejection complications.”

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694 Therapy (2006) 3(6)

Priority Paper Alerts A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain.

Wernicke JF, Pritchett YL, D’Souza DN et al. Neurology 67(8), 1411–1420 (2006).

This randomized, double-blind, controlled trial aimed to evaluate the efficacy of the serotonin and norepinepherine reuptake inhibitor, duloxetine, in the reduction of pain and secondary outcome measures in a group of patients with diabetic peripheral neuropathic pain (DPNP). Administration of duloxetine 60 mg (once and twice daily) provided an improvement in the management of DPNP with a rapid onset of action. The trial further confirms previous findings that the drug is effective and safe for the management of DPNP at doses of 60 mg once and twice daily.

Evidenced-based treatment of opioid-dependent patients.

Van den Brink W, Haasen C. Can. J. Psych. 51(10), 635–646 (2006).

By a process of screening of all available published studies on the treatment of opioid dependence, this trial concluded that opioid dependence is a chronic, relapsing disorder that is difficult to cure. However, effective treatments are currently available to stabilize patients, which results in an increase in life expectancy and quality of life.

Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.

Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. N. Engl. J. Med. 355(18), 1851–1862 (2006).

Describes two trials, the National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial, which examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer in 2391 women with early breast cancer.NEAT compared four cycles of epirubicin, followed by four cycles of CMF, with six cycles of CMF alone. The BR9601 trial examined four cycles of epirubicin, followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. Comparison of the trials concluded that epirubicin plus CMF is more effective than CMF alone as adjuvant treatment for early breast cancer.

Artificial pancreas to control insulin levels in young patients

with Type 1 diabetes

A team of scientists from the Univer-sity of Cambridge (Cambridge, UK)have begun work on the develop-ment of an artificial pancreas for usein children and adolescents withType 1 diabetes. It is hoped that the‘closed-loop’ device, composing aglucose sensor with an insulin pump,will be able to regulate the highlyvariable blood glucose levelsobserved in children and adoles-cents, by measuring glucose levels ona ‘minute-to-minute’ basis and calcu-lating the correct dose of insulin tobe delivered by the pump. Clinicaltrials of the device are due to beginin January 2007.

Lead researcher with the group,Roman Hovorka, explained “Insulinneeds to be more accurately releasedto attain near-normal levels of bloodglucose and to reduce the risk of dan-gerous low blood glucose levels – thegreatest fear for parents of people with

diabetes as it can result in hospitaliza-tion, coma and rarely, permanentbrain damage or death, if not treatedin a timely manner.”

He continued that the use of anartificial pancreas would “enable thejuveniles to maintain healthier, morestable blood sugar levels.”

It is hoped that the trials will pro-vide those involved with the ability tomonitor their blood glucose at homeusing the device after 2 years, and toprovide commercial availabilitywithin the next 4–7 years.

It is estimated by the AmericanDiabetes Association that one in threepeople born in the USA after the year2000 will develop diabetes in theirlifetime. In addition, Type 1 diabetesis now one of the most common dis-eases of childhood, more so than can-cer, multiple sclerosis and cysticfibrosis, and can reduce lifeexpectancy by up to 15 years.

HIV gene therapy shows promise as alternative to antiretroviral drugs

The many complications and side-effects, in addition to the mountingresistance to antiretroviral drugs,have highlighted the importance ofthe development of an alternative totherapy for the millions of HIV suf-ferers worldwide. It is for this reasonthat the results from a recent trial offive patients treated at the Universityof Pennsylvania (PA, USA) withHIV gene therapy, have been greetedwith optimism and hope.

Researchers have treated patientswho had previously not respondedto antiretroviral therapy with a disa-bled form of the HIV virus carryingadded genetic material to block

reproduction. Treatment over the9-month period resulted in the sta-bilization and, in one case, sus-tained, dramatic decrease, in viralload, suggesting a future for the useof gene therapy in place ofantiretroviral drugs.

The results of the trial have beenmet with caution, however, as the trialwas not large enough nor sufficient tomeasure long-term side effects, withBruce Levin, Researcher with thegroup, commenting “Just because thishas produced encouraging results inone or two patients doesn’t mean itwill work for everyone. We havemuch more work to do.”

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Risk of development of chronic fatigue syndrome linked to early childhood trauma

According to results from two studies,published in the November issue of theArchives of General Psychiatry, traumaexperienced during childhood, in addi-tion to emotional instability at anypoint in life, may potentially be riskfactors for the development of chronicfatigue syndrome (CFS).

There are an estimated 1 milliondiagnosed cases of CFS in the USA,with millions more suffering from con-ditions similar to the disease but notreaching the strict requirements fordiagnosis. CFS is observed more fre-quently in women between the ages of10 and 59 years and is estimated to costthe US economy US$9 billion annually.

“We’re talking about the biological underpinnings of a

real and very debilitating illness.”

Speaking independently of the studyresults, Nancy Klimas of the University ofMiami Miller School of Medicine (FL,USA), commented: “We’re not talkingabout a bunch of stressed-out people.We’re talking about the biological under-pinnings of a real and very debilitating ill-ness.” She added that the purpose ofstudies such as these is to “remove thestigma of a psychiatric overlay and put itback in biology, where it belongs.”

Participants in one of the studies wereasked to complete a questionnaire onchildhood trauma (sexual, physical emo-tional, emotional neglect and physicalneglect) and psychiatric symptoms, suchas depression and anxiety, in addition tomedical testing.

However, the results have been metwith a note of caution as they aremerely preliminary, with CharlesGoodstein of the New York Univer-sity School of Medicine commentingthat “These studies bear out what wehave learned in medicine and in psy-chiatry: illnesses of all types are deter-mined in large part by an interplay ofgenetically determined predispositions

and environmental factors.” However,he added that “These are interestingelementary papers.”

“Illnesses of all types are determined in large part by an interplay of genetically

determined predispositions and environmental factors.”

Dr Goodstein also commented on thedifficulty in diagnosing the disease “CFSremains an elusive condition...it seriouslyincapacitates patients, but physicians arestumped by the lack of objective signs onphysical examination.”

In addition to the results from thesestudies, the US CDC recently launchedan awareness campaign for the disease,which still suffers from the stigma previ-ously associated with it. The relative diffi-culty in diagnosing the disease has in thepast led to claims of hypochondriasis andwas even dubbed as ‘yuppie flu’ when itwas first recognized in the late 1980s.

The CDC and NIH have also recentlyannounced plans for a US$4 millionresearch program that aims to study thecauses of CFS, as well as potential treat-ment options. The CDC have estimatedthat as many as 80% of people with CFSmay not be aware that they are sufferingfrom the disease as the symptoms,including headache, sore throat and mus-cle pain, are so common in the generalpopulation. Susan Levine, a CFS special-ist, added that “This physical disease isquite serious and causes profoundly inca-pacitating problems in those sufferingfrom the disorder.”

The CDC have also issued advise tosufferers to avoid the use of herbal rem-edies, such as comfrey, kava, chaparral,bitter orange, licorice root andyohimbe, due to their potential danger.

It is hoped that studies such as these, aswell as increasing public awareness andperception of the disease, may help toidentify at-risk groups and result in earlierdiagnosis and potential treatment. The

current study compared 43 patients withCSF with 60 control subjects chosenfrom a sample of over 56,000 adults inthe Wichita area (KA, USA).

The study found that patients withCFS reported a three- to eightfold higherlevel of exposure to childhood traumaand psychiatric symptoms comparedwith controls. However, the most notableresults were seen in the prevalence ofemotional and sexual abuse, whichincreased the risk of CFS by 77%.

‘...as many as 80% of people with CFS may not be aware that

they are suffering from the disease as

the symptoms, including headache, sore throat and

muscle pain, are so common in the general population.’

Christine Heim, lead author of thestudy, commented that “Not all peoplewith CFS had histories of childhoodtrauma, and not all of the people who hadchildhood trauma had CFS.” She contin-ued that “It’s not the whole picture. Theremust be some sort of resilience, and if weknew what those were, that would beimportant for prevention.” In addition,Nancy Klimas noted that “It’s importantto see that CFS has subgroups…it’s reallyimportant not to merge all these observa-tions into one solid, big group.”

A second study examined a group of19,192 Swedish twins, of which 1570had CFS. Again, it was demonstratedthat those who had experienced emo-tional stress at an early age were morelikely to have CFS, and those whoclaimed that they experienced day-to-day stress were between 64 and 65%more likely to develop CFS than thosewho did not.

Data published previously by theCDC in the journal Pharmacogenomics,indicated that people who suffer fromCFS have a genetic make up that affectsthe body’s ability to adapt to change.

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696 Therapy (2006) 3(6)

Norepenipherine and the stress response linked to accelerated cancer growth

A report, published in the Novemberissue of Cancer Research, has impli-cated norepinephrine (NE), a hor-mone involved in the stress response,in cancer metastasis and acceleratedtumor growth.

It had already been shown by AnilSood, of the University of Texas MDAnderson Center (TX, USA), that NEcaused the production of matrix met-alloproteinases (MMPs) and vascularendothelial growth factor (VEGF) inovarian cancer cells. These recent find-ings further illustrate that the effect ofNE on cancerous cells is not just lim-ited to ovarian cancer and may well bea common factor in all cancer cellgrowth and metastasis.

Ronald Glaser of Ohio State Univer-sity (OH, USA), and lead author of thearticle, commented “This opens up an

entirely new way of looking at stress andcancer that’s different from currentinterpretations.”

The researchers treated nasopharyngealcarcinoma (NPC) cell lines with NE toinvestigate the effects of NE on theexpression of two MMPs, MMP-2 andMMP-9, which play a part in cell scaffoldbreakdown, and VEGF, involved in thegrowth of blood vessels. As anticipated,following treatment with NE, the cells allproduced MMP-2, MMP-9 and VEGF.The group tested several different types ofNPC tumors, all of which expressed boththe MMPs and VEGF. Glaser com-mented that “From this we can say thatthere is a likelihood that all NPC tumorswill have these receptors as well.”

Eric Yang, a coauthor of the paperadded, “MMP-2 and MMP-9 con-tribute to the aggressiveness of these

tumors. It isn’t clear exactly how theyare operating but they may work withVEGF to facilitate blood vesselgrowth in new tumors so that theycan grow.”

The researchers also investigated theaffects of propanol on tumor cells fol-lowing treatment with both NE andnoradrenaline, and Glaser pointed out,“This suggests a new approach to possi-bly fight some cancers – the prescribingof β–blocker-type drugs that wouldblock these receptors and perhaps slowthe progression of the disease.”

He continued that “Using thisapproach may not cure this cancer butperhaps we could slow down itsgrowth, making the tumor more sensi-tive to anticancer therapy, and there-fore extending the patient’s lifespanand improve their quality of life.”

Antimalarial drug shows potential in treating vCJD

A team of German chemists have madean exciting discovery, which mayadvance the treatment of prion disease.

The rare and fatal human neuro-degenerative condition, Creutzfeldt-Jakob disease (CJD), is unique. Prionsplay the role of the infectious agent,which replicates without nucleic acids,instead inducing the conversion of anormal prion protein to a misfolded iso-form. The conversion of cellular prionprotein (PrPC) to pathogenic scrapieprotein (PrPSc) is conformational.

Previous research highlighted thecapabilities of the antimalarial drug,quinacrine, to destroy malformed pri-ons and abolish prion infectivity in cellculture models, but has shown little suc-cess in vivo. Other drugs proved to beineffective when applied to prion-infected rodents as they lackedblood–brain barrier permeability.

Heterocyclic compounds, such asquinacrine, an acrine derivative, targetlipid metabolism, which controls

PrPC conversion. Quinacrine acts asan effective antioxidant and executesits antiprion activity by redistributingcholesterol from the plasma mem-brane to the intracellular compart-ment, which causes destabilizing ofmembrane domains, although theexact mechanism of antiprion actionremains unclear. The drug is currentlyin clinical trials as a therapy for humanprion diseases, which are due to end inMay 2007.

The team of chemists, lead byGmeiner, have synthesized 18 novelcompounds in an attempt to highlightsynergistic antiprion effects. Theagents are structural chimeras ofquinacrine and the tricyclic anti-depressant, imipramine, which alsohas antiprion activity. The novel classof potential pharmaceuticals have an‘unprecedented’ ability to destroy themisfolded proteins and have beenshown to greatly increase the antiprionefficacy of quinacrine. A recent study

that appeared in the November issueof the Journal of Medicinal Chemistrydescribes the chemical synthesis andbioassays of a focused library of boththe compounds involved.

An analog containing an unsubsti-tuted acrine moiety combined withan ethylene spacer proved to exhibitthe strongest potency, with an EC50value of 20 nM and full antiprionactivity of 75 nM when comparedwith quinacrine.

According to the National CJD Sur-veillance Unit, in the UK alone, therehave been 150 deaths attributed to thedisease since 1990. The nature of thedisease, including the late-onset symp-toms, make it difficult to treat. In addi-tion, it is not yet known whether theneurodegenerative process can bereversed after the prions have beenremoved. The synthesis of these com-pounds is a step in the right directionand provides hope for future drug trialsfor prion disease treatment.

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New research demonstrates the importance of the diagnosis of diastolic abnormalities in patients with heart failure

Results from a recent study have revealedthat the incidence of heart failure due todiastolic abnormalities is much higherthan previously thought. In fact, thestudy, carried out by researchers at theMayo Clinic (MN, USA), showed thatin a group of 556 people being treatedfor heart failure, 80% had diastolicabnormalities and 55% had normal ornear-normal ejection fraction (EF). Inaddition, 37% of patients were found tohave a combined systolic and diastolicmalfunction. However, patients with alow EF were found to have moremoderate or severe diastolic dys-function than those with apreserved EF.

The findings, publishedin the November 8th issueof JAMA, contradict cur-rent recommendations toexamine for systolicabnormalities in patientswith heart failure. Vero-nique L Roger, Consult-ant in cardiovasculardisease and member ofthe research group, high-lighted the importance ofthese findings for the physi-cian “What this means is thatthe practicing physician has torecognize that heart disease is not adisease, but a spectrum.”

The results of the study have alsohighlighted the lack of current treatmentoptions for heart failure due to diastolicabnormalities. Barry Borlaug, Consult-ant in cardiovascular disease at the MayoClinic, commented “This is a majorpublic health problem…half of all heart-failure patients have preserved ejectionfraction. There is not much in the way ofproven therapies for it. The Roger studyshows that mortality for both conditionsis the same, about 6% in the course ofthe study.”

Study limitations included a degreeof population bias since the patientswere identified through Mayo Clinicelectronic medical records. In addition,

the data is not transferable to under-represented ethnic groups. However, itis hoped that the trial could potentiallyprovide a benchmark for comparisonacross different populations.

In another report in the same issue ofJAMA, researchers from the Universityof California (CA, USA) demonstratedthe importance of systolic blood pres-sure. It found that upon admission to

hospital for heart failure, patients witha higher systolic blood pressure hadmuch better outcomes than thosewhose systolic pressure was low.

The cohort study examined datafrom the Organized Program to InitiateLifesaving Treatment in HospitalizedPatients with Heart Failure (OPTI-MIZE-HF) registry, which includedover 48,000 people treated for heartfailure across 259 hospitals in the USAin 2003 and 2004. It was found thatthe in-hospital risk of mortalityincreased by 21% for each 10-mm dropin systolic blood pressure.

Gregg Fonarow, Professor of cardio-vascular medicine and science and mem-ber of the research group, commented onthe significance of these findings, “Whatthe results imply is that patients withsystolic blood pressure under 120 clearlyrequire more intensive monitoring andmore intensive therapy both in and out ofthe hospital…they remain at high risk for60–90 days after discharge.”

He added that even though thesepatients require a more aggressive

drug-treatment approach theywere “less likely to be treated

with these agents.” Heconcluded that “We

need further researchon improving theoutcome for

patients hospital-ized for heart fail-

ure with lowsystolic pressure.”

Adding hisapproval to the

findings of thesetwo separate stud-

ies, Per Hildebrandtof Roskilde Univer-

sity Hospital(Roskilde, Denmark)

added in an Editorial forthe journal that the studies

have important clinical implica-tions. He added that heart failure due

to preserved, EF and diastolic dysfunc-tion deserve the same attention previ-ously afforded to heart failure withreduced left ventricular EF.

These two new studies add impor-tant new evidence to the issue of diag-nosis, treatment and prognosis ofpatients with heart failure. The diseasecurrently affects an estimated 15 mil-lion people worldwide and is one ofthe leading causes of hospitalization.

In the UK alone, heart disease andrelated complications have been esti-mated to cost GB£29 billion per year,representing 60% of National HealthService spending.