G a l l e r y

In an information-rich era,dominated by talk of ContinuedMedical Education and revalidation,medical professionals consistently demonstrate a healthy appetite forknowledge.Although gaining accessto Physicians in the UK has becomea great challenge as the healthdemands of a growing and ageingpopulation intensifies, and the burden of NHS reform drives new priorities for healthcare practitioners, the need for highquality information on medicalinnovation remains high. In fact,in such a fast-moving and competitive market, where prescribing decisions at all levels suffer unparalleled scrutiny, sourcingcredible and reliable clinical infor-mation is perhaps more importantthan ever.

The information exchange betweenmedical representatives and clinicians remains a vital cog in the machine of pharmaceuticalcommunication. But how do youadd value to that dialogue? And,crucially, is there a method throughwhich interaction can be enhancedto compliment the commercialaims of the representative and satis-fy clinicians’ appetite for informa-tion? The answer, of course, is yes. Itmay be a traditional approach in amodern era, but the old-fashionednewsletter could just be the answer.

Care & Cure Medical Publishing,which was launched back in 1975,has been producing single-spon-sored newsletters for distributionto medical professionals all over theworld for thirty years.These publications have commonly been delivered into the market by medical representatives, as invaluable leave-pieces.

Editorial content is chiefly licensedfrom Reuters Health andMedscape, WebMD for two of themost popular editions, namely,Reuters News and Ask The Experts.In addition, Care & Cure has built anarchived literature database for itsnewsletters comprising of New In,Clinical Digest,The Experts’View,Conference Highlights and WorldReport.

Hester Wilken, Publisher ofSpecialist Medical Journals at Care& Cure, believes its tried-and-testedapproach is of real benefit to medical representatives, particularlyin an environment where accessingPhysicians is becoming increasinglychallenging.“Care & Cure newsletters are disease and/or specialty-specific.This helps us provide objective and valuable content which doctors appreciate.Crucially, newsletters are publishedon a quarterly basis, providing salesprofessionals with the opportunityfor another appointment with thedoctor.”

Newsletters are kept deliberatelyshort, providing concise yet valuableinformation in a digestible formatfor busy clinicians.Although content

remains independent, provision ismade for ‘keywords’, and healthyinteraction between ProductManagers and Care & Cure isencouraged to ensure appropriatecommercial objectives are satisfied.

Care & Cure’s 32-year experienceof developing newsletters forhealthcare practitioners has seen itdevelop significant expertise in thisarea.This is reflected both in thequality of its publications, and theresponse from its readers.Underpinning this is a commitmentto editorial excellence.“The editorial content of all our newsletters is of paramount importance,” says Hester Wilken.“The editors of Care & Curealways ensure that information provided is of the highest possiblestandard and relevance.With overthirty years’ experience, they knowwhat doctors find useful, what pharmaceutical companies findimportant and, critically, where tosource the most up-to-date information. Most significant of all,they know how to pull this information together into a formatthat medical representatives’customers find accessible and valuable.”

For further information on Care & Cure, visit www.careandcure.ccor email: hester@careandcure.cc

Feeding your customers’healthy appetiteNeed to know how to satisfy your customers’ appetite for knowledge, and

get a foot in the door for your next appointment?

Care & Cure may have the answer.

13November 07

Commissioned Profileg

CARE & CURE

of sleep behaviours described in Alzheimer’s D isease

(AD ) patients. T he purpose of a study by L ee et al was to

examine whether patient and spouse/caregiver reports of

daytime sleepiness in AD were associated with lower

functional status in those patients. T he authors utilised

the E pworth Sleepiness Scale to assess reported daytime

sleepiness and a modification of the L awton and Brody

scale to assess functional status in a group of 137 AD

patients. T he authors also examined typical bedtimes and

wakeup times via questionnaire. H igher levels of daytime

sleepiness were associated with greater impairments in

functional status. T hese results were independent of

level of cognitive impairment, as assessed with M ini-

Me ntal State E xam, and they were also detectable when

the authors limited analyses to data reported only by

spouse/caregiver. F indings were not associated with

medication use. AD patients also had earlier bedtimes

and later wake-up times than a comparison group. T hey

conclude that even apart from its association with im-

paired cognition, daytime sleepiness was associated with

functional impairment in AD patients. Although daytime

sleep may represent a welcome relief for caregivers, its

presence may be associated with greater impairment in

instrumental activities and may warrant intervention.NE W analy s is o f ac tiv ities of d a ily

liv ing in frontotempora l dementiaa nd A lzheimer ’s dis ea s e 3T he objective of a study by M ioshi et al was to evaluate

activities of daily living (AD L s) in three clinical variants

of frontotemporal dementia and the relationship to

cognitive dysfunction. F ifty-nine patients and caregivers

No .55

New InALZHEIMER’SNE W lo ok at the r elation o f

c ognitiv e ac tiv ity to r is k o fdevelo pin g A lz heimer ’s d is eas e 1

F requent cognitive activity in old age has been associated

with reduced risk of Alzheimer’s disease (AD ), but the

basis of the association is uncertain. I n a study by W ilson

et al more than 700 old people underwent annual clinical

evaluations for up to 5 years. At baseline, they rated

current and past frequency of cognitive activity with the

current activity measure administered annually there-

after. T hose who died underwent a uniform postmortem

examination of the brain. A myloid burden, density of

tangles, and presence of L ewy bodies were assessed in

eight brain regions and the number of chronic cerebral

infarctions was noted. D ur ing follow- up, 90 people

developed AD . M ore frequent participation in cognitive

activity was associated with reduced incidence of AD

(H R = 0.58; 95% C I : 0.44, 0.77); a cognitively inactive

person (score = 2.2, 10th percentile) was 2.6 times more

likely to develop AD than a cognitively active person

(score = 4.0, 90th percentile). T he association remained

after contr ol l ing for past cognitive activity, l i fespan

socioeconomic status, current social and physical activity,

and low baseline cognitive function. F requent cognitive

activity was also associated with reduced incidence of

mild cognitive impairment and less rapid decline in

cognitive function. Among 102 persons who died and

had a brain autopsy, neither global nor regionally specific

measures of neuropathology were related to level of

cognitive activity before the study, at study onset, or

during the course of the study. T he authors concluded

that the level of cognitively stimulating activity in old age

is related to risk of developing dementia.NE W a s s es s ment of d ay tim es le epines s a nd func tional

impairment in A lzh eimer ’s d is eas e 2

D aytime sleep has been noted to accompany dementing

illness and is more pronounced as dementia severity in-

creases. A lthough acknowledged by caregivers, sleepi-

ness during the daytime is among the least troublesome

Targeted Newsletters

A RTHRITIS N EW S No.6

Por David DouglasNUE VA Y OR K (R euters Health 12-07-2007) - E l tratamiento de laartritis reumatoide (AR ) con antagonistas del factor de necrosis tumoralFNT (T NF, por sus siglas en inglés) tiene un impacto favorable en lasupervivencia, informan investigadores españoles en la publicaciónmédica Annals of the Rheumatic Diseases."L a inflamación sistémica que se presenta en los pacientes con artritisreumatoide se asocia a un exceso de mortalidad debido principalmentea fallecimientos por causas cardiovasculares,” declaró a Reuters Healthel investigador principal, Dr. Juan J. Gómez-R eino. "A l controlar lainflamación rigurosamente con antagonistas del T NF se mejora estedesenlace clínico.”E l Dr. Gómez-R eino, del Hospital Clínico Universitario, A . Choupana,en Santiago, y sus colegas estudiaron los datos de dos bases dedatos nacionales de A R . Una incluía a 4,459 pacientes que recibíantratamientos biológicos. L a otra, comprendió pacientes a quienes se les había iniciado tratamientoantes de que tales agentes estuvieran disponibles y se les había dadoposiblemente seguimiento. Toda la información sobre los pacientes aquienes subsecuentemente se les había iniciado en antagonistas del T NF,

fue censurada después de la primera dosis. E n total, se incluyó a 789 pacientes. Una comparación entre cohortes que cubrió un seguimiento de más de2,400 pacientes-años demostró que los sucesos cardiovasculares fueronsignificativamente mayores en el cohorte sin antagonistas del T NF(riesgo relativo, 5 a 7). E sto también resultó ser cierto del cáncer (riesgorelativo, 2 a 9). Sin embargo, la tasa de infección grave fue significativamente mayoren los pacientes con antagonistas del T NF. No obstante, la mortalidadgeneral fue más baja en este grupo.E n muerte por todas las causas, el riesgo relativo fue 0.32. Para sucesoscardiovasculares el riesgo relativo fue 0.58. L os valores correspondientespara infección y muerte en relación con cáncer fueron 0.52 y 0.36,respectivamente.E l Dr. Gómez-R eino agregó que el efecto favorable en la mortalidad“ representa una ventaja adicional de estos compuestos, aparte demejorar las manifestaciones y los síntomas articulares.”

Ann Rheum Dis 2007; 66: 880-885

Los antagonistas del T NF disminuyen las muertes por enfermedades cardiovasculares en lospacientes con artritis reumatoide

NUE VA Y OR K (R euters Health 25-06-2007) - L a tasa de infecciónbacterial grave en los pacientes con artritis reumatoide (A R ) no esmayor entre aquellos que toman bloqueadores del factor de necrosistumoral (T NF) alfa, en comparación con los que toman metotrexato,indica un estudio clínico reciente. "Aún cuando las infecciones oportunistas han sido asociadas a la terapiade antagonistas del TNF alfa, la asociación con las infecciones bacterialesgraves, una causa mucho más común de morbilidad en esta población, noha sido evaluada completamente,” mencionan el Dr. SebastianSchneeweiss y sus colegas de Harvard Medical School, en B oston enun número de la revista médica Arthritis & Rheumatism.E n una cohorte de 15,597 pacientes con A R , que iniciaron con unfármaco antirreumático modificador de la enfermedad (FA R ME oDMAR D, por sus siglas en inglés), entre 1995 y 2003, los investigadoresno observaron ningún aumento en la tasa de infecciones bacteriales entrelos que iniciaron con terapia de antagonistas del T NF alfa, encomparación con los que comenzaron con terapia de metotrexato. “E steresultado fue independiente del uso simultáneo de medicamentosDMA R D y persistió después de ajustar para otros factores pronóstico,”informan los investigadores. E n general, la incidencia de infecciones bacteriales graves promedió

2.2 por 100 pacientes-años en esta población. L os investigadores mencionan que, consistente con otros estudiosclínicos, la terapia de glucocorticoides duplicó la tasa de infeccionesbacteriales graves en comparación con la de metotrexato, indepen-dientemente del uso previo de medicamentos DM A R D, con unarelación clara de respuesta de dosis a dosis mayores de 5 miligramospor día. "E ste umbral para el uso seguro de glucocorticoides de dosis bajascon respecto a las consecuencias de infecciones corrobora los resul-tados de un metanálisis de estudio clínico aleatorizado,” señalan el Dr. Schneeweiss y sus colegas. E n resumen, los investigadores manifiestan que sus resultados sonconsistentes con por lo menos dos hipótesis: “ primero, que en laatención habitual, los médicos parece que pueden controlar bien la A Rcon terapia de antagonistas del T NF alfa en relación al riesgo deinfecciones graves; y segundo, las mejorías en el funcionamiento de lospacientes con las terapias de antagonistas del T NF alfa y metotrexatopueden contrarrestar algunos de los efectos inmunodepresores de estosfármacos.”

Arthritis Rheum 2007; 56: 1754-1764

No se observó aumento en el riesgo de infección con la terapia de antagonistas del T NF en la AR

R espuesta del Dr . Joel E . R ichter, MD

P res idente del Depa rtamento de Gas troenterología de la Cle vela nd C linic Foun dation; profeso r

de medicina en el C leveland C linic F oundation Health S cienc e C enter de la U nivers idad E statal

de Ohio.

Desde hace mucho, tanto pacientes como médicos son conscientes de la relación que

existe entre los síntomas por reflujo y el cómo, cuándo y qué alimentos se consumen.

La comida puede agravar estos síntomas a través de distintos mecanismos, entre

ell os: (1) el aumento del volumen gástrico, que produce distensión gástrica y

relajación transitoria del esfínter esofágico inferior; (2) la reducción de la presión en el esfínter esofágico inferior; y (3) la

irri tación directa de la mucosa esofágica. [1] A pesar de lo dicho, creo que existe una tendencia a excederse en las

recomendaciones alimentarias en los pacientes con ER GE. Pienso que los factores más importantes son la reducción del

tamaño de la cena, no ingerir alimentos durante varias horas antes de irse a la cama, y, si la persona es obesa, diseñar una

dieta para lograr la pérdida de peso.

En la posición vertical, el principal causante de la relajación transitoria del esfínter esofágico inferior es la distensión

gástrica que se produce tras una comida. Esto explica el aumento del reflujo fisiológico, especialmente después de una cena

copiosa. Por lo tanto, una simple reducción del tamaño de l a comida ofrece l a posibilidad de mejorar el manejo de la

ER GE. Si dicha comida resulta ser baja en grasas y alta en proteínas, se aumentará aún más la presión en el esfínter

esofágico inferior y se reducirá la cantidad de reflujo ácido. N o son aconsejables las comidas copiosas antes de irse a dormir,

ya que aumentan el volumen gástrico y fomentan el reflujo gastroesofágico, que además está asociado con una mala

eliminación del ácido durante la noche. A mis pacientes les aconsejo que ingieran una cena saludable, pero que no coman

ni beban nada, salvo agua, tres o cuatro horas antes de irse a la cama.

Los médicos normalmente aconsejan a los pacientes obesos con ER GE que pierdan peso, aunque no existen estudios

clínicos que respalden totalmente dicha recomendación. Una encuesta de grandes dimensiones realizada en N oruega sobre

salud pública [2] encontró una fuerte relación dosis-respuesta entre un aumento del índice de masa corporal (I MC) y los

síntomas de reflujo en ambos sexos, con una relación significativamente fuerte en las mujeres. E l riesgo de reflujo

aumentaba significativamente entre l as personas severamente obesas (I MC > 35) (para hombres, razón de posibilidades

[OR ], 3.3; intervalo de confianza [I C] del 95%, 2.4-4.7 y para las mujeres, OR , 6.3; I C del 95%, 4.9-8.0) frente a las

persona con un I MC < 25. La relación entre I MC y los síntomas de reflujo fue más fuerte entre mujeres premenopáusicas

comparadas con las posmenopáusicas, aunque el empleo de la terapia hormonal en la posmenopausia aumentaba la fuerza

de la relación. Es interesante notar que la reducción de peso estaba asociada con una reducción del riesgo de padecer

síntomas por reflujo. Basándonos en este importante estudio, con más de 60,000 sujetos adultos, creo que necesitamos

insistir más a la hora de recomendar la pérdida de peso a nuestros pacientes. Sin embargo, es importante ser práctico. A

lo largo de mi práctica, he observado que los pacientes expresan un empeoramiento de sus síntomas a partir de cierto

Pregunta

¿Qué recomendaciones

alimentarias le haría a los

pacientes con enfermedad por

reflujo gastroesofágico

(ER GE)?

GastroenterologyNo. 8Ask Experts

theAsk Expertsthe

content provided by

ATE Ga s t r oenl ogy #8

a Mex 9/ 28/0 6 12: 21 PM

NE W YOR K (R euters Health 19-04-2007) - The intraocular

pressure (IOP ) response to topical medications does not dif fer

signif icantly between whites and Af rican A mericans with ocular

hypertension, according to a report in the Archives of Ophthal-

mology.

“Cli nicians should not choose a particular ocular hypotensive

medicati on for a patient based on race,” D r. S teven L .

Mansberger told Reuters Health. “We believe that dosing sche-

dule, side effects, cost, ef! cacy, and other factors are more

important considerations.”

Dr. Mansberger from the D evers E ye Institute/Dis coveries in

Sight, Portland, Oregon, and associates note that open angle

glaucoma is about three times more prevalent in A frican Ameri-

cans than in whites, and there have been reports that intraocular

pressure in A frican American individuals responds less to

topical beta-antagonists and more to prostaglandin analogs.

To investigate, the team compared the IO P response of A frican-

A merican and white patients to these medications in initial

therapeutic trials in the Ocular H ypertension Treatment Study.

A mong participants who received non-selective beta-adrenergic

antagonists, there was no difference by race in the mean baseline

IOP or the mean IOP after 4 to 6 weeks of treatment. T he mean

percentage change in IO P was also similar for the two races, the

results indicate.

R esults were similar among participants who received prosta-

glandin analogues, the researchers note, except that A frican-

A merican patients showed a greater mean percentage I OP

decrease ( 30.3% ) f rom baseline than white patients did

(24.8%).

For both treatments, multiple regression analy ses fai led to

identify race as a predictor of outcome, the report indicates, but

higher baseline IOP and thinner central corneal thickness were

associated with greater decreases in IOP with treatment.

“Previous research shows conflicting results when examining

the IOP response of ocular hypotensive medications in different

racial groups,” Dr. M ansberger explained. “ Most papers show

no difference, or when they do, the analysis did not control for

baseline IOP and central corneal thickness — the factors most

associated with IOP response.”

Studies examining IO P response to medications “should control

for baseline IO P and central corneal thickness when comparing

results between groups,” Dr. Mansberger concluded.

Response to glaucoma medications does not differ by race 1

OPHTHAL MOLOGY

NEWSOPHTHALMOLOGY

NEWS No.11

C ontains ar ticles from

The aim of a trial by A zuara B lanco et al was to compare the

diagnostic performance of accredited glaucoma optometrists

(AG O) for both the diagnosis of, and decision to treat glaucoma

with that of routine hospital eye care against a reference stan-

dard of expert opinion, i.e. consultant ophthalmologist with a

special i nterest in glaucoma.

A directly comparative, masked, performance study was per-

formed in Grampian, S cotland. O ne hundred and sixty f ive

people were invited to participate and, of those, 100 (61%) were

examined. People suspected of having glaucoma underwent a

full ophthalmic assessment both in a newly established, com-

munity optometry led, glaucoma management scheme and in a

consultant led hospital eye service within a month.

T he agreement between the AG O and the consultant ophthal-

mologist in the diagnosis of glaucoma was substantial (89%,

kappa = 0.703, SE = 0.083). The agreement regarding the need

for treatment was also substantial (88%, kappa= 0.716, SE = 0.076).

T he agreement between the trainee ophthalmologists and the

consultant ophthalmologist in the diagnosis of glaucoma and

treatment recommendation were moderate (83%, kappa = 0.541,

SE = 0.098, SE = 0.98; and 81%, kappa = 0.553, SE = 0.90,

respectively).

T he diagnostic accuracy of the optometrists in detecting glau-

coma in this population was high for specif icity (0.93 [95%

CI 0. 85 to 0.97]) but lower for sensitivity at 0.76 (95% C I 0.57 to

0.89) . T he performance was si mil ar when accuracy was

assessed for treatment recommendation (sensitivi ty, 0.73[95%

CI 0.57 to 0.85]; specif icity 0.96[95% CI 0.88 to 0.99]).

T he differences in sensitivity and specif icity between A GO and

junior ophthalmologist was not statistically signif icant.

I n conclusion community optometrists trained in glaucoma

provided satisfactory decisions regarding diagnosis and

initiation of treatment for glaucoma. With such additional

training in glaucoma optometrists are at least as accurate as

junior ophthalmologists but some cases of glaucoma are

missed.

Accuracy of accredited glaucoma optometrists in diagnosis and treatment of glaucoma 2

EUROPE EUROPE EUROPE

Contains

Conference Reports

Ex em esta ne af te r t am oxi fen im pro ves breast cancer s ur vival

By Martha K errN EW YOR K ( Reuters Health 18-12-2006) - Treatment with the aromatase inhibitor exemestane

after 5 years of tamoxifen, the standard adjuvant hormonal therapy for early-stage breast cancer,

signi!cantly improves relapse-free survival, according to the latest !ndings from the National

Surgical Adjuvant Breast and Bowel Project, Breast -33 (N SABP; B-33).

Results of the B-33 were presented at the 29th Annual San Antonio Breast Cancer Symposium.

The findings reveal that exemestane following tamoxifen reduces breast cancer recurrence “by

about half,” reported Dr.Terry Mamounas of the Aultman Health Foundation of Canton, Ohio.

B-33 was launched in May 2001. It was a randomised, placebo-controlled tr ial of exemestane,

25 mg or ally daily, initiated after five years of tamoxifen in 1,598 post-menopausal women

with clinical stage T1-3 hormone receptor-positive, non-metastatic breast cancer. W omen were

cancer-free at the time of r andomisation.W omen were initially randomised to two years o f exemestane therapy or placebo, which was

extended to five years adjuvant therapy in 2002. In 2003, a tr ial of another aromatase inhibitor,

letrozole, showed strong bene!ts, causing B-33 to be unblinded and placebo candidates were

allowed to cross over to the exemestane arm of treatment.

Despite cr oss-over, exemestane treatment had a relative risk of disease-free survival of 0.68

(P = 0.07, not significant) and a relative risk of 0.50 in recurrence-free survival (P = 0.03), but no

reduction in overall survival (P = 0 .63, not signi!cant) compared to placebo at a median follow-

up of 30 months.Fatigue, arthralgia and bone pain were the most common grade 3/4 complaints. Gr ade 4 toxicity

and fractures were similar in each arm, however a higher incidence of grade 3 tox icity was

reported with exemestane treatment (P = 0.03).

“This provides another piece of the puzzle with an aromatase inhibitor used as adjuvant tr eat-

ment of hormone-positive breast cancer,” Dr. Mamounas told Reuters Health in an interview just

prior to his presentation of the B-33 results.

The fact that patients were allowed to cross over t o active treatment after two years showed

that results with exemestane “are comparable whether given up-front or delayed,” Dr. Mamounas

noted.“T his gives women with breast cancer another option in aromatase inhibitor therapy,” he com-

mented. “Practice patterns may soon be to send women to the switch earlier, after 2 to 3 years

(of tamoxifen therapy), or to start the aromatase inhibitor up-front.”

Mamounas E, Jeong J-H,Wickerham L et alBene!t from exemestane (EXE) as extended adjuvant therapy after 5 years of tamoxifen (TAM):

intent-to-treat analysis of NSABP B-3329th annual meeting of the San Antonio Breast Cancer Symposium

Abstract No. 49

Ho m ocysteine and breast cancerPlasma homocysteine levels may be used as a prognostic marker in br east cancer patients accor-

ding to a study presented at the 29th Annual San Antonio Breast Cancer Symposium.

The study,conducted by Ge rmano and colleagues, found a correlation between prognostic factors

such as tumour si ze and histological grade and homocysteine blood levels.

29th A nnual S an A ntonioB reast C ancerS ym posium

29th A nnual S an A ntonioB reast C ancerS ym posium

Conference H ighlightsOncology

Issue N o. 3

Aus 5/ 16/ 07

EXPERT’S VIEWHIV AIDS No 12

THE

Question

I understand that in apatient who has a drug-resistant virus and stopstherapy, over time thedominant genotype mayrevert to a wild-type geno-type. What is the time-frame for this process, andwhat factors may in!uenceit? If a patient was initiallyinfected with a drug-resist-ant virus, will the resistancemutations persist for longerbecause there is noarchived wild-type virus togrow out?

Several studies show that wild-type virus replacesdrug-resistant virus after cessation of antiretroviraltherapy. In the majority of cases, this phenomenonrepresents the outgrowth of residual wild-typevirus, not true genetic reversion; that is, thisprocess is not due to the back-mutation of themany accumulated drug resistance mutations,which would take many years.In fact, replacement of drug-resistant virus bywild-type occurs only in about two thirds ofpatients. According to a recent study by Deeksand colleagues,[1] the time frame for outgrowth ofwild-type virus ranged from 2-16 weeks. Factorsgoverning the time to outgrowth of sensitive virushave not yet been de"ned, but most likely relateto the relative "tness of the predominant resistantstrain and residual wild-type strain in the absenceof drug, as well as the titre of residual wild-typevirus (ie, what fraction of the total virus load iswild-type). Some resistant viruses appear to beovergrown by wild-type more rapidly than others.For example, lamivudine-resistant virus with theM184V mutation is rapidly replaced by wild-type,as are protease inhibitor-resistant viruses. Bycontrast, zidovudine-resistant viruses are relativelystable in the population for long periods of time,as are viruses that carry non-nucleoside reversetranscriptase inhibitor (NNRTI)-resistancemutations. If there is no archived wild-type virus,then the outgrowth of wild-type virus doesdepend on true genetic reversion (back-mutation) at each of the mutant alleles, whichtakes many months to occur.Two abstracts at the8th Conference on Retroviruses andOpportunistic Infections addressed this point.Daar and colleagues[2] presented a poster thatdescribed a patient who acquired a multi-drug-resistant virus with mutations in the protease andreverse transcriptase genes. After the initialprimary infection period, the steady-state virusload was approximately 1000 copies/mL.However, over the next several months virus load

increased to 30,000 copies/mL, coinciding withreversion of the virus to wild-type. Back-mutationdoes not always regenerate the original wild-typesequence. García-Lerma and co-workers[3] fromthe Centres for Disease Control and Preventionidenti"ed 10 newly infected patients with unusualmutations at codon 215. A change from threonine(T) to tyrosine (Y) or phenylalanine (F) at thisposition is associated with zidovudine resistance.This resistance mutation requires a change at 2nucleotides within the 215 codon (eg, ACC toTAC). Novel variants reported in this posterincluded 215D, 215C, 215S, and 215E, which arethought to represent intermediates of a 215Yrevertant (ie, only 1 of the 2 nucleotides at codonreverted to wild-type). Presence of thesemutations most likely indicates transmission of azidovudine-resistant virus, but the clinicalsigni"cance of these unique mutations in terms offuture response to thymidine analogs is notknown.

References1. Deeks SG, Wrin T, Liegler T, et al.Virologic and

immunologic consequences of discontinuing combi-nation antiretroviral-drug therapy in HIV-infectedpatients with detectable viremia. N Engl J Med.2001;344:472-480.

2. Daar ES, Pitt JA, Nichols S,et al.Viral evolution in anuntreated patient who acquired multi-drug-resistantHIV during primary infection. Program and abstractsof the 8th Conference on Retroviruses andOpportunistic Infections; February 4-8, 2001;Chicago, Illinois. Abstract 427.

3. García-Lerma G, Nidtha S, Blumo# K, Weinstock H,Heneine W. Unusual mutations at codon 215 ofHIV-1 reverse transcriptase in treatment-naive, HIV-1-infected persons: prevalence, drug susceptibility, and replicative "tness. Program andabstracts of the 8th Conference on Retrovirusesand Opportunistic Infections; February 4-8, 2001;Chicago, Illinois. Abstract 426.

Responsefrom Daniel R. Kuritzkes, MD

Associate Professor of Medicine, Harvard Medical School; Director of AIDS Research, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

Hester Wilken

Care & Cure in brief

Features of Care & Cure newsletters include:1. Single sponsored - newslettersare concise and contain valuableinformation which medical professionals could read through in 10 minutes.

2. Editorial content - newslettersare objective, comprising high-quality information designed to suit a particular audience, ie,Doctors and Pharmacists.

3. Frequency and Flexibility of distribution – Care & Cure offers 4 newsletters per annum andendeavors to match medical salesprofessionals’ sales cycles.

4.Tailor-made - newsletters mayinclude brand/company logos andnames on the front page or in theimprint. We offer customisednewsletters that not only informand update but also reflect theproduct logo and face of the pharmaceutical companies we represent.

5.The newsletters are a uniquemarketing tool, which not onlyhelps to open doors for medicalrepresentatives but also helps tokeep the doctor updated withimportant trends and happenings inhis field.

6.We provide sufficient informationfor doctors to read in one sitting – with one page for sponsor advertisement.

CARE & CURETargeted Newsletters

ARTHRITIS NEWS No.5

Autor: Will Boggs, licenciado en medicinaNUEVA YORK (Reuters Health 11-06-2007) - Según un artículopublicado en Arthritis & Rheumatism, la enfermedad reumática infla-matoria y el tabaquismo van asociados a los infiltrados aórticos.Según declaraba la Dra. Ivana Hollan a Reuters Health: “Los pacientescon enfermedades reumáticas inflamatorias presentan una inflamaciónmás pronunciada de las capas media y adventicia de la aorta (asinto-mática) que los pacientes que no padecen estas enfermedades”. Estapuede ser una de las causas de la aceleración de su ateroesclerosis y desu susceptibilidad a padecer enfermedades de la válvula cardíaca y a laformación de aneurismas”. La Dra. Hollan del Hospital de Enfermedades Reumáticas de Lille-hammer, Noruega, y sus colaboradores, compararon muestras de aortaobtenidas durante intervenciones de implante de bypass coronario pro-cedentes de 61 pacientes con enfermedad reumática inflamatoria y de51 pacientes control que no padecían esta enfermedad. Según informan los autores, un porcentaje más alto de pacientes conenfermedad reumática inflamatoria (47%), en comparación con loscontroles (20%), presentaba infiltrados de células mononucleares en lacapa adventicia interna de las muestras aórticas, y sólo los pacientescon enfermedad reumática inflamatoria presentaban estos infiltradosde células mononucleares en la capa media. Según los resultados, la infiltración inflamatoria crónica en placas y

los infiltrados de células mononucleares submesoteliales se dieron confrecuencias similares en ambos grupos. La enfermedad reumática inflamatoria y el tabaquismo fueron losúnicos elementos de predicción significativos de la aortitis en losanálisis multivariantes. Según el estudio, en el grupo de los pacientes con artritis reumatoide,el tratamiento con corticoesteroides parecía prevenir los infiltrados decélulas mononucleares en la capa adventicia interna, sin embargo, esteefecto no producía resultados de significancia estadística en otrossubgrupos de pacientes con enfermedad reumática. En palabras de la Dra. Hollan: “Debido a la falta de estudios en estamateria, sabemos muy poco sobre la aortitis asintomática y de su im-pacto en el pronóstico”. Si aumenta la inflamación vascular crónica,aumenta el riesgo de una ateroesclerosis más severa, o si predice unamayor formación de aneurismas o de enfermedad de la válvula aórtica,será necesario realizar un seguimiento y un tratamiento apropiados”. El grupo planea hacer un seguimiento a estos pacientes, añadía ladoctora “para estudiar el riesgo de complicaciones cardiovasculares yfallecimiento, según el grado de la aortitis crónica”.

Arthritis Rheum 2007; 56: 2071-2078

Enfermedades reumáticas: fumar contribuye a la generación de aortitis

Autor: David DouglasNUEVA YORK (Reuters Health 26-01-2007) - El tratamiento con elantagonista TNF-alpha, infliximab (Remicade), consigue resultadosclínicos excelentes en la mayoría de los pacientes con psoriasis de placade moderada a severa; y la terapia rutinaria de mantenimiento ofrecemejor control de la enfermedad que el tratamiento administrado sólocuando se necesita (intermitente), según informa un equipo investiga-dor en el Journal of the American Academy of Dermatology.El Dr. Alan Menter, responsable de la investigación, explicaba a ReutersHealth que “usando infliximab como monoterapia se observaron res-puestas muy rápidas; y la psoriasis desapareció o casi desapareció enla mayoría de los pacientes después de administrar tres infusiones a las10 semanas de evaluación. Los resultados se mantuvieron durante elaño de duración del estudio en un 70% de los pacientes, sin que seobservaran complicaciones relacionadas con la seguridad”.El Dr. Menter, del Centro Médico de la Universidad de Baylor deDallas, y sus colaboradores, administraron de forma aleatoria un trata-miento de inducción con infliximab de 3 mg/kg, de 5 mg/kg o placeboa 835 pacientes con psoriasis de placa de moderada a severa. Al cabode 14 semanas, a los pacientes tratados con infliximab se les aplicó denuevo, de forma aleatoria, un tratamiento de mantenimiento continuo(cada 8 semanas) o intermitente según correspondiera.

En la décima semana del periodo de inducción el 75.5% de los pacien-tes con el tratamiento de 5 mg/kg y el 70.3% de los de 3 mg/kg consi-guieron una puntuación en el índice de severidad y extensión de lapsoriasis (PASI, del inglés Psoriasis Area and Severity Index) de 75.Las proporciones correspondientes a un PASI de 90 fueron de 45.2%y 31.7%. Sólo el 1.9% de los pacientes placebo consiguió un PASI de 75.De la semana 16 a la 50, la mediana de mejora en el índice de PASI fuede 89.6% en el grupo de 5 mg/kg con tratamiento continuo y de 76.4%en el de 5 mg/kg con tratamiento intermitente. En el grupo de los 3mg/kg, las proporciones correspondientes fueron de 80.6% y 72.4%.Infliximab fue bien tolerado por la mayoría de los pacientes, y lamayoría de los efectos secundarios se ajustaron a los ya conocidos.Estos efectos incluyen: síntomas parecidos a los del lupus, condicionesdesmielinizantes, una posible asociación con linfomas y dos casos detuberculosis.Los investigadores concluyen diciendo que, en general, el tratamientode mantenimiento con infliximab produjo mejor respuesta en los paci-entes que la terapia intermitente.

J Am Coll Dermatol 2007; 56: 31.e1-31.e15

La psoriasis se controla mejor con la terapia programada con infliximab

In previous analyses of primary eff icacy data from tworandomised clinical trials, standard-dosing regimens of thedorzolamide/timolol f ixed combination (COSOPT) andlatanoprost (XALATAN) were shown to have equivalentefficacy with regard to reduction in mean daytime diurnalintraocular pressure (IOP). Fechtner R. D. et al performed additional post hoc analysesof pooled data from these studies to compare further theefficacy of the two treatments. The studies used identical 3-month, parallel group, randomised, observer-masked andpatient-masked, multicentre designs. Patients with a baselineIOP 24 mmHg were randomised to either the 2% dorzola-mide/0.5% timolol combination eye drops twice daily (n = 273) or 0.005% latanoprost eye drops once daily (n = 271). The IOP measurements were made at 8 AM, 10 AM, 2 PM,and 4 PM at the baseline visit and then on each of the 3monthly assessment days. The following measures wereanalysed on a post hoc basis: 1) percentages of patientsmeeting target levels of IOP reduction; 2) mean IOP

reduction in those patients with high IOP (≥30 mmHg) atbaseline; 3) mean IOP at each of the assessment time pointsduring a day. A total of 259 patients in the dorzolamide/timolol group and268 patients in the latanoprost group were included in theeff icacy analysis. At 3 months, both treatments showedsimilar eff icacy with regard to the percentages of patientswho achieved target levels of IOP reduction (e.g., 40% IOPreduction in 15% of dorzolamide/timolol combination patientsand 13% of latanoprost patients), mean IOP reduction inthose patients with high IOP at baseline (dorzolamide/timolol combination, 12.5 mmHg, latanoprost, 12.6 mmHg),and mean IOP at each time point during the day. By the measures used in this analysis, the dorzolamide/timolol combination and latanoprost were equally effectiveat lowering IOP in patients with ocular hypertension orglaucoma.

J Ocul Pharmacol Ther, 2005; 21:242-249

Efficacy of the dorzolamide/timolol fixed combination versus latanoprost in the treatment ofocular hypertension or glaucoma

The influence of diclofenac ophthalmic solution on the intraocular pressure-lowering effect oftopical 0.5% timolol and 0.005% latanoprost in primary open-angle glaucoma patients

OPHTHALMOLOGYNEWS

OPHTHALMOLOGYNEWS

No.7

Contains articles from

The goal of a randomised, prospective, masked clinical studyconducted by Costagliola C. et al was to verify the influenceof a non-steroidal anti-inflammatory drug ophthalmic solutionon intraocular pressure reduction induced by 0.5% timololand 0.005% latanoprost eye drops in patients affected byprimary open-angle glaucoma. Thirty-two glaucomatous patients, compensated with 0.5%timolol, were randomised into two study groups (A and B).Timolol was continued for the first 2 weeks in all subjects. Onthe 15th day, in both groups timolol was replaced by latano-prost, and this regimen lasted up to the end of the follow-up(8 weeks). At the beginning of the 2nd week of the study, group A,additionally started a 5-week therapy with topical 0.1%diclofenac; during the same period, group B received placeboeye drops with identical modalities. Intraocular pressure was recorded at 7-day intervals duringthe first 7 weeks and at the 10th week. Non-steroidal anti-inflammatory drug and placebo did not modify the effect of

timolol on intraocular pressure. In both groups, latanoprostinduced a significant decrease in intraocular pressure. Diclofenac-treated patients exhibited a marked fall inintraocular pressure (P < 0.01), whereas in placebo-treatedpatients, this diminution was less noticeable (P < 0.05). Afterdiclofenac withdrawal, in group A, intraocular pressuresignif icantly increased (P < 0.01), remaining approxi-mately at the same level up to the end of the study. Ingroup B, at the same checks no signif icant variations inintraocular pressure occurred. In primary open-angle glaucoma patients, diclofenac signifi-cantly enhances the hypotensive effect of latanoprost, withoutinfluence on timolol efficacy. Because non-steroidal anti-inflammatory drugs are widely employed in medical practice,supplementary ophthalmologic checks should be scheduledduring the co-administration of these compounds and prosta-glandin analogues.

Exp Eye Res, 2005; 81:610-615

WORLDREPORT

No.4

Keeping the patientwell: new options inthe maintenancetherapy* of bipolardisorder 1

Treatment regimens for the long-term man-agement of bipolar disorder frequentlyinvolve a combination of pharmacologicaltherapies. Although combinations may beefficacious, monotherapy treatment wouldoffer a simplified treatment regimen as wellas potentially improved tolerability and maytherefore improve adherence to medication.Young AH, 2008, reports that, among theexisting pharmacological treatments for thechronic management of bipolar disorder,atypical antipsychotics have become morepopular due in part to a perceived superi-ority of risk/benefit profile compared withother treatments. A number of these agentsnow have formal indications: for example,aripiprazole and olanzapine are licensed for maintenance as monotherapy, based onevidence of recurrence prevention of manicepisodes in patients with previous episodes of mania. Quetiapine is the only atypicalantipsychotic currently approved in theUnited States and several other countries forthe monotherapy treatment of both bipolarmania and depression*, however, the use ofthis agent as a maintenance treatment hasnot yet been approved by regulatory bodies.Evidence supporting the efficacy of long-term quetiapine monotherapy is provided by a recent double-blind, placebo-controlledstudy (EMBOLDEN I)4. An initial 8-weekacute phase (n = 794) was followed by a continuation phase lasting 26–52 weeks,during which patients received quetiapine300 mg/day, 600 mg/day or placebo.Quetiapine significantly increased the timeto recurrence of any mood event during thecontinuation phase, compared with placebo

(HR: 0.56, 95% CI: 0.39 to 0.82) and wasgenerally well tolerated. These findingssuggest that quetiapine monotherapy is aneffective maintenance treatment for bipolardisorder.

Clinical trial design inthe long-termtreatment of bipolardisorder: patientconsiderations 2

The persistent nature of bipolar disorder and the considerable impact of symptomrecurrence warrant the evaluation of long-term treatments that may delay or preventrecurrence to improve patient outcomes andquality of life. Importantly, consideration ofthe appropriate design of such trials is criticalto ensure the provision of accurate andclinically relevant findings. The design of a recent randomised, double-blind study(D1447C00127), which evaluated the long-term efficacy and safety of quetiapine incombination with lithium or divalproex(QTP+Li/DVP), aimed to mirror clinicalpractice. This study, together with another of identical design [D1447C00126]3, is oneof the longest clinical trials providingefficacy data for the maintenance treatmentof bipolar I disorder. In this study, patients(index episode manic*, mixed* or depressed*)received open-label QTP+Li/DVP to estab-lish clinical stability for ≥12 weeks, a designcharacteristic that differs from previousmaintenance studies in bipolar disorder.Stabilised patients were then randomised todouble-blind treatment with QTP+Li/DVP,or placebo+Li/DVP for up to 104 weeks.Initially, 1,953 patients entered the pre-randomisation phase; of these, 623 wererandomised and received ≥1 dose of studytreatment. The combination of QTP+Li/DVP was significantly better than

placebo+Li/DVP at preventing new moodepisodes. QTP+Li/DVP was generally welltolerated. This study more accurately re-flects ‘real world’ treatment than previousmaintenance studies.

Quetiapine withlithium/divalproex canbe an effective long-term treatment optionfor bipolar I disorder 3

This study, by Vieta E et al, 2008, examinedthe efficacy and safety of quetiapine incombination with lithium or divalproex, vs.placebo + lithium/divalproex in the preven-tion of recurrent mood events in bipolar Ipatients, most recent episode mania*, depres-sion*, or mixed*. Patients received open-label quetiapine (400–800 mg/day; flexible,divided doses) with lithium or divalproex(target serum concentrations 0.5–1.2 mEq/land 50–125 µg/ml, respectively) for up to 36 weeks to achieve at least 12 weeks ofclinical stability. Patients were subsequentlyrandomised to double-blind treatment withquetiapine (400–800 mg/day) + lithium/divalproex (QTP+Li/DVP) or placebo +lithium/divalproex (placebo+Li/DVP) for up to 104 weeks. The primary endpoint wastime to recurrence of any mood event.Treatment with QTP+Li/DVP significantlyincreased the time to recurrence of any moodevent compared with placebo+Li/DVP. Theproportion of patients having a mood eventwas markedly lower in the quetiapine than inthe placebo group (18.5% versus 49.0%).The hazard ratio for time to recurrence of a mood event* was 0.28 (P < 0.001), a mania*event 0.30 (P < 0.001), and a depression*event 0.26 (P < 0.001) corresponding to riskreductions of 72%, 70%, and 74%, respect-ively. During the randomisation phase, the

Psychiatry

of sleep behaviours described in Alzheimer’s Disease(AD) patients. The purpose of a study by Lee et al was toexamine whether patient and spouse/caregiver reports ofdaytime sleepiness in AD were associated with lowerfunctional status in those patients. The authors utilisedthe Epworth Sleepiness Scale to assess reported daytimesleepiness and a modification of the Lawton and Brodyscale to assess functional status in a group of 137 ADpatients. The authors also examined typical bedtimes andwakeup times via questionnaire. Higher levels of daytimesleepiness were associated with greater impairments infunctional status. These results were independent oflevel of cognitive impairment, as assessed with Mini-Mental State Exam, and they were also detectable whenthe authors limited analyses to data reported only byspouse/caregiver. Findings were not associated withmedication use. AD patients also had earlier bedtimesand later wake-up times than a comparison group. Theyconclude that even apart from its association with im-paired cognition, daytime sleepiness was associated withfunctional impairment in AD patients. Although daytimesleep may represent a welcome relief for caregivers, itspresence may be associated with greater impairment ininstrumental activities and may warrant intervention.

NEW analysis of activities of dailyliving in frontotemporal dementiaand Alzheimer’s disease 3

The objective of a study by Mioshi et al was to evaluateactivities of daily living (ADLs) in three clinical variantsof frontotemporal dementia and the relationship tocognitive dysfunction. Fifty-nine patients and caregivers

No.55

New InALZHEIMER’S

NEW look at the relation ofcognitive activity to risk ofdeveloping Alzheimer’s disease 1

Frequent cognitive activity in old age has been associatedwith reduced risk of Alzheimer’s disease (AD), but thebasis of the association is uncertain. In a study by Wilsonet al more than 700 old people underwent annual clinicalevaluations for up to 5 years. At baseline, they ratedcurrent and past frequency of cognitive activity with thecurrent activity measure administered annually there-after. Those who died underwent a uniform postmortemexamination of the brain. Amyloid burden, density oftangles, and presence of Lewy bodies were assessed ineight brain regions and the number of chronic cerebralinfarctions was noted. During follow-up, 90 peopledeveloped AD. More frequent participation in cognitiveactivity was associated with reduced incidence of AD(HR = 0.58; 95% CI: 0.44, 0.77); a cognitively inactiveperson (score = 2.2, 10th percentile) was 2.6 times morelikely to develop AD than a cognitively active person(score = 4.0, 90th percentile). The association remainedafter controlling for past cognitive activity, lifespansocioeconomic status, current social and physical activity,and low baseline cognitive function. Frequent cognitiveactivity was also associated with reduced incidence ofmild cognitive impairment and less rapid decline incognitive function. Among 102 persons who died andhad a brain autopsy, neither global nor regionally specificmeasures of neuropathology were related to level ofcognitive activity before the study, at study onset, orduring the course of the study. The authors concludedthat the level of cognitively stimulating activity in old ageis related to risk of developing dementia.

NEW assessment of daytimesleepiness and functionalimpairment in Alzheimer’s disease 2

Daytime sleep has been noted to accompany dementingillness and is more pronounced as dementia severity in-creases. Although acknowledged by caregivers, sleepi-ness during the daytime is among the least troublesome

THE

EXPERT’S VIEWQuestion:A 68-year-old female wasdiagnosed with triple-negative invasive ductalbreast cancer (grade 3 cells).She underwent a lumpecto-my with axillar clearingthat removed the originaltumor (size, 1.5cm).Another tumor with thesame histology (size, 0.5cm)was discovered and removedduring the surgery. Nonode involvement or distantmetastases were noted.What treatment should follow the surgery? Whatkind of chemotherapy?Radiotherapy? Both? Whatsequence?

contains content from

In view of the potential for false-negative results of ER/PR (up to 20%) and HER2 (up to 10%) testswhen assays are performed by less experienced labs and the resulting risk of denying adjuvant therapywith antiestrogens and/or anti-HER2 therapy to patients who could be helped by them, my initial reac-tion when reviewing a pathology report like this is to touch base with the pathologist who performed theassays to make sure that the tumor is indeed triple-negative.

In this specific patient, a description of a high-grade tumor (grade 3) makes a triple-negative diagnosismore plausible. Her staging takes into account the size of the largest tumor (1.5cm) and the negative axil-lary clearing for a final diagnosis of stage 1 (pT1N0), albeit high-risk (high-grade, triple-negative).The available data on lumpectomy alone without radiation therapy (RT) show an increased risk of locore-gional recurrence (but similar overall survival) in stage 1 breast cancer but are limited to women over age70 years with ER-positive disease who received adjuvant tamoxifen.[1] Therefore, assuming reasonablehealth and resulting good life expectancy, I would encourage this patient to consider RT for completionof breast conservation, which will not only reduce the risk of locoregional recurrence but also potentiallyimprove her overall survival.[2]

Along these lines, I would also offer some adjuvant chemotherapy. The Oxford Overview was recentlyupdated in 2005-2006, and a preliminary oral report by Sir Richard Peto at the San Antonio BreastCancer Symposium in December 2006 suggests an almost 6% absolute reduction in the risk of recurrenceevents at 15 years (~36% vs 42%, HR 0.78) favoring polychemotherapy vs no chemotherapy for womenin the age group from 60-69 years. In fact, a survival analysis from the 2000 Oxford Overview[3] showeda 20% reduction in the annual odds of death for women in the age group from 50-69 years who weretreated with an anthracycline, which translated into a 4.4% absolute improvement in overall survival(79.4% vs 75%) after 15 years.

For this patient with a T1cN0, ER-negative, grade 3 tumor, and with an average comorbidity for age,Adjuvant! Online[4] suggests a 65% chance of being alive at 10 years, a 19.2% risk of death from othercauses, and a 15.8% risk of death due to breast cancer. In her case, Adjuvant! Online indicates a 3.7% reduction in the risk of death at 10 years with an anthracycline regimen like doxorubicin andcyclophosphamide (AC) for 4 cycles or of 4.1% with AC followed by a taxane.

Therefore, my personal preference would be to proceed with RT for completion of breast conservationafter several cycles of polychemotherapy. I would initially consider a regimen such as AC, but it would bereasonable also to offer an alternative regimen, such as docetaxel and cyclophosphamide[5] if there are con-cerns about an increased risk of long-term cardiac toxicity (eg, history of hypertension, diabetes, etc.).

References

1. Hughes KS, Schnaper LA, Berry D et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of ageor older with early breast cancer. N Engl J Med 2004; 351: 971-977

2. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in the extent of surgery for early breast canceron local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087-2106

3. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687-1717

Response from Antonio C. Wolff, MD, FACPAssociate Professor, Oncology Breast Cancer Program, The Sidney Kimmel Comprehensive Cancer Center,

Johns Hopkins University, Baltimore, Maryland

Oncology No.1