PRACTICAL POINTERS
PRIMARY CARE
“ME TOO” PRODUCTS—FRIEND OR FOE?
OMEGA 3 FATTY ACIDS AND CARDIOVASCULAR
DISEASE
MEMANTINE TREATMENT IN PATIENTS WITH
MODERATE TO SEVERE ALZHEIMER DISEASE
RISKS OF TESTOSTERONE-REPLACEMENT
THERAPY
HYPOGONADISM IN ELDERLY MEN—WHAT TO DO
UNTIL THE EVIDENCE COMES
HELICOBACTER PYLORI ERADICATION TO
PREVENT GASTRIC CANCER
FOLIC ACID AND THE PREVENTION OF
NEURAL TUBE DEFECTS
CORONARY ARTERY CALCIUM SCORE COMBINED
WITH FRAMINGHAM RISK SCORE
EFFECTS OF AN AD LIBITUM LOW-FAT,
HIGH-CARBOHYDRATE DIET
EFFECTS OF STRONTIUM IN WOMEN WITH
POSTMENOPAUSAL OSTEOPOROSIS
EFFICACY AND SAFETY OF LOW-DOSE
ASPIRIN IN POLYCYTHEMIA VERA
DAILY ASPIRIN—ONLY HALF THE ANSWER FOR
POLYCYTHEMIA VERA
“WAKEFULNESS ENHANCER” ROUSES CONCERN
SHOPPING ‘TIL WE DROP—WHAT IS WRONG
WITH IT?
ARCHIVES INTERNAL MEDICINE EDITED BY RICHARD T. JAMES JR. MD
ANNALS
INTERNAL MEDICINE 400
AVINGER LANE, SUITE 203
Rjames6556@aol.com DAVIDSON
N2 28036 USA
www.practicalpointers.org
The epidemic of childhood obesity has been attributed largely
to a decline in total energy expenditure (TEE).
This study postulated that the lifestyle of contemporary young children is
sedentary.
Levels of TEE were low at ages 3 and 5 in both sexes.
Lifestyles in this sample of youngsters were sedentary. This would increase
risk of obesity. Their total energy expenditure was significantly lower than
the UK estimate average requirement for energy for children.
Children typically spent only 20-25 min per day in
moderate to vigorous physical activity. Present recommendations are that they
should accumulate at least 60 min daily. “There is a widespread perception
among parents and health and educational professionals that young children are
spontaneously active. Actually, modern children establish a sedentary lifestyle
at an early age.”
Prevalence of childhood obesity has increased strikingly in
recent years.
The nature of human physiology is such that it is extremely
difficult, if not impossible, to maintain a healthy bodyweight with a low level
of physical activity.
Obesity arises from an imbalance in which energy intake
exceeds energy expenditure. This means that sedentary people must maintain a
low intake of energy to avoid obesity. Human physiology did not develop to
support restriction of energy intake. It is difficult for most people to do so
consistently over time
We have to teach children (and adults) to use their
intellect to push back against the environment. Such a change can be done by
eating a little less and being a little more physically active than ordinarily.
Small changes would counter the natural tendency to succumb to the environment.
“We suggest that weight gain in 90% of the US adult
population could be prevented by reducing positive energy balance by only 100
kcal per day.” Small and achievable changes in behavior can have a big impact.
Me-too products create competition among drug and device
manufacturers. Competition is a powerful driver for better quality and lower
costs. Health care leaders who struggle
to provide good care with limited resources see me-too products not as a
problem, but as an important part of the solution.
The first product in a new class defines the baseline value
equation. [Value = benefit / harm-cost] The manufacturer may set a high price
and may have no trouble selling the product at its asking price. When a second
product in the same class comes along, its manufacturers must offer a better
value. That product must lead to a better outcome or it must be less expensive.
For market forces to really work, physicians have to choose
products as if costs matter.
“If it were
not for the nicotine in tobacco, people would be little more inclined to smoke
than they are to blow bubbles.”
Experimenting with smoking usually begins in the early
teenage years. It is driven predominantly by psychosocial motives. Smoking a
cigarette is a symbolic act of rebellion, and a statement of independence. The desired image is sufficient for the
novice smoker to tolerate the aversion of the first few cigarettes, after which
the pharmacological factors assume much greater importance. As the force from
the psychological symbolism subsides, the pharmacological effect takes over to
sustain the habit. Absorption of nicotine from the lung and transfer to the
brain is almost instantaneous and complete.
Tolerance soon develops, and chronic users probably do
not obtain absolute improvements in performance, cognitive processing, or mood.
A plausible explanation for why smokers perceive cigarettes to be calming may
come from a consideration of the effects of nicotine withdrawal. Smokers start
to experience impairment of mood and performance within hours of their last
cigarette, and certainly overnight. These effects are completely alleviated by
smoking a cigarette.
“Early cessation is especially important.”
Omega 3 fatty acids (O3FA) from fish and fish oils can protect against coronary heart
disease (CHD). In this era of
polypharmacy, many persons believe that simple dietary interventions or
nutritional supplements may be a more natural and acceptable method of
providing benefits.
The American Heart Association recommends:
Patients without
documented CHD should eat a variety of fish (preferably oily) at least twice
weekly. Diet should also include vegetable oils.
Patients with
documented CHD should consume 1 g of O3FA and O6FA daily.
Physicians may prescribe 2-4 g/d of O3FA and O6FA
daily, provided as capsules, for patients with hypertriglyceridemia.
In October 2003, the FDA approved memantine (Namenda) for treatment of moderate to
severe AD. Memantine is a blocker of the receptor for aspartate. It is a new
class of drug.
This study hypothesized that adding memantine (Namenda) to donepezil (Aricept ) would result in clinical
benefit and would be well tolerated.
Memantine resulted in significant statistical, but
only slight clinical benefit when added to donepezil. It appeared safe.
Investigators, as in this report, often stress
statistically significant improvement, not clinical improvement. This may be
misleading. In my view, the outcome of this study is disappointing.. The
investigators place a spin on benefits by noting the statistically significant
outcomes. This may appear to be an impressive result, but it is not clinically
important.
Hypogonadism is a clinical condition in which low levels of
serum testosterone are found in association with specific signs and
symptoms: diminished libido and sense
of vitality, erectile dysfunction, , depression, anemia, and reduced muscle
mass and bone density. Prescriptions for testosterone supplementation have increased
substantially over the past decade.
Reports indicate that testosterone replacement may produce a
wide range of benefits: improvement in
libido, bone density, muscle mass, body composition, mood, erythropoiesis, and
cognition.
No studies have yet been initiated to assess benefits and
risks, especially possible stimulation of prostate cancer. But, “Despite
decades of research, there is no compelling evidence that testosterone has a
causative role in prostate cancer”. There is no compelling evidence to
suggest that men with higher testosterone levels are at greater risk of PC or
that treating men with hypogonadism with exogenous androgens increases risk.
Nevertheless, the authors advocate routine biopsy in all men presenting for
replacement therapy
Should primary care clinicians deal with this problem? Should
they refer patients seeking therapy to a urologist with considerable
experience? At the present stage of
development, I would follow the second course.
The value of a therapy has been described as: Value =
benefits
harms-costs
I believe the benefits are somewhat nebulous and unknown
long-term. Harms are potentially great. Cost is considerable considering
consultation and laboratory fees as well as the cost of the testosterone.
A long-awaited report from the Institute of Medicine (IOM)
concluded that there is insufficient evidence that testosterone benefits
elderly men.
Many studies document that serum testosterone levels decrease
as men age. In contrast to the precipitous and profound decrease in estradiol
concentrations in women at the menopause, the decrease in testosterone levels
in men occurs moderately and gradually over a period of several decades—from
about 600 ng/dL at age 30 to about 400 at age 80. One study reported that about 20% of men over age 60 had total
serum testosterones below the normal range for young men.
A still unanswered question is whether this decrease is
physiologic (perhaps conveying a benefit) or pathologic (causing harm).
Another unanswered question is whether increasing the
low-level testosterone in elderly men to the level of younger men will exacerbate testosterone-dependent diseases such
as prostate cancer and benign prostatic hyperplasia.
Over 7 years, in a subgroup of patients without any precancerous lesions in the stomach, eradication
significantly reduced risk of developing GC.
Other investigators suggest that Hp-infected patients with
normal findings on endoscopy are at risk of development of GC. Therefore, in
high-risk populations, all patients with H
pylori infection with no precancerous lesions should consider the use of
eradication treatment for gastric cancer prevention.
Further studies are required to determine the role of
eradication in those with precancerous lesions.
A public health policy should include both the mandatory
fortification of flour and a recommendation that all women planning a pregnancy
take 5 mg a day. Each year about a
quarter of a million pregnancies result in the birth of an infant with NTD, or
an abortion performed because of such a defect. 85% of them could be prevented if all women took 5-mg daily
before pregnancy and during the first trimester.
A high percentage of women of childbearing age have
unplanned pregnancies. Since the beginning of pregnancy cannot be predicted in
these women, I believe a good case can be made to recommend all women at risk
for pregnancy routinely take FA daily. Primary care clinicians should take the
opportunity to so advise their younger women patients regardless of the reason
for the consultation.
The benefit/harm-cost ratio of FA is high. Although overall risk is low, benefit may be
great for individuals The harm is nil. Cost is low. Considering the devastating
effect of NTD for the child and the family, I believe women at risk of
pregnancy should be informed and be able to choose if the cost and
inconvenience of taking 5-mg daily FA is reasonable. RTJ
In an intermediate-to-high-risk cohort with coronary risk
factors, the risk of a non-fatal MI or CHD death in those with a FRS risk score
over 20% was 14 times that of those with a FRS of less than 10%.
The CACS significantly modified the risk prediction in all
categories of the FRS score of at least 10%,
but not when the FRS was less
than 10%. When the CRCS was more than 300, the increment in predicted risk was
equal to a 3% to 9% increase in the 10-year event risk compared with FRS alone
for every category of FRS estimate. The risk of a non-fatal MI or CHD death in
those with a CACS over 300 was 4 times that of participants with a CACS of zero.
Would adding CACS determination modify my approach to the
patient? I believe it would have no
effect. My advice about risk-factor
control would remain the same as that predicted by the FRS alone.
Primary care clinicians have a broad base of risk factors to
estimate prognosis. We do not yet adequately apply them to individual patients.
I do not believe adding another factor will be of any clinical advantage. RTJ
This is a select abstraction of an interesting article. It
describes what might be considered the obverse of the Atkins (high fat, low
carbohydrate) diet.
The HCLF diet consisted of 18% fat; 19% protein; and 63%
carbohydrate.
Subjects on the HCLF diet consumed about 600 K/cal daily less
than those in the liberal control diet.
“Low-fat, high-carbohydrate diets may reduce body
weight via reduced food intake, since complex carbohydrate-rich foods are more
satiating and less energy dense than higher-fat foods.”
Food choices in the HCLF diet were limited—no sweets
and few snacks allowed. I doubt many free-living overweight persons would
adhere to the diet for very long.
I consider this an interesting, but not a clinically
significant study. It was performed under strict observation. Food was provided by a metabolic kitchen. It
lasted only 12 weeks. There were few subjects.
Weight-loss diets have become a multimillion dollar industry.
There are many types of diet and approaches to dieting. Gullible overweight
persons in the USA seek a quick fix. There is none. None of the diets works
consistently over time. Most individuals gradually gain back any weight lost,
regardless of the diet.
A calorie is a calorie, is a calorie, is a calorie. RTJ
Strontium ranelate is an orally active agent recently re-introduced for
treatment of osteoporosis. It consists of two atoms of strontium and an organic
moiety. It acts in a dual manner to stimulate formation of new bone and
decrease bone resorption.
SR treatment
of postmenopausal osteoporosis led to early and sustained reductions in risk of
vertebral fractures. In a high-risk group of women with osteoporosis, the NNT
to prevent one new vertebral fracture over 3 years = 10
There were no significant differences between groups
in the incidence of serious adverse effects.
Diarrhea was more common in the SR group (6%). Withdrawals were similar. There
was no change in vitamin D metabolites.
“The current trial
establishes the efficacy of strontium ranelate, a familiar element relaunched
as a new compound, in reducing the risk of vertebral fractures and its role in
the armamentarium of therapy for osteoporosis.”
The increase in the red cell mass in PV causes hyperviscosity
of the blood, a major determinant of circulatory disturbance. PV is associated
with an increase in thromboxane synthesis. This suggests that
thromboxane-dependent platelet activation is a major cause of thrombosis.
Thrombotic complications are a major cause of illness and
death in untreated patients.
Long-term, low-dose aspirin, used as primary prevention,
safely prevents thrombotic complications in patients with PV. NNT to prevent
myocardial infarction, stroke, major venous thrombosis, pulmonary embolism, or
death from cardiovascular causes over 3 years = 21 to 34.
Major bleeding events associated with low-dose aspirin
occurred in one in 26.
PV is the most common of the chronic myeloprolipherative disorders.
Primary care clinicians will likely refer patients to a hematologist, but may
be responsible for long-term follow-up. RTJ
Thrombosis causes much of the illness and death in patients
with polycythemia vera. No part of the
vascular system is spared. There is a predilection for peripheral arterioles
and cerebral and abdominal vessels. Thrombosis develops in about 40% of
patients, most often before or at the time of diagnosis. Rates of fatal
thrombosis may be high. Most arterial thrombi occur in small vessels and can
cause erythromelalgia and ocular migraine. PV also is a leading cause of
hepatic vein thrombosis. Attempts to control erythrocytosis by phlebotomy often
fail to diminish the high rate of thrombosis.
Increased blood viscosity is a paramount cause of
large-vessel arterial and venous thrombosis. It is in the large vessels that
the negative effect of high hematocrit is most pronounced.
An apparently normal hematocrit may not be normal in patients with this disease.. A safe target is
under 45% in men and under 42% in women. Viscosity of the blood rises
dramatically at hematocrit levels above 45%.
The
drug maker Cephalon has made an
unusual request. It wants the FDA to approve a drug, not for a condition or a
disease, but for a symptom—sleepiness. Not just routine sleepiness, but
excessive, or “profound sleepiness”—the kind that makes drivers crash.
The drug is modafinil. It is marketed as Provigil. It is already approved for the treatment of narcolepsy.
Modafinil somehow—no one knows how—targets the hypothalamus and other
sleep-regulating areas of the brain. Patients feel more alert without
“hyperarousal”.
According to sales figures, more and more sleep experts,
psychiatrists, and primary care clinicians are prescribing modafinil for
sleepiness for conditions other than narcolepsy. Depression tops the list.
Cephalon’s trials reported few adverse effects. A handful of
patients discontinued because of headache and nausea. Modafinil induces the P450 system in the liver and may affect
metabolism of many drugs. Caution is advised in patients with left ventricular
hypertrophy, ischemic heart disease and hypertension. There is an abuse
potential. The drug has psychoactive and euphoric effects in some patients.
Modafinil is classified as a schedule IV drug. Long-term
studies are limited. The drug blurs the lines between illness and enhancement.
Provigil taken regularly costs several hundreds of dollars per
month. The company is ramping up for a marketing blitz which includes
direct-to-consumer advertising.
I do not believe primary care clinicians should
prescribe this drug. Wait for further experience. RTJ
This article is based on a collection of essays edited by
Allen Kanner and Tim Kasser--Psychology
and Consumer Culture: the Struggle for a Good Life in a Materialistic World.
“A culture of consumption, which exalts the
acquisition of material goods over almost all other values, is causing severe
psychological harm” “People who orient their lives in pursuit of the goals that
consumer society tells us to pursue are less happy.”
People who are materialistic report less satisfaction with
life, less feeling of vitality, and lower energy compared with those who prize
“intrinsic” values (personal development, family relationships, and community
involvement). They report more problems with depression, anxiety, and alcohol
and tobacco use.
Conversely, people who place a higher value on
self-knowledge, family, and friendship, are happier and have higher quality relationships,
and a greater sense of freedom.
Since the 1950s, as our economy has grown, happiness has not
changed at all. And depression and anxiety have gone up. More wealth is not
going to make us happier. It’s about
improving other aspects of our world.
I asked myself—Why did I abstract this article? What has it to do with primary care
medicine? I am not sure of the answer. Perhaps it may provide some guidance to
physicians and their families. It may enable some primary care clinicians to
provide guidance to troubled patients. RTJ
=================
1-1 TOTAL ENERGY
EXPENDITURE AND PHYSICAL ACTIVITY IN YOUNG SCOTTISH CHILDREN
The epidemic of childhood obesity has been attributed largely
to a decline in total energy expenditure (TEE). This study postulated that the lifestyle
of contemporary young children is sedentary.
In 1999 and 2000 recruited a socioeconomically representative
sample of 78 children aged 3 years. Measured TEE, mean physical activity, and
sedentary behavior. Repeated the measurements 2 years later at age 5 in 72 of
the children.
At age 3, mean physical activity level and TEE did not differ
between sexes. At age 5, mean physical activity and TEE were significantly
higher in boys:
Age
3 girls Age 3 boys Age 5 girls Age 5 boys
Time spent in sedentary behavior (%) 81 76 78 73
Both girls and boys age 3 Both
girls and boys age 5
Median time in light-intensity activity (%) 18 20
Moderate/vigorous activity (%) 2 4
Levels of TEE were low at ages 3 and 5 in both sexes,
especially in girls. Lifestyles in this sample of youngsters were sedentary.
This would increase risk of obesity. Their TEE was significantly lower than the
UK estimate average requirement for energy for children.
Children typically spent only 20-25 min per day in moderate to
vigorous physical activity. Present recommendations are that they should
accumulate at least 60 min daily. “There is a widespread perception among
parents and health and educational professionals that young children are
spontaneously active. Actually, modern children establish a sedentary lifestyle
at an early age.
Prevalence of childhood obesity has increased strikingly in
recent years.
Comment:
The authors describe sophisticated methods for measuring TEE, physical activity, and sedentary
behavior. I did not understand the techniques involved. I took their word for
them. See text for details. RTJ
========================================================================
It Is Extremely Difficult, If Not
Impossible, To Maintain A Healthy Bodyweight With A Low Level Of Physical
Activity.
1-2 PHYSICAL
ACTIVITY AND OBESITY
This editorial comments and expands on the preceding study.
The nature of human physiology is such that it is extremely
difficult, if not impossible, to maintain a healthy bodyweight with a low level
of physical activity. Technological advances have eliminated many reasons for
physical activity. Our environment encourages inactivity. It is unlikely that
we can (or want to) change the environment back to one that requires high
levels of physical activity. This means we have to teach children (and adults)
to use their intellect to push back against the environment. Such a change can
be done by eating a little less and being a little more physically active than
ordinarily. Small changes would counter the natural tendency to succumb to the
environment.
Obesity arises from an imbalance in which energy intake exceeds
energy expenditure. This means that sedentary people must maintain a low intake
of energy to avoid obesity. Human physiology did not develop to support
restriction of energy intake. It is difficult for most people to do so
consistently over time. Our environment encourages energy intake by providing
good-tasting, convenient, and inexpensive food. “Sedentary children . . . will
probably not be able to maintain energy balance and avoid obesity only by
restricting energy intake. Preventing obesity in these children will require
both reduction in energy intake and increase in physical activity. “The good news
is that it may take only small changes to prevent obesity.”
“Excessive gain in weight can be prevented by small changes in
behavior.” The average US citizen is gaining about 2 pounds a year. This gain
could occur from as little as 20-50 kcal a day ingested in excess of energy
expended. “We suggest that weight gain in 90% of the US adult population could
be prevented by reducing positive energy balance by only 100 kcal per day.”
This would equate to a little more walking (about 2000 more steps) or eating a
few less bites of food (or preferably both).
It would take a bit more to change behavior in children. The point is
that small and achievable changes in behavior can have a big impact. Walking
2000 additional steps daily and eliminating 100 kcal (eg, drinking water or a
diet drink instead of a sugared fizzy drink). Combining these two small changes
can save 200 kcal per day. Prevention of obesity is easier than treatment.
Physicians Must Be Aware Of The Costs Of
The Drugs They Prescribe.
1-3 “ME TOO” PRODUCTS—FRIEND OR FOE?
A second drug-eluting stent, another drug for erectile
dysfunction, another statin drug. Medical journals seem filled with research
articles that induce a sense of déjà vu.
Critics assert that these market latecomers often differ trivially
from earlier products and that the billions of dollars spent on marketing
me-too products could be spent in better ways. They say that these products add
little to a physician’s arsenal while driving up the costs of health care.
There is another side to the story. Me-too products create
competition among drug and device manufacturers. Competition is a powerful
driver for better quality and lower costs.
Health care leaders who struggle to provide good care with limited
resources see me-too products not as a problem, but as an important part of the
solution.
The health care “valuation equation” is sometimes summarized
as: Value = benefit *
cost.
(*
or better—benefit/harm-cost RTJ )
The equation is quite useful for understanding how drugs and
devices enter the market—or why attempts to bring them to the market may fail.
The first product in a new class defines the baseline value equation. The
manufacturer may set a high price and may have no trouble selling the product
at its asking price. When a second product in the same class comes along, its
manufacturers must offer a better value. That product must lead to a better
outcome or it must be less expensive. The current monthly costs of statins that
are expected to lower LDL-cholesterol by 45% are lower for products that
received FDA approval more recently. Costs are also lower for other recently
introduced me-too drugs.
Why don’t we see real price wars driving health costs much
lower? The biggest reason is the rapid
rate of medical progress. This causes the value to increase through steady
increases in the top half of the equation. A second or third entrant may offer
real advantages. At some point, however, technology improves and a new entrant
represents only a minimal improvement. At that point, the top part of the
equation is frozen, and the action shifts to the bottom. The manufacturer can
succeed only by competing on price. The pressure on manufacturers of 3rd
and 4th entrants to come up with a product that really improves
outcomes or lowers cost will be tremendous.
But manufacturers have learned that physicians and patients are
usually reluctant to switch from a medication that is working. So the older
drug price may remain high. And the
drug company makes larger profits by selling their drug to fewer patients at a
high price than they would with more patients paying less.
For market forces to really work, physicians have to choose
products as if costs matter.
Comment:
Primary care clinicians must be aware of the costs of the
drugs they prescribe. Current costs can be easily obtained from drug store’s
web pages. The cost of a drug containing twice the needed dose may be much less
than twice the cost. A pill cutter can
save hundreds of dollars yearly. RTJ
Nicotine
Causes An Extremely Strong Addiction Very Rapidly
1-4 WHY PEOPLE SMOKE
Cigarette smoking is primarily a manifestation of
nicotine addiction. Smokers have individual preferences for their level of
nicotine intake. They regulate the way they puff and inhale to achieve their
desired nicotine dose. “If it were not for the nicotine in tobacco, people
would be little more inclined to smoke than they are to blow bubbles.”
In addition to addiction, social, economic, personal, and
political influences all play an important part in determining patterns of
smoking prevalence and cessation. Family and wider social influences are often
critical in determining who starts smoking, who gives it up, and who continues.
Why do people start smoking?
Experimenting with smoking usually begins in the early teenage
years. It is driven predominantly by psychosocial motives. Smoking a cigarette
is a symbolic act conveying “I am no longer my mother’s child” and “I am tough”. Children who are
attracted to this adolescent assertion of perceived adulthood or rebelliousness
tend to come from backgrounds that favor smoking (eg, high levels of smoking by
parents, siblings and peers; relatively deprived neighborhoods; schools where
smoking is common). They also tend not to be succeeding according to their own
or society’s terms. They have impaired
self esteem, are overweight, or are poor achievers at school.
The desired image is sufficient for the novice smoker to
tolerate the aversion of the first few cigarettes, after which the
pharmacological factors assume much greater importance. “As the force from the
psychological symbolism subsides, the pharmacological effect takes over to
sustain the habit.”* Within a year or
so of starting to smoke, children inhale the same amount of nicotine per
cigarette as adults, experience craving for cigarettes when they cannot smoke,
make attempts to quit, and report experiencing the whole range of nicotine
withdrawal symptoms. By age 20, 80% of cigarette smokers regret that they ever
started. But, many will continue to smoke for a substantial proportion of their
lives. (*All above quotations are from Philip Morris.)
Physical and psychological
effects of nicotine:
Absorption of nicotine from the lung is almost instantaneous
and complete. With each inhalation an arterial bolus of nicotine reaches the
brain faster than by intravenous injection. (See box p 277) Nicotine has a distribution half-life of 15-20
minutes and a terminal half life of 2 hours. Smokers therefore maintain a
pattern of repetitive and transient high blood nicotine concentrations from
each cigarette. Regular hourly cigarettes are needed to maintain raised
concentrations. Overnight, blood levels fall to close to those of non-smokers.
Nicotine activates receptors which are widely distributed in
the brain. It induces the release of
dopamine. This effect is the
same as that produced by amphetamines and cocaine. Nicotine is also a
psychomotor stimulant. In new users it speeds simple reaction time and improves
performance of tasks of sustained attention. However, tolerance soon develops,
and chronic users probably do not obtain absolute improvements in performance,
cognitive processing, or mood. Smokers typically report that cigarettes calm
them down when they are stressed, and help them concentrate and work more efficiently,
but little evidence exists that nicotine provides effective self medication for
adverse mood states or for coping with stress.
A plausible explanation for why smokers perceive cigarettes to
be calming may come from a consideration of the effects of nicotine withdrawal.
Smokers start to experience impairment of mood and performance within hours of
their last cigarette, and certainly overnight. These effects are completely
alleviated by smoking a cigarette. Smokers go through this process thousands of
times over the course of their smoking career. This may lead them to identify
cigarettes as effective self relief rather than any absolute improvement.
Symptoms of nicotine
withdrawal:
Much of the intractability of cigarette smoking is thought to
stem from withdrawal symptoms—irritability, restlessness, feeling miserable,
impaired concentration, and increased appetite—as well as craving for
cigarettes. These symptoms begin within hours and are maximal during the first
week. Most then resolve over 3 to 4 weeks, but hunger can persist for months.
Cravings, sometimes intense, can persist for months. Nicotine replacement
reliably attenuates the severity of withdrawal.
An intimate coupling of behavior rituals and sensory aspects of
smoking with nicotine uptake gives ample opportunity for secondary
conditioning. Each puff is linked to the sight of the packet, the smell of the
smoke, and the scratch of the throat some 70 000 times each year. Smokers are
concerned that if they quit they would not know what to do with their hands.
Other factors encourage smoking: being married to a smoker; being part of a social network in a
socially disadvantaged group among whom the prevalence of smoking is so high as
to constitute a norm.
The natural course of cigarette smoking is typically the onset
of regular smoking in adolescence, followed by repeated attempts to quit. Each
year about a third of adult smokers try to quit, usually unaided, and typically
relapsing within days. In general, less
than 3% of attempts to quit result in sustained cessation.
Regulation of nicotine intake:
Smokers show a strong tendency to regulate their nicotine
intakes within narrow limits. They avoid intakes that are too low (withdrawal
symptoms), or too high (nicotine overdose). Within individuals, nicotine
preferences emerge early and seem to be stable over time. The phenomenon of
nicotine titration is responsible for the failure of intakes to decline after
switching to cigarettes with low tar and nicotine. Compensatory puffing and
inhalation, operating at a subconscious level, ensure that nicotine intakes are
maintained. As nicotine and tar delivery in smoke are closely related,
compensatory smoking likewise maintains tar intake. This defeats any potential
health gain from low tar cigarettes.1
Socioeconomic
status and nicotine addiction.
An emerging phenomenon of the utmost significance is the
increasing association of continued smoking with markers of social disadvantage.
Affluent persons are much more likely to quit. Smokers who are poor tend to
have higher levels of nicotine intake and are substantially more dependent. It
is evident that future progress in reducing smoking is increasingly going to
have to tackle the problems posed by poverty.
Smoking as a chronic disease:
Cigarette dependence is a chronic relapsing condition that for
many users extends over decades. Successful interventions need to tackle the
interacting constellations of factors—personal, family, socioeconomic, and
pharmacological—that sustain use and can act as major barriers to cessation.
1 Some have
wondered why the nicotine content of cigarettes is not artificially increased
in the manufacturing process. This would supply the needed nicotine and
automatically lower the intake of carcinogens. Nicotine itself is not
carcinogenic.
I presume this would lead to all sorts of ethical and legal
complications.
The first article in this
clinical review The Problem of Tobacco
Smoking by Richard Edwards,
University of Manchester, UK (BMJ January
24, 2004; 328 : 217-219) comments:
Cigarette smoking is one of the biggest avoidable causes of
death and disability and one of the biggest threats of current and future world
health. “For most smokers, quitting smoking is the single most important thing
they can do to improve their health. Encouraging smoking cessation is one of
the most effective and cost effective things that doctors and other health
professionals can do to improve health and prolong their patient’s lives.
Cessation has substantial and immediate long-term health
benefits for smokers of all ages. The excess risk of death from smoking falls
soon after cessation and continues to do so for at least 15 years. Former
smokers live longer than continuing smokers, no matter what age they stop.
Smokers who stop before age 35 have about the same length of life as non-smokers.
Stopping before age 30 removes 90% of the lifelong risk of lung cancer. The
risk of heart disease decreases quickly after cessation. Within a year, risk is
halved. Within 15 years, the risk is almost the same as never-smokers.
Stopping before or in the first 3 to 4 months of pregnancy
protects the fetus against the reduced birth weight associated with smoking.
Preoperative cessation reduces perioperative mortality and complications.
“Early cessation is especially important.”
1-5 OMEGA 3
FATTY ACIDS AND CARDIOVASCULAR DISEASE—Fishing For A Natural Treatment
Omega 3 fatty acids (O3FA) from fish and fish oils can protect against coronary heart
disease (CHD). In this era of
polypharmacy, many persons believe that simple dietary interventions or
nutritional supplements may be a more natural and acceptable method of
providing benefits.
The optimum intake of O3FA is not established. Their method of
action is not understood. Some studies report no association, particularly in
populations with already moderate fish consumption. Concerns about
environmental contamination of fish have been raised.
These investigators performed a literature search and reviewed
the evidence regarding associations between O3FA and CHD.
Epidemiological and
observational studies:
Over 30 years ago, it was established that Greenland Inuits had
a low mortality from CHD despite a diet rich in fat (especially O3FA in fish,
seal, and whale). Fatty fish (mackerel, herring, salmon, sardines and trout)
are a rich source of O3FA and O6FA. Two to three servings a week should provide
about 1 g/d of O3FA.
Most studies have shown an inverse association between fish
consumption and CHD. A high concentration of O3FA reduces rate of sudden death.
A systemic review of 11 prospective cohort studies concluded that fish intake
reduced mortality due to CHD in populations at increased risk.
The Diet and Reinfarction Trial (DART) randomized over 200 men
with a recent myocardial infarction. Men who received advice on fish had a 29%
reduction in mortality over 2 years, mainly due to a reduction in death from
CHD. An Italian study reported a relative risk reduction of 30% in
cardiovascular death, and a 45% reduction in sudden death over 3.5 years. Benefits were apparent within 4 months.
Mechanism of action:
Several possible mechanisms have been proposed. None is
established. The predominant effect may be antiarrhythmic. O3FA are readily
incorporated into atherosclerotic plaques. This may make plaques less
vulnerable to rupture. O3FA also have a direct effect on endothelial function.
A modest reduction in BP has been reported.
O3FA reduce triglycerides in a dose-dependent manner. The reduction may
reach 30%. Effects on cholesterol are small.
Clinical implications:
O3FA from fish or fish oil supplements should be considered for
secondary prevention of patients
after MI. Diet should include at least 2 servings of oily fish weekly. Fish oil
capsules should be considered for those unable to tolerate fish or are unable
to change their diet effectively. “Approved pharmaceutical grade capsules
should be prescribed . . .”
The bottom line:
The American Heart Association recommends:
Patients without
documented CHD should eat a variety of fish (preferably oily) at least twice
weekly. Diet should also include vegetable oils.
Patients with
documented CHD should consume 1 g of O3FA and O6FA daily, preferably from oily
fish.
Physicians may prescribe 2-4 g/d of O3FA daily,
provided as capsules, for patients with hypertriglyceridemia.
Terminology of polyunsaturated fatty acids:
Number of carbon atoms (eg, C18) Number of double bonds (eg, 6) Position of first double bond from CH3 end
(eg, n-3; omega 3)
Omega 3 fatty acids Food
source
Plant derived:
Linolenic acid C18: 3 n-3 Flaxseed, soybean, walnut, and
rapeseed (canola) oil
Marine derived:
Eicosapentanoic acid C20: 5 n-3 Fish;
shellfish
Docosahexanoic acid C22:
6 n-3
Omega 6 fatty acids:
Plant derived: Linoleic
acid C18 4 n-6 Corn,
safflower, and sunflower oils.
Derived from linoleic acid ;
Arachidonic acid C20 4 n-6
Docosapentanoic acid
C22 5 n-6
Omega
3 FA and omega 6 FA are essential polyunsaturated fatty acids. O6FA are
abundant in the Western diet in the form of vegetable oils rich in linoleic
acid. Omega 9 fatty acids are in olive oil, peanuts, avocados, and almonds.
Comment:
Omega 3 and Omega 6 are included in the healthy Mediterranean
diet which has been reported convincingly to reduce risk of CHD. Persons with and without CHD should consume more fish.
There was a flurry of
interest in over-the-counter fish oil capsules about 10 years ago. My
pharmacist says that there is still some demand, but it has decreased.
The article presents several websites and reviews. RTJ
1-6 MEMANTINE
TREATMENT IN PATIENTS WITH MODERATE TO SEVERE ALZHEIMER DISEASE ALREADY
RECEIVING DONEPEZIL
The FDA has limited treatment for Alzheimer disease (AD) to monotherapy with
anti-cholinesterase inhibitors. In October 2003, the FDA approved memantine for
treatment of moderate to severe AD. Memantine is a blocker of the receptor for
aspartate. It is a new class of drug.
An open-label study suggested that a combination of memantine
with various anti-cholinesterase drugs was well tolerated. This study
hypothesized that adding memantine (Namenda)
to donepezil (Aricept ) would result
in clinical benefit and would be well tolerated.
Conclusion: Memantine resulted in significant
statistical, but only slight clinical benefit when added to donepezil. It
appeared safe.
STUDY
1. Randomized, controlled trial compared memantine vs
placebo in over 400 patients (mean age = 75)
All had moderate to severe AD. (Mini-mental State Examination scores 5
to 14. Mean = 10) All were already receiving stable doses of
donepezil. (Mean = 10 mg.)
2. Randomized to:
1) Memantine (titrated up to 20 mg dally) + continued donepezil, or 2)
Placebo + continued donepezil.
3. Outcome measures included: Measure of change in cognition and
activities of daily living, and clinician’s + caregiver’s impression of change.
1. Changes from baseline over
24 weeks:
Baseline 24 weeks
Placebo Memantine Placebo Memantine
SIB 1 80 78 -2.4 +
1.0
ADL 2 35.8 35.5 -3.3 -1.7
CIBIC-Plus 3 4.66 4.41 4.64 4.38
NPI 4 13.4 13.4 +
2.9 - 0.5
BGP Care dependency subscale 5 9.8 9.5 + 2.2 +
0.6
2 ADL
(activities of daily living) is a 19-item inventory focusing on activities of
daily living in later stages of dementia. Possible scores range from 0 to
54—higher scores reflect higher functioning. (Note that this measure declined in the memantine group, but not
as great as in the placebo group.
3 CIBC-Plus
(clinicians interview-based impression of change plus caregiver input) assesses
the clinician’s impression of effect of medication on overall clinical status, and incorporates caregiver
observations on a scale from 1 (marked improvement) to 7 (a marked worsening).
(Note that the change in CIBC-Plus in the memantine group was from 4.41
to 4.38 – hardly a clinical benefit. They do state that the P value = 0.03
4 NPI (neuropsychiatric inventory) assesses
frequency and severity of behavioral symptoms based on an interview with the
caregiver. Score ranges from 0 to 144. Higher scores reflect greater symptoms.
5 BGP
(behavioral scale for geriatric patients) assesses observable aspects of
cognition, function, and behavior. (A higher score reflects worse function.)
(The investigators
stressed that all differences in outcomes were statistically significant. But,
are they clinically significant? They
state—“No clinically significant differences were detected between treatment
groups in the mean change to end point.” Note the difference in the CIBIC-Plus
was slight—from 4.41 to 4.38 in the memantine group. (P value = 0.03.)
Although statistically significant, hardly of clinical significance.)
1. “Efficacy of memantine was significantly better than placebo treatment for treatment of moderate to severe AD in community-dwelling patients. Specifically, measures of cognitive function, activities of daily living behavior, and clinical global status were significantly improved with memantine compared with placebo.”
2. No pharmacokinetic or pharmacodynamic interactions were observed between donepezil and memantine. They act in different ways. Memantine has an effect on the glutamate-aspartate receptor system; donepezil affects cholinesterase
3. The long-term benefits were not addressed by this
study.
Comment:
Sponsored by Forrest
Laboratories. My pharmacy quotes $155
for a month’s supply of memantine (20 mg daily). An interesting
sidelight—memantine is a relative of the old drug used for influenza—amatadine.
Memantine has also been reported to lead to benefit in
patients with vascular dementia and mixed dementia.
There is evidence that the excitatory effect of glutamate
plays a role in the pathogenesis of AD. Memantine is a low-affinity blocker of
aspartate receptors. This may prevent excitatory amino acid neurotoxicity
without interfering with the physiological actions of glutamate for memory and
learning.
Investigators, as in this report, often stress
statistically significant improvement, not clinical improvement. This may be
misleading. In my view, the outcome of this study is disappointing. The
investigators place a spin on benefits by noting the statistically significant
outcomes. This may appear to be an impressive result, but it is not clinically
important.
It may be that families will encourage this approach, hoping
that their loved one may be an outlier, and receive more benefit.
I would be interested in a study comparing effects of these
drugs in patients with mild or possibly beginning AD — those with frequent
occurrence of “senior moments”
(temporary forgetfulness of names of well-known friends and past events which
they recalled immediately when they were younger). RTJ
As “Baby
Boomers” Age, Many Will Request Replacement Therapy
1-7 RISKS OF
TESTOSTERONE-REPLACEMENT THERAPY AND RECOMMENDATIONS FOR MONITORING.
Review articles are too long
to abstract concisely. I enjoy reading them and sometimes abstract a few points
which are new to me, which I had forgotten, or which I consider important and
deserving emphasis
Hypogonadism is a clinical condition in which low levels of
serum testosterone are found in association with specific signs and
symptoms: diminished libido and sense
of vitality, erectile dysfunction, reduced muscle mass and bone density,
depression, and anemia.
It is estimated to affect up to 4 million men in the USA.
Prevalence increases with age. Few men receive replacement therapy. About 50% of
men over age 80 and 30% of men age 70-79 have low serum levels. (Defined as a total serum testosterone under
325 ng/dL. Are these “low” levels physiologic or pathologic? I vote for
physiologic. RTJ)
Reports indicate that testosterone replacement may produce a
wide range of benefits: improvement in
libido, bone density, muscle mass, body composition, mood, erythropoiesis, and
cognition.
Recent interest has been fueled by medical awareness of the
effects of hypogonadism, media attention regarding hormone replacement,
marketing of new topical testosterone formulations, and the desire of “baby
boomers” to maintain vigor and health into their more mature years.
Controversy remains regarding indications for testosterone
supplementation in aging men. The most controversial topic is the issue of
risk. No studies have yet been initiated to assess benefits and risks,
especially possible stimulation of prostate cancer. Despite the controversy,
prescriptions for testosterone supplementation have increased substantially
over the past decade.
This review discusses what is known and not known about
regarding risks and to provide recommendations for monitoring men who receive
it.
Injectable, transdermal, buccal, and oral formulations are
available in the USA. Injectable preparations are typically given at a dose of
100 mg once a week. This produces high
peak levels and a “roller coaster” effects on symptoms.
A transdermal-patch preparation is available to deliver 5 to 10
mg. It requires daily application. Relatively uniform blood levels are
achieved. Levels above the physiologic range should be discouraged. (Note this is replacement to the level of
younger men, not above. RTJ)
Oral preparations are discouraged because of adverse effects on
the liver.
The author discusses many possible risks especially on benign
prostatic hyperplasia (BPH) and
prostate cancer (PC).