·
1700BC
Earliest evidence of diagnostic medicine
in
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180 In his
Methodus Medendo,
Greek physician Galen devises a system of
medicine that will influence medical thinking for over a thousand years
·
980-1037 Avicenna writes The Canons of Medicine,
becomes principal European medical text until 1650
·
1493–1541 Swiss
physician Philippus Aureolus
Paracelsus rejects the prevalent
medical belief of his time that physical illnesses are caused by an imbalance
of the body's four "humors" (melancholic, choleric, sanguine, and
phlegmatic). He proposes instead that the body is weakened by external
conditions and toxic agents, and may be treated with a number of chemical
remedies. Although influenced by contemporary mysticism and the occult,
Paracelsus' medical observations lay the foundation
for modern diagnostic methods.
·
1618 William Harvey describes the circulation
of the blood
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1659 The syringe is developed in
·
1778 Franz Mesmer
uses hypnotism.
·
1796 Smallpox vaccination using cowpox is
developed by Dr. Edward Jenner
·
1842 Crawford Long uses first anesthetic
(ether). 1846 W. T. Morton uses ether as anesthetic
·
1861 Louis Pasteur's theory of germs proposed. 1885 Pasteur develops a vaccine for rabies. He also develops pasteurization, the heat treatment of
food to prevent contamination by bacteria, and vaccines for cattle, sheep, and
chicken.
·
1865 Joseph Lister begins antiseptic surgery
·
1865 Claude Bernard's classic on scientific
method, An Introduction to the Study of Experimental Medicine, is published. Bernard's first
important work was on the functions of the pancreas gland. A second
investigation - perhaps his most famous was on the glycogenic function of the
liver; in the course of this he was led to the conclusion, which throws light
on the causation of diabetes mellitus. Milieu intérieur,
internal environment, was the original concept of Bernard that led to the
concept of homeostasis.
·
1882 In
·
1895 Wilhelm Roentgen discovers x-rays.
Already in 1896 several hospitals had x-ray facilities, and x-ray photographs
were ruled as acceptable evidence in courts in
·
1899 Aspirin
is first marketed
·
1900 Sigmund Freud’s The Interpretation of Dreams. 1917 Freud’s Introduction to Psychoanalysis.
·
Walter Cannon, professor of physiology at Harvard, first described the concept of homeostasis. 1915 Cannon describes the “fight or flight” response of the
sympathetic nervous system. 1932 He publishes an account of his
theory of homeostasis in The Wisdom of
the Body. He also developed the barium swallow (Upper GI X-ray series).
·
1918
Worldwide influenza epidemic strikes; by 1920, nearly 20 million are dead. In
·
1921 Dr. Frederick Banting, with Charles Best and J.J.R. Macleod, isolated insulin
·
1927
Herman Blumgart, a
·
1928 Penicillin, 1st antibiotic. Dr.
Alexander Fleming notices mold inhibits Staph aureus from growing, mold identified as Penicillium,
later extracts penicillin
·
1944 Kidney dialysis is invented in the
·
1954 Dr. Jonas Salk develops the polio vaccine
·
1954 The
first successful human organ transplant:
Drs. Joseph Murray and J. Hartwell Harrison transplanted a kidney to a patient
from his twin brother.
·
1960 The
first heart pacemaker is made in the
·
1963 Michael E. De Bakey
implants artificial heart in
human for first time at
·
1967 Dr. Christiaan Barnard performs the first successful heart transplant in
·
1977
Scientists at Genentech (Boyer and Swanson) report
using genetically-engineered bacteria containing human insulin gene to produce
insulin. Later the first recombinant
human insulin (Humulin) is sold by Eli Lilly
(insulin was previously made from bovine pancreatic extracts)
·
1977 The
Magnetic Resonance Imaging (MRI)
scanner is developed by Raymond Damadian
·
1978 Birth
of the first child conceived by in vitro
fertilization (
·
1980
Smallpox is declared eradicated
·
1981 AIDS
(Acquired Immunodeficiency Syndrome) is first described. 1983 HIV virus is identified. 1987
AZT, the first HIV antiviral is developed.
·
1982 First
artificial heart implanted at the
University of Utah Medical Center
Clinical Trials
·
Clinical trials (synonyms: clinical studies, research protocol)
evaluate new drugs, medical devices, or other interventions (e.g. procedures)
on patients in strictly scientifically controlled settings
·
Trials may be designed to assess the safety and efficacy
of an experimental therapy, to assess whether the new intervention is better
than standard therapy, or to compare the efficacy of two standard interventions.
·
Clinical trials are required for
regulatory authority approval of new treatment, i.e. the US Food and Drug
Administration, Health
·
The trial objectives and design are usually documented in
a clinical trial protocol.
·
Clinical trials must involve the informed consent of participating human subjects.
·
All interventional studies must be approved by an ethics
committee (in the
·
In the
Study design
·
The randomized
controlled trial (RCT) provides the most compelling evidence of a causal
relationship between the treatment and the effect
o Each study subject is
randomly assigned to receive either the subject treatments or control arm
(another treatment or placebo)
o RCTs may be double-blinded,
single-blinded, or nonblinded
depending on whether either subject or experimenter know which arm the subject
is enrolled in
·
Observational studies, such as the cohort study and the
case-control study provide less compelling evidence than the randomized
controlled trial.
·
These are fundamental distinctions in evidence-based
medicine.
·
Size: Small clinical trials may be "sponsored"
by single physicians or a small group of physicians, and are designed to test
simple questions. Other clinical trials require large numbers of participants
followed over long periods of time, and the trial sponsor is more likely to be
a commercial company or a government, or other academic, research body. It is
sometimes necessary to organize multicenter trials,
which may be international.
Phases
·
Pharmaceutical clinical trials are commonly classified
into four phases
·
Phase I trials consist of a
small (20-80) group of healthy volunteers designed to assess the safety,
tolerability, pharmacokinetics, and pharmacodynamics
of a therapy. These trials are almost always conducted in an inpatient clinic,
where the subject can be observed by full-time medical staff. The subject is
usually observed until several half-lives of the drug have passed. Phase I
trials also normally include dose-ranging studies so that doses for clinical
use can be refined. The tested range of doses will usually be a small fraction
of the dose that causes harm in animal testing. Phase
I trials most often include healthy volunteers, however there are some
circumstances when patients are used, such as with oncology (cancer) and HIV
drug trials. In Phase I trials of new cancer drugs, for example, patients with
advanced cancer are used. These trials are usually offered to patients who have
had other types of therapy and who have few, if any, other treatment choices.
·
Phase II trials are performed on
larger groups (20-300) and are designed to assess clinical efficacy of the
therapy; as well as to continue Phase I assessments in a larger group of
volunteers and patients. The development process for a new drug commonly fails
during Phase II trials due to the discovery of poor efficacy or toxic effects.
·
Phase III studies are randomized
controlled trials on large patient groups (300–3,000 or more depending upon the
condition) and compare the efficacy of the new therapy with current 'Gold
Standard' treatment. Phase III trials are the most expensive, time-consuming
and difficult trials to design and run. Once a drug has proven satisfactory
over Phase III trials, the information makes up the "regulatory
submission" that is provided for review to various regulatory authorities
in different countries.
·
Phase IV trials involve the
post-launch safety surveillance of a drug to detect any rare or long-term
adverse effects over a much larger patient population and timescale than was
possible during the initial clinical trials. Such adverse effects detected by
Phase IV trials may result in the withdrawal or restriction of a drug - recent
examples include cerivastatin (Baycol
and Lipobay), troglitazone
(Rezulin) and rofecoxib (Vioxx).
o
Vioxx was approved in 1999.
In 2004, Merck voluntarily withdrew rofecoxib from
the market because of concerns about increased risk of heart attack and stroke
associated with long-term, high-dosage use. Rofecoxib
was one of the most widely used drugs ever to be withdrawn from the market with
sales revenue of US$2.5 billion
·
An Investigational Device Exemption (IDE)
allows the investigational device to be used in a clinical study in order to
collect safety and effectiveness data required to support a Premarket
Approval (PMA) application or a Premarket Notification
[510(k)] submission to the FDA. IDEs also include
clinical evaluation of certain modifications or new intended uses of already
marketed devices. All clinical evaluations of investigational devices, unless
exempt, must have an approved IDE before the study is initiated. It also
requires IRB approval, informed consent, labelling
“for investigational use only, and monitoring and reporting of results.
·
Links: www.clinicaltrials.gov
·
Evidence-based medicine (EBM) is an attempt to more
uniformly apply the scientific method to medical practice.
·
With a high-tech
health-care system that costs the nation $2 trillion a year, there is little or
no evidence that widely used treatments for many diseases, from cardiovascular
diseased to back pain to prostate cancer, actually work better than various
cheaper alternatives.
·
Using
"evidence-based medicine" (a term he coined), Dr. David Eddy, a heart
surgeon turned mathematician and health-care economist, showed that the annual
chest X-ray was worthless, doctors had little clue about the success rate of
procedures such as surgery for enlarged prostates, and the practice of
preventing women from giving birth vaginally if they had previously had a
cesarean was traced to the recommendation of one doctor. He cites a figure that
only 15% of what doctors do is backed by hard evidence.
o As a consultant on Blue Cross's insurance coverage
decisions, Eddy testified on the insurer's behalf in high-profile court cases,
such as bone marrow transplants for breast cancer. Women and doctors demanded
the treatment, even though there was no evidence it
saved lives. Insurers who refused coverage usually lost in court. When clinical
trials were actually done, they showed that the treatment, costing from $50,000
to $150,000, didn't work.
o Eddy uses computer simulations to run virtual
clinical trials.
·
Up to one-third
of clinical studies lead to conclusions that are later overturned, according to
a recent paper in JAMA. Difficulties are highlighted by an eight-year study of
low-fat diets that cost upward of $400 million. Most subjects failed to stick
to the low-fat regimen, making it tough to draw conclusions. In addition, the
study failed to take stock of different kinds of fats, some of which are now
known to have beneficial effects. Many trials fall into similar traps.
·
In 1993, the
federal government's Agency for Health Care Policy & Research convened a
panel to develop guidelines for back surgery. A prominent back surgeon protested
to Congress, and lawmakers slashed funding for the agency.
·
In studies where
one group of patients hears the full story while other patients simply receive
their doctors' instructions, a key difference emerges. The well-informed
patients opt for more invasive, aggressive approaches 23% less often, on
average, than the other group. In some cases, the drop is much bigger -- 50% to
60%.
·
Systematic reviews of randomized, double-blind,
placebo-controlled trials are generally regarded as the highest level of medical
evidence by evidence-based medicine professionals.
o A systematic review is a
summary of the healthcare literature that uses explicit methods to perform a
literature search and critical appraisal of individual studies to identify the
valid and applicable evidence, and then uses appropriate techniques to combine
these valid studies. Most are are based on an
explicit quantitative meta-analysis of available data
o The best-known source of
systematic reviews of is the Cochrane Collaboration, a group of over 6,000
health care specialists. Cochrane
reviews, based on explicit meta-analyses, are published in the Cochrane
Database of Systematic Reviews section of the Cochrane Library.
·
Clinical guidelines briefly identify, summarize
and evaluate the best evidence and most current data about treatments’
effectiveness, risk/benefit and cost-effectiveness in order to standardize care
and improve the quality of care. They are usually published by professional
associations or governmental agencies. They arose in the
·
Professor Archie Cochrane, a Scottish epidemiologist
through his advocacy caused increasing acceptance of the concepts behind
evidence-based practice. Cochrane's work was honoured
through the naming of the Cochrane Centres and
the Cochrane Collaboration, founded in 1993. The explicit methodologies used to
determine "best evidence" were largely
established by the
·
In contrast, patient testimonials, case reports, and even
expert opinion have little value as proof because of the placebo effect, the
biases inherent in observation and reporting of cases, difficulties in
ascertaining who is an expert, and more.
·
The concept of number needed to treat (NNT) is
increasingly part of evidence-based medicine. NNT is a numerical indicator of
the effectiveness of a therapy. For example, an NNT of 4 means if 4 patients
are treated, only one would respond. An NNT of 2 or 3 indicates that a
treatment is quite effective, but an NNT of 20 to 40 can still be considered
clinically effective.
·
Randomized
trials ended the use of some common treatments: the use of bone marrow
transplant in breast cancer, use of antiarrythmics (flecainide, ecainide) after MI,
many inotropics (except digoxin)
used for heart failure, liberal blood transfusions, and hormone replacement
therapy for decreasing heart disease
·
Criticisms: EBM applies to populations, not necessarily
to individuals. Even if several top-quality studies are available, questions
always remain about how far, and to which populations, their results are "generalizable". In The limits of evidence-based medicine,
Tonelli argues that "the knowledge gained from
clinical research does not directly answer the primary clinical question of
what is best for the patient at hand." Tonelli
suggests that proponents of evidence-based medicine discount the value of clinical
experience.
o In some cases, such as
in open-heart surgery, conducting randomized controlled trials would be
unethical, although observational studies are designed to address these
problems to some degree.
o In managed healthcare
systems, evidence-based guidelines have been used as a basis for denying
insurance coverage for some treatments which are held by the physicians
involved to be effective, but of which randomized
controlled trials have not yet been published.
Levels of Evidence
Systems to stratify evidence by quality have been developed, such as this
one by the U.S. Preventive Services Task Force:
·
Level I: Evidence obtained from at least one properly
designed randomized controlled trial.
·
Level II-1: Evidence obtained from well-designed
controlled trials without randomization.
·
Level II-2: Evidence obtained from well-designed cohort
or case-control analytic studies, preferably from more than one center or
research group.
·
Level II-3: Evidence obtained from multiple time series
with or without the intervention. Dramatic results in uncontrolled trials might
also be regarded as this type of evidence.
·
Level III: Opinions of respected authorities, based on
clinical experience, descriptive studies, or reports of expert committees.
·
Links: National Guideline Clearinghouse, Guidelines International Network, Cochrane Library
·
Biologics or biologic therapies are a new class of
drugs produced through genetic manipulation.
o They can be made only by
a living system and have large, complex molecular structures. They are mostly
produced using cell culture.
o They include standard
single molecule drugs, as well as antibodies and vaccines.
o Biologics include Alefacept
(Amevive), Etanercept (Enbrel), Adalimumab (Humira), Infliximab (Remicade®) and Raptiva. These act
as immunosuppressants by blocking the inflammation
causing action of TNF-alpha. These drugs have only recently begun to receive approval
by the US FDA
·
An example of pharmacogenomics in
diagnostics is the use of multigene analysis to
predict the need for chemotherapy in certain breast cancers.
·
Knowledge of a patient’s genetic makeup can sometimes help avoid
adverse drug reactions, as a study earlier this year showed for warfarin
·
In drug development, genomics can already salvage a drug that
might otherwise be abandoned, as demonstrated by gefitinib,
which has little benefit for the majority of those with lung cancer but may
prove lifesaving in the sizable minority with a specific genotype
Stem Cells
·
Stem cells are cells that retain the ability to renew themselves
through cell division and can differentiate
into a wide range of specialized cell types.
·
The two broad categories of mammalian stem cells exist: embryonic
stem cells, derived from blastocysts, and adult
stem cells, which are found in adult tissues.
Embryonic Stem Cells
·
Embryonic stem cell lines (ES cell lines) are cultures of
cells derived from the inner cell mass (ICM) of a blastocyst.
o A blastocyst
is an early stage embryo - approximately 4 to 5 days old in humans and
consisting of 50-150 cells.
o ES cells are pluripotent, and give rise during development to
all derivatives of the three primary germ layers: ectoderm, endoderm and
mesoderm, or into any of the more than 200 cell types of the adult body.
o When given no stimuli
for differentiation, ES cells will continue to divide in vitro and each
daughter cell will remain pluripotent.
o Embryonic stem cell
research is particularly controversial because, with the present state of
technology, starting a stem cell line requires the destruction of a human
embryo and/or therapeutic cloning. Most researchers use embryos that were
created but not used in in vitro fertility treatments
which are slated to be destroyed, or stored indefinitely.
o Researchers at Advanced
Cell Technology of Worcester, Mass., succeeded in obtaining stem cells from
mouse embryos without killing them. If this technique and its reliability are
improved, it would alleviate many of the ethical problems related to embryonic
stem cell research
o The patents covering
much work on human embryonic stem cells are owned by the Wisconsin Alumni
Research Foundation (WARF). WARF does not charge academics to study human stem
cells but does charge commercial users. WARF sold Geron
Corp. exclusive rights to work on human stem cells but later sued Geron Corp. to recover some of the previously sold rights.
·
In the European Union, stem cell research using the human
embryo is permitted in
· 2001