Case%201:%20Thalidomide

1
Case 1 Thalidomide
2

• Thalidomide
• C13H10N2O4
• Prescribed to pregnant women to combat morning
  sickness and as an aid to help them sleep.

3

• Thalidomide
• C13H10N2O4
• Prescribed to pregnant women to combat morning
  sickness and as an aid to help them sleep.
• Sold from 1957 to 1961 in almost fifty
  countries.

4

• Thalidomide
• C13H10N2O4
• Prescribed to pregnant women to combat morning
  sickness and as an aid to help them sleep.
• Sold from 1957 to 1961 in almost fifty
  countries.
• Inadequate tests were performed to assess the
  drug's safety approximately 10,000 children were
  born with severe malformities.

5

• Testing
• Scientists could not find any antibiotic
  activity, or any other encouraging effects, in
  mice and rats.

6

• Testing
• Scientists could not find any antibiotic
  activity, or any other encouraging effects, in
  mice and rats.
• Seemed to be harmless outrageously high doses
  did not kill rodents, rabbits, cats, or dogs.

7

• Testing
• Scientists could not find any antibiotic
  activity, or any other encouraging effects, in
  mice and rats.
• Seemed to be harmless outrageously high doses
  did not kill rodents, rabbits, cats, or dogs.
• Although no anticonvulsant effect was found,
  patients reported experiencing a deep sleep.
  Other patients said they felt calming and
  soothing effects.

8

• Testing
• Scientists could not find any antibiotic
  activity, or any other encouraging effects, in
  mice and rats.
• Seemed to be harmless outrageously high doses
  did not kill rodents, rabbits, cats, or dogs.
• Although no anticonvulsant effect was found,
  patients reported experiencing a deep sleep.
  Other patients said they felt calming and
  soothing effects.
• One author later said that Thalidomide was
  introduced by the method of Russian Roulette.
  Practically nothing was known about the drug at
  the time of its marketing.

9
An employee of Chemie Grünenthal brought home
samples of the new drug for his pregnant wife,
and ten months before thalidomide was put on the
market in Germany, on Christmas Day in 1956,
their child was born without ears. Years later,
the father learned that his daughter was the
first living victim of the epidemic of
thalidomide-induced infant malformations and
deaths.
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Frances Oldham Kelsey, Ph.D., M.D.
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Case 2 DES
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• DES
• Diethylstilbestrol
• C18H20O2
• First synthesized in early 1938 by English
  university research funded by the MRC (who had a
  policy against patenting drugs discovered using
  public funds).

13

• DES
• Diethylstilbestrol
• C18H20O2
• First synthesized in early 1938 by English
  university research funded by the MRC (who had a
  policy against patenting drugs discovered using
  public funds).
• It was inexpensive to synthesize (from coal
  tar), and was produced by over 300 pharmaceutical
  companies.

14

• DES
• Diethylstilbestrol
• C18H20O2
• First synthesized in early 1938 by English
  university research funded by the MRC (who had a
  policy against patenting drugs discovered using
  public funds).
• It was inexpensive to synthesize (from coal
  tar), and was produced by over 300 pharmaceutical
  companies.
• Its price was kept low from the beginning by
  competition.

15

• DES
• Diethylstilbestrol
• C18H20O2
• First synthesized in early 1938 by English
  university research funded by the MRC (who had a
  policy against patenting drugs discovered using
  public funds).
• It was inexpensive to synthesize (from coal
  tar), and was produced by over 300 pharmaceutical
  companies.
• Its price was kept low from the beginning by
  competition.
• DES (in tablets up to 5 mg) was approved by the
  FDA on September 19, 1941 for 4 indications
  gonorrheal vaginitis, atrophic vaginitis,
  menopausal symptoms, and postpartum lactation
  suppression.

16

• DES
• Diethylstilbestrol
• C18H20O2
• In 1941, DES found to be the first effective
  drug for treatment of metastatic prostate cancer.

17

• DES
• Diethylstilbestrol
• C18H20O2
• In 1941, DES found to be the first effective
  drug for treatment of metastatic prostate cancer.
• It was first prescribed by physicians to prevent
  miscarriages (in women who had had previous
  miscarriages) in the 1940s as an off-label use.
  On July 1, 1947, the FDA approved use for
  miscarriage.

18

• DES
• Diethylstilbestrol
• C18H20O2
• In 1941, DES found to be the first effective
  drug for treatment of metastatic prostate cancer.
• It was first prescribed by physicians to prevent
  miscarriages (in women who had had previous
  miscarriages) in the 1940s as an off-label use.
  On July 1, 1947, the FDA approved use for
  miscarriage.
• In the US, an estimated 5-10 million persons were
  exposed to DES during 1941-1971, including women
  who were prescribed DES while pregnant and the
  female and male children born of these
  pregnancies.

19

• DES
• Diethylstilbestrol
• C18H20O2
• In 1960, DES was found to be more effective than
  androgens in the treatment of advanced breast
  cancer in postmenopausal women. DES was the
  hormonal treatment of choice for advanced breast
  cancer in postmenopausal women for two decades.

20

• DES
• Diethylstilbestrol
• C18H20O2
• In 1960, DES was found to be more effective than
  androgens in the treatment of advanced breast
  cancer in postmenopausal women. DES was the
  hormonal treatment of choice for advanced breast
  cancer in postmenopausal women for two decades.
• In the 1990s, the only approved indications for
  DES were treatment of advanced prostate cancer
  and treatment of advanced breast cancer in
  postmenopausal women.

21

• DES
• Diethylstilbestrol
• C18H20O2
• In 1960, DES was found to be more effective than
  androgens in the treatment of advanced breast
  cancer in postmenopausal women. DES was the
  hormonal treatment of choice for advanced breast
  cancer in postmenopausal women for two decades.
• In the 1990s, the only approved indications for
  DES were treatment of advanced prostate cancer
  and treatment of advanced breast cancer in
  postmenopausal women.
• The last remaining U.S. manufacturer of DES, Eli
  Lilly, stopped making and marketing DES in 1997.

22
Testing DES was originally considered effective
and safe for both the pregnant woman and the
developing baby. A double-blind study in 1953 of
pregnant women (unselected for history of
miscarriage) was not published until six years
after DES received FDA approval for prevention of
miscarriage. Even though it found that pregnant
women given DES had just as many miscarriages and
premature deliveries as the control group, DES
continued to be aggressively marketed and
routinely prescribed (though in decreasing
frequencysales peaked in 1953 and by the late
1960s six of seven leading textbooks of
obstetrics said DES was ineffective at preventing
miscarriage).
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Effects First generation Women prescribed DES
while pregnant are at a modestly increased risk
for breast cancer.
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Effects First generation Women prescribed DES
while pregnant are at a modestly increased risk
for breast cancer. Second generation A new
study shows DES daughters as having a 2.5 fold
increase in breast cancer after age 40. Women
exposed to DES before birth (in the womb), known
as DES Daughters, are at an increased risk for
clear cell adenocarcinoma (CCA) of the vagina and
cervix, reproductive tract structural
differences, pregnancy complications,
infertility, and auto-immune disorders. Although
DES Daughters appear to be at highest risk for
clear cell cancer in their teens and early 20s,
cases have been reported in DES Daughters in
their 30s and 40s.
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car thefts in Avon and Somerset 1998 car thefts in Avon and Somerset 1998
owners' birthdates thefts days thefts/day expected
May 21-June 21 811 32 25.34 762.5644
April 21-May 20 794 30 26.47 714.9041
June 22-July 23 785 32 24.53 762.5644
July 24-August 23 756 31 24.39 738.7342
March 21-April 20 754 31 24.32 738.7342
February 20-March 20 730 29 25.17 691.074
August 24-September 23 719 31 23.19 738.7342
December 23-January 20 696 29 24.00 691.074
September 24-October 22 686 29 23.66 691.074
January 21-February 19 671 30 22.37 714.9041
October 23-November 22 657 31 21.19 738.7342
November 23-December 22 639 30 21.30 714.9041
8698 365 23.83014
26
car thefts in Avon and Somerset 1998 car thefts in Avon and Somerset 1998
owners' birthdates thefts days thefts/day expected
May 21-June 21 811 32 25.34 762.5644
April 21-May 20 794 30 26.47 714.9041
June 22-July 23 785 32 24.53 762.5644
July 24-August 23 756 31 24.39 738.7342
March 21-April 20 754 31 24.32 738.7342
February 20-March 20 730 29 25.17 691.074
August 24-September 23 719 31 23.19 738.7342
December 23-January 20 696 29 24.00 691.074
September 24-October 22 686 29 23.66 691.074
January 21-February 19 671 30 22.37 714.9041
October 23-November 22 657 31 21.19 738.7342
November 23-December 22 639 30 21.30 714.9041
8698 365 23.83014
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car thefts in Avon and Somerset 1998 car thefts in Avon and Somerset 1998
owners' birthdates thefts days thefts/day expected
May 21-June 21 811 32 25.34 762.5644
April 21-May 20 794 30 26.47 714.9041
June 22-July 23 785 32 24.53 762.5644
July 24-August 23 756 31 24.39 738.7342
March 21-April 20 754 31 24.32 738.7342
February 20-March 20 730 29 25.17 691.074
August 24-September 23 719 31 23.19 738.7342
December 23-January 20 696 29 24.00 691.074
September 24-October 22 686 29 23.66 691.074
January 21-February 19 671 30 22.37 714.9041
October 23-November 22 657 31 21.19 738.7342
November 23-December 22 639 30 21.30 714.9041
8698 365 23.83014