Showing posts with label Drugs. Show all posts
Showing posts with label Drugs. Show all posts
Drug Development
Drug Development
This process starts with the synthesis of
novel chemical compounds. Substances
with complex structures may be obtained
from various sources, e.g., plants
(cardiac glycosides), animal tissues
(heparin), microbial cultures (penicillin
G), or human cells (urokinase), or by
means of gene technology (human insulin).
As more insight is gained into structure-
activity relationships, the search
for new agents becomes more clearly
focused.
Preclinical testing yields information
on the biological effects of new substances.
Initial screening may employ
biochemical-pharmacological investigations
(e.g., receptor-binding assays
p. 56) or experiments on cell cultures,
isolated cells, and isolated organs. Since
these models invariably fall short of
replicating complex biological processes
in the intact organism, any potential
drug must be tested in the whole animal.
Only animal experiments can reveal
whether the desired effects will actually
occur at dosages that produce little
or no toxicity. Toxicological investigations
serve to evaluate the potential for:
(1) toxicity associated with acute or
chronic administration; (2) genetic
damage (genotoxicity, mutagenicity);
(3) production of tumors (onco- or carcinogenicity);
and (4) causation of birth
defects (teratogenicity). In animals,
compounds under investigation also
have to be studied with respect to their
absorption, distribution, metabolism,
and elimination (pharmacokinetics).
Even at the level of preclinical testing,
only a very small fraction of new compounds
will prove potentially fit for use
in humans.
Pharmaceutical technology provides
the methods for drug formulation.
Clinical testing starts with Phase I
studies on healthy subjects and seeks to
determine whether effects observed in
animal experiments also occur in humans.
Dose-response relationships are
determined. In Phase II, potential drugs
are first tested on selected patients for
therapeutic efficacy in those disease
states for which they are intended.
Should a beneficial action be evident
and the incidence of adverse effects be
acceptably small, Phase III is entered,
involving a larger group of patients in
whom the new drug will be compared
with standard treatments in terms of
therapeutic outcome. As a form of human
experimentation, these clinical
trials are subject to review and approval
by institutional ethics committees according
to international codes of conduct
(Declarations of Helsinki, Tokyo,
and Venice). During clinical testing,
many drugs are revealed to be unusable.
Ultimately, only one new drug remains
from approximately 10,000 newly synthesized
substances.
The decision to approve a new
drug is made by a national regulatory
body (Food & Drug Administration in
the U.S.A., the Health Protection Branch
Drugs Directorate in Canada, UK, Europe,
Australia) to which manufacturers
are required to submit their applications.
Applicants must document by
means of appropriate test data (from
preclinical and clinical trials) that the
criteria of efficacy and safety have been
met and that product forms (tablet, capsule,
etc.) satisfy general standards of
quality control.
Following approval, the new drug
may be marketed under a trade name
(p. 333) and thus become available for
prescription by physicians and dispensing
by pharmacists. As the drug gains
more widespread use, regulatory surveillance
continues in the form of postlicensing
studies (Phase IV of clinical
trials). Only on the basis of long-term
experience will the risk: benefit ratio be
properly assessed and, thus, the therapeutic
value of the new drug be determined.
This process starts with the synthesis of
novel chemical compounds. Substances
with complex structures may be obtained
from various sources, e.g., plants
(cardiac glycosides), animal tissues
(heparin), microbial cultures (penicillin
G), or human cells (urokinase), or by
means of gene technology (human insulin).
As more insight is gained into structure-
activity relationships, the search
for new agents becomes more clearly
focused.
Preclinical testing yields information
on the biological effects of new substances.
Initial screening may employ
biochemical-pharmacological investigations
(e.g., receptor-binding assays
p. 56) or experiments on cell cultures,
isolated cells, and isolated organs. Since
these models invariably fall short of
replicating complex biological processes
in the intact organism, any potential
drug must be tested in the whole animal.
Only animal experiments can reveal
whether the desired effects will actually
occur at dosages that produce little
or no toxicity. Toxicological investigations
serve to evaluate the potential for:
(1) toxicity associated with acute or
chronic administration; (2) genetic
damage (genotoxicity, mutagenicity);
(3) production of tumors (onco- or carcinogenicity);
and (4) causation of birth
defects (teratogenicity). In animals,
compounds under investigation also
have to be studied with respect to their
absorption, distribution, metabolism,
and elimination (pharmacokinetics).
Even at the level of preclinical testing,
only a very small fraction of new compounds
will prove potentially fit for use
in humans.
Pharmaceutical technology provides
the methods for drug formulation.
Clinical testing starts with Phase I
studies on healthy subjects and seeks to
determine whether effects observed in
animal experiments also occur in humans.
Dose-response relationships are
determined. In Phase II, potential drugs
are first tested on selected patients for
therapeutic efficacy in those disease
states for which they are intended.
Should a beneficial action be evident
and the incidence of adverse effects be
acceptably small, Phase III is entered,
involving a larger group of patients in
whom the new drug will be compared
with standard treatments in terms of
therapeutic outcome. As a form of human
experimentation, these clinical
trials are subject to review and approval
by institutional ethics committees according
to international codes of conduct
(Declarations of Helsinki, Tokyo,
and Venice). During clinical testing,
many drugs are revealed to be unusable.
Ultimately, only one new drug remains
from approximately 10,000 newly synthesized
substances.
The decision to approve a new
drug is made by a national regulatory
body (Food & Drug Administration in
the U.S.A., the Health Protection Branch
Drugs Directorate in Canada, UK, Europe,
Australia) to which manufacturers
are required to submit their applications.
Applicants must document by
means of appropriate test data (from
preclinical and clinical trials) that the
criteria of efficacy and safety have been
met and that product forms (tablet, capsule,
etc.) satisfy general standards of
quality control.
Following approval, the new drug
may be marketed under a trade name
(p. 333) and thus become available for
prescription by physicians and dispensing
by pharmacists. As the drug gains
more widespread use, regulatory surveillance
continues in the form of postlicensing
studies (Phase IV of clinical
trials). Only on the basis of long-term
experience will the risk: benefit ratio be
properly assessed and, thus, the therapeutic
value of the new drug be determined.
Drug Sources
Until the end of the 19th century, medicines
were natural organic or inorganic
products, mostly dried, but also fresh,
plants or plant parts. These might contain
substances possessing healing
(therapeutic) properties or substances
exerting a toxic effect.
In order to secure a supply of medically
useful products not merely at the
time of harvest but year-round, plants
were preserved by drying or soaking
them in vegetable oils or alcohol. Drying
the plant or a vegetable or animal product
yielded a drug (from French
“drogue” – dried herb). Colloquially, this
term nowadays often refers to chemical
substances with high potential for physical
dependence and abuse. Used scientifically,
this term implies nothing about
the quality of action, if any. In its original,
wider sense, drug could refer equally
well to the dried leaves of peppermint,
dried lime blossoms, dried flowers
and leaves of the female cannabis plant
(hashish, marijuana), or the dried milky
exudate obtained by slashing the unripe
seed capsules of Papaver somniferum
(raw opium). Nowadays, the term is applied
quite generally to a chemical substance
that is used for pharmacotherapy.
Soaking plants parts in alcohol
(ethanol) creates a tincture. In this process,
pharmacologically active constituents
of the plant are extracted by the alcohol.
Tinctures do not contain the complete
spectrum of substances that exist
in the plant or crude drug, only those
that are soluble in alcohol. In the case of
opium tincture, these ingredients are
alkaloids (i.e., basic substances of plant
origin) including: morphine, codeine,
narcotine = noscapine, papaverine, narceine,
and others.
Using a natural product or extract
to treat a disease thus usually entails the
administration of a number of substances
possibly possessing very different activities.
Moreover, the dose of an individual
constituent contained within a
given amount of the natural product is
subject to large variations, depending
upon the product‘s geographical origin
(biotope), time of harvesting, or conditions
and length of storage. For the same
reasons, the relative proportion of individual
constituents may vary considerably.
Starting with the extraction of
morphine from opium in 1804 by F. W.
Sertürner (1783–1841), the active principles
of many other natural products
were subsequently isolated in chemically
pure form by pharmaceutical laboratories.
The aims of isolating active principles
are:
1. Identification of the active ingredient(
s).
2. Analysis of the biological effects
(pharmacodynamics) of individual ingredients
and of their fate in the body
(pharmacokinetics).
3. Ensuring a precise and constant dosage
in the therapeutic use of chemically
pure constituents.
4. The possibility of chemical synthesis,
which would afford independence from
limited natural supplies and create conditions
for the analysis of structure-activity
relationships.
Finally, derivatives of the original constituent
may be synthesized in an effort
to optimize pharmacological properties.
Thus, derivatives of the original constituent
with improved therapeutic usefulness
may be developed.
were natural organic or inorganic
products, mostly dried, but also fresh,
plants or plant parts. These might contain
substances possessing healing
(therapeutic) properties or substances
exerting a toxic effect.
In order to secure a supply of medically
useful products not merely at the
time of harvest but year-round, plants
were preserved by drying or soaking
them in vegetable oils or alcohol. Drying
the plant or a vegetable or animal product
yielded a drug (from French
“drogue” – dried herb). Colloquially, this
term nowadays often refers to chemical
substances with high potential for physical
dependence and abuse. Used scientifically,
this term implies nothing about
the quality of action, if any. In its original,
wider sense, drug could refer equally
well to the dried leaves of peppermint,
dried lime blossoms, dried flowers
and leaves of the female cannabis plant
(hashish, marijuana), or the dried milky
exudate obtained by slashing the unripe
seed capsules of Papaver somniferum
(raw opium). Nowadays, the term is applied
quite generally to a chemical substance
that is used for pharmacotherapy.
Soaking plants parts in alcohol
(ethanol) creates a tincture. In this process,
pharmacologically active constituents
of the plant are extracted by the alcohol.
Tinctures do not contain the complete
spectrum of substances that exist
in the plant or crude drug, only those
that are soluble in alcohol. In the case of
opium tincture, these ingredients are
alkaloids (i.e., basic substances of plant
origin) including: morphine, codeine,
narcotine = noscapine, papaverine, narceine,
and others.
Using a natural product or extract
to treat a disease thus usually entails the
administration of a number of substances
possibly possessing very different activities.
Moreover, the dose of an individual
constituent contained within a
given amount of the natural product is
subject to large variations, depending
upon the product‘s geographical origin
(biotope), time of harvesting, or conditions
and length of storage. For the same
reasons, the relative proportion of individual
constituents may vary considerably.
Starting with the extraction of
morphine from opium in 1804 by F. W.
Sertürner (1783–1841), the active principles
of many other natural products
were subsequently isolated in chemically
pure form by pharmaceutical laboratories.
The aims of isolating active principles
are:
1. Identification of the active ingredient(
s).
2. Analysis of the biological effects
(pharmacodynamics) of individual ingredients
and of their fate in the body
(pharmacokinetics).
3. Ensuring a precise and constant dosage
in the therapeutic use of chemically
pure constituents.
4. The possibility of chemical synthesis,
which would afford independence from
limited natural supplies and create conditions
for the analysis of structure-activity
relationships.
Finally, derivatives of the original constituent
may be synthesized in an effort
to optimize pharmacological properties.
Thus, derivatives of the original constituent
with improved therapeutic usefulness
may be developed.
Pharmacology History
Since time immemorial, medicaments
have been used for treating disease in
humans and animals. The herbals of antiquity
describe the therapeutic powers
of certain plants and minerals. Belief in
the curative powers of plants and certain
substances rested exclusively upon
traditional knowledge, that is, empirical
information not subjected to critical examination.
Claudius Galen (129–200 A.D.) first attempted
to consider the theoretical
background of pharmacology. Both theory
and practical experience were to
contribute equally to the rational use of
medicines through interpretation of observed
and experienced results.
“The empiricists say that all is found by
experience. We, however, maintain that it
is found in part by experience, in part by
theory. Neither experience nor theory
alone is apt to discover all.”
The Impetus
Theophrastus von Hohenheim (1493–
1541 A.D.), called Paracelsus, began to
quesiton doctrines handed down from
antiquity, demanding knowledge of the
active ingredient(s) in prescribed remedies,
while rejecting the irrational concoctions
and mixtures of medieval medicine
medicine.
He prescribed chemically defined
substances with such success that professional
enemies had him prosecuted
as a poisoner. Against such accusations,
he defended himself with the thesis
that has become an axiom of pharmacology:
“If you want to explain any poison properly,
what then isn‘t a poison? All things
are poison, nothing is without poison; the
dose alone causes a thing not to be poison.”
Early Beginnings
Johann Jakob Wepfer (1620–1695)
was the first to verify by animal experimentation
assertions about pharmacological
or toxicological actions.
“I pondered at length. Finally I resolved to
clarify the matter by experiments.”
Foundation
Rudolf Buchheim (1820–1879) founded
the first institute of pharmacology at
the University of Dorpat (Tartu, Estonia)
in 1847, ushering in pharmacology as an
independent scientific discipline. In addition
to a description of effects, he
strove to explain the chemical properties
of drugs.
“The science of medicines is a theoretical,
i.e., explanatory, one. It is to provide us
with knowledge by which our judgement
about the utility of medicines can be validated
at the bedside.”
Consolidation – General Recognition
Oswald Schmiedeberg (1838–1921),
together with his many disciples (12 of
whom were appointed to chairs of pharmacology),
helped to establish the high
reputation of pharmacology. Fundamental
concepts such as structure-activity
relationship, drug receptor, and
selective toxicity emerged from the
work of, respectively, T. Frazer (1841–
1921) in Scotland, J. Langley (1852–
1925) in England, and P. Ehrlich
(1854–1915) in Germany. Alexander J.
Clark (1885–1941) in England first formalized
receptor theory in the early
1920s by applying the Law of Mass Action
to drug-receptor interactions. Together
with the internist, Bernhard
Naunyn (1839–1925), Schmiedeberg
founded the first journal of pharmacology,
which has since been published
without interruption. The “Father of
American Pharmacology”, John J. Abel
(1857–1938) was among the first
Americans to train in Schmiedeberg‘s
laboratory and was founder of the Journal
of Pharmacology and Experimental
Therapeutics (published from 1909 until
the present).
Status Quo
After 1920, pharmacological laboratories
sprang up in the pharmaceutical industry,
outside established university
institutes. After 1960, departments of
clinical pharmacology were set up at
many universities and in industry.
have been used for treating disease in
humans and animals. The herbals of antiquity
describe the therapeutic powers
of certain plants and minerals. Belief in
the curative powers of plants and certain
substances rested exclusively upon
traditional knowledge, that is, empirical
information not subjected to critical examination.
Claudius Galen (129–200 A.D.) first attempted
to consider the theoretical
background of pharmacology. Both theory
and practical experience were to
contribute equally to the rational use of
medicines through interpretation of observed
and experienced results.
“The empiricists say that all is found by
experience. We, however, maintain that it
is found in part by experience, in part by
theory. Neither experience nor theory
alone is apt to discover all.”
The Impetus
Theophrastus von Hohenheim (1493–
1541 A.D.), called Paracelsus, began to
quesiton doctrines handed down from
antiquity, demanding knowledge of the
active ingredient(s) in prescribed remedies,
while rejecting the irrational concoctions
and mixtures of medieval medicine
medicine.
He prescribed chemically defined
substances with such success that professional
enemies had him prosecuted
as a poisoner. Against such accusations,
he defended himself with the thesis
that has become an axiom of pharmacology:
“If you want to explain any poison properly,
what then isn‘t a poison? All things
are poison, nothing is without poison; the
dose alone causes a thing not to be poison.”
Early Beginnings
Johann Jakob Wepfer (1620–1695)
was the first to verify by animal experimentation
assertions about pharmacological
or toxicological actions.
“I pondered at length. Finally I resolved to
clarify the matter by experiments.”
Foundation
Rudolf Buchheim (1820–1879) founded
the first institute of pharmacology at
the University of Dorpat (Tartu, Estonia)
in 1847, ushering in pharmacology as an
independent scientific discipline. In addition
to a description of effects, he
strove to explain the chemical properties
of drugs.
“The science of medicines is a theoretical,
i.e., explanatory, one. It is to provide us
with knowledge by which our judgement
about the utility of medicines can be validated
at the bedside.”
Consolidation – General Recognition
Oswald Schmiedeberg (1838–1921),
together with his many disciples (12 of
whom were appointed to chairs of pharmacology),
helped to establish the high
reputation of pharmacology. Fundamental
concepts such as structure-activity
relationship, drug receptor, and
selective toxicity emerged from the
work of, respectively, T. Frazer (1841–
1921) in Scotland, J. Langley (1852–
1925) in England, and P. Ehrlich
(1854–1915) in Germany. Alexander J.
Clark (1885–1941) in England first formalized
receptor theory in the early
1920s by applying the Law of Mass Action
to drug-receptor interactions. Together
with the internist, Bernhard
Naunyn (1839–1925), Schmiedeberg
founded the first journal of pharmacology,
which has since been published
without interruption. The “Father of
American Pharmacology”, John J. Abel
(1857–1938) was among the first
Americans to train in Schmiedeberg‘s
laboratory and was founder of the Journal
of Pharmacology and Experimental
Therapeutics (published from 1909 until
the present).
Status Quo
After 1920, pharmacological laboratories
sprang up in the pharmaceutical industry,
outside established university
institutes. After 1960, departments of
clinical pharmacology were set up at
many universities and in industry.
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