Η ΒΑΣΙΚΗ ΚΑΙ ΚΛΙΝΙΚΗ ΑΞΙΟΛΟΓΗΣΗ ΤΩΝ ΦΑΡΜΑΚΩΝ

Η ΑΝΑΚΑΛΥΨΗ ΤΩΝ ΦΑΡΜΑΚΩΝ

Η ΑΝΑΚΑΛΥΨΗ ΤΩΝ ΦΑΡΜΑΚΩΝ
 Smith, Kline & French

•Smith, Kline & French was a pharmaceutical company, which is now part
of GlaxoSmithKline.

•In 1830, John K. Smith opened a drugstore in Philadelphia, and his younger brother,
George, joined him in 1841 to form John K Smith & Co.
• In 1865, Mahlon Kline joined Smith and Shoemaker, as John K Smith and Co had
become in the meantime, as a bookkeeper. In 1875, he took on additional responsibilities
as a salesman and added many new and large accounts, as a reward the company,
Mahlon K Smith and Company, was renamed into Smith, Kline and Company.
•In 1891, Smith, Kline and Company acquired French, Richards and Company, which
provided the company with a greater portfolio of consumer brands. In 1929 Smith, Kline
and French Company was renamed into Smith Kline and French Laboratories and the
company put more focus on research in order to sustain its business.
• In 1968, the company acquired Recherche et Industrie Thérapeutiques inBelgium and
changed its name in SmithKline-RIT.
•SmithKline acquired Allergan in 1982, an eye and skincare business, and merged
with Beckman Instruments, Inc., a company specializing in diagnostics and
measurement instruments and supplies. After the merger the company was
renamed SmithKline Beckman.
•SmithKline Beckman and The Beecham Group plc merged in 1989 to form SmithKline
Beecham plc.
There was still controversy regarding the physiology of acid secretion in 1964
when a team at Smith Kline & French Laboratories in England started a project
to prove the existence of more than one receptor for histamine and to find a
substance capable of blocking the effects not blocked by the commonly used
antihistamines. The team was convinced that histamine was the final
mediator of acid secretion. After 8 years, James Black and his coworkers
published evidence of the first histamine2-receptor antagonist, burimamide. As
this substance was not suitable for oral therapy, the research continued.
Metiamide was synthesized with promising clinical effects but questionable
safety. The final answer was cimetidine (Tagamet), approved in England in
November 1976. Cimetidine was a breakthrough in the treatment of peptic ulcers.
In this article I focus on the human factors lying behind many of the decisions
made during the years of research. Without personal courage under stressful
conditions, the H2-receptor antagonists might never have reached the market.
 Η ΑΝΑΚΑΛΥΨΗ ΤΩΝ ΦΑΡΜΑΚΩΝ

ΕΝΑΡΞΗ ΤΟΥ ΕΡΕΥΝΗΤΙΚΟΥ ΠΡΟΓΡΑΜΜΑΤΟΣ: ΣΥΝΘΕΣΗ ΚΑΙ

ΜΕΛΕΤΕΣ ΣΧΕΣΗΣ ΔΟΜΗΣ ΔΡΑΣΤΙΚΟΤΗΤΑΣ ΤΟΥ ΦΑΡΜΑΚΟΥ
 ΜΕΙΟΝΕΚΤΗΜΑΤΑ ΤΟΥ ΠΡΟΚΛΙΝΙΚΟΥ ΕΛΕΓΧΟΥ

• Ο δοκιμαστικός έλεγχος της τοξικότητας είναι χρονοβόρος και

δαπανηρός ($41Μ, 2-5 έτη ανά φάρμακο).

• Χρησιμοποιούνται μεγάλοι αριθμοί πειραματόζωων

• Η επέκταση δεδομένων τοξικότητας από τα ζώα στον άνθρωπο δεν

είναι εντελώς αξιόπιστη.
ΚΥΡΙΕΣ ΠΑΡΑΜΕΤΡΟΙ ΠΟΥ ΠΡΟΣΔΙΟΡΙΖΟΝΤΑΙ
ΣΕ ΜΙΑ ΠΡΟΚΛΙΝΙΚΗ ΜΕΛΕΤΗ ΤΟΞΙΚΟΤΗΤΑΣ
ΠΟΣΟΤΙΚΕΣ ΠΑΡΑΜΕΤΡΟΙ
ΠΟΥ ΠΡΟΣΔΙΟΡΙΖΟΝΤΑΙ
ΣΕ ΜΙΑ ΠΡΟΚΛΙΝΙΚΗ
ΜΕΛΕΤΗ ΤΟΞΙΚΟΤΗΤΑΣ
SINGLE BLIND TRIALS
In a single-blind experiment, the individual subjects do not know whether they
are so-called "test" subjects or members of an "experimental control" group
whereas the experimenters need not be blind. However, there is a risk that
subjects are influenced by interaction with the researchers — known as the
experimenter's bias. Single-blind trials are especially risky in psychology and
social science research, where the experimenter has an expectation of what the
outcome should be, and may consciously or subconsciously influence the behavior
of the subject.
A classic example of a single-blind test is the "Pepsi challenge."
A marketing person prepares several cups of cola labeled "A" and "B". One set of
cups has Pepsi, the others have Coca-Cola.
The marketing person knows which soda is in which cup but is not supposed to
reveal that information to the subjects.
Volunteer subjects are encouraged to try the two cups of soda and polled for
which ones they prefer.
The problem with a single-blind test like this is the marketing person can give
(unintentional or not) subconscious cues which bias the volunteer.
In addition it's possible the marketing person could prepare the separate sodas
differently (more ice in one cup, push one cup in front of the volunteer, etc.) which
can cause a bias.
If the marketing person is employed by the company which is producing the
challenge there's always the possibility of a conflict of interests where the
marketing person is aware that future income will be based on the results of the
test.
 Double-blind trials

In a double-blind experiment, neither the individuals nor the researchers

know who belongs to the control group and the experimental group.

Only after all the data have been recorded (and in some cases, analyzed) do
the researchers learn which individuals are which.

Performing an experiment in double-blind fashion is a way to lessen the

influence of the prejudices and unintentional physical cues on the results (the
placebo effect, observer bias, and experimenter's bias).

Random assignment of the subject to the experimental or control group is a

critical part of double-blind research design. The key that identifies the
subjects and which group they belonged to is kept by a third party and not
given to the researchers until the study is over.
The phenomenon of an inert substance resulting in a patient's medical
improvement is called the placebo effect.
The phenomenon is related to the perception and expectation which the patient
has; if the substance is viewed as helpful, it can heal, but if it is viewed as
harmful, it can cause negative effects, which is known as the nocebo effect.
The basic mechanisms of placebo effects have been investigated since 1978,
when it was found that the opioid antagonist naloxone could block placebo
painkillers, suggesting that endogenous opioids are involved.
 Levine, J.D., Gordon, N.C., Fields, H.L. The mechanism of placebo analgesia, Lancet , 1978, 2, 654-657
Abstract
The effect of naloxone on dental postoperative pain was studied to examine the hypothesis that endorphins mediate placebo
analgesia. All patients had extraction of impacted mandibular third molars with diazepam, N2O, and local block with
mepivacaine. 3 h and 4 h after surgery naloxone or a placebo was given under randomised, double-blind conditions. Pain was
evaluated on a visual analogue scale. Patients given naloxone reported significantly greater pain than those given placebo.
Patients given placebo as their first drug were either placebo responders, whose pain was reduced or unchanged, or
nonresponders whose pain increased. Naloxone given as a second drug produced no additional increase in pain levels in
nonresponders but did increase pain levels of placebo responders. Nonresponders had a final mean pain rating identical to
that of responders who received naloxone as their second drug. Thus the enhancement of reported pain produced by
naloxone can be entirely accounted for by its effect on placebo responders. These data are consistent with the hypothesis that
endorphin release mediates placebo analgesia for dental postoperative pain.

Body produces
Endorphines (opioids)
to reduce pain No pain
GREAT PAIN

Morphine

The placebo group: Non-responders

Dental surgery Post-surgery Placebo Responders
27 male Responds in two
24 female pain different ways

Naloxone LESS PAIN

After 3 h An Opioid
Antagonist
Naloxone

GREAT PAIN

GREAT PAIN
Thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it
was withdrawn due to teratogenicity and neuropathy. The drug is a potent
teratogen in rabbits and primates including humans: severe birth defects may
result if the drug is taken during pregnancy.

Thalidomide, launched by Grünenthal on 1st October 1957, was found to act as

an effective tranquilizer and painkiller and was proclaimed a "wonder drug" for
insomnia, coughs, colds and headaches. It was also found to be an effective
antiemetic which had an inhibitory effect on morning sickness, and so
thousands of pregnant women took the drug to relieve their symptoms.

At the time of the drug's development it was not thought likely that any drug
could pass from the mother across the placental barrier and harm the developing
fetus.

In the late 1950s and early 1960s, more than 10,000 children in 46 countries
were born with deformities such as phocomelia, as a consequence of
thalidomide use.
Thalidomide is racemic – it contains both left- and right-
handed isomers in equal amounts. The (R) enantiomer is
effective against morning sickness but the (S) is
teratogenic and causes birth defects. The enantiomers
can interconvert in vivo – that is, if a human is given pure
(R)-thalidomide or (S)-thalidomide, both isomers will later
be found in the serum – therefore, administering only
one enantiomer will not prevent the teratogenic
effect.
The mechanism of thalidomide's teratogenic action has led to over 2000
research papers and the proposal of fifteen or sixteen plausible mechanisms.
A theoretical synthesis in 2000 suggested the following mechanism:
Thalidomide intercalates (inserts itself) into DNA in G-C (guanine-
cytosine) rich regions. Owing to its glutarimide part, (S) thalidomide fits
neatly into the major groove of DNA at purine sites. Such intercalation
impacts upon the promoter regions of the genes controlling the
development of limbs, ears, and eyes such as IGF-I and FGF-2. Therefore,
by inhibiting the chain of events, thalidomide causes the truncation of limb
development.

Guanine-Cytosine
"Squiggly lines = position of attachment to the nucleic acid chains of DNA or RNA.
The dimers have exactly the same long dimension, enabling them to fit equally well into the three dimensional
structures derived from them.
This steric "fit" is crucial to maintaining the helical structure of DNA
Woody Allen as an inmate taking an experimental drug that turned him into a rabbi…
(from “Take the money and run”)
1. Από την ημερομηνία κατάθεσης του NDA μέχρι την έγκριση του
διπλώματος ευρεσιτεχνίας παρέρχονται μέχρι και 54 έτη.
2. Τα δικαιώματα της πατέντας διαρκούν maximum 5 έτη
3. Μετά την πάροδο αυτού του χρονικού διαστήματος το περιεχόμενο της
πατέντας δεν είναι πλέον προστατευόμενο και οποιαδήποτε εταιρεία
μπορεί να παράγει και να κυκλοφορήσει εμπορικά το φάρμακο ως
αντίγραφο (γενόσημο, generic drug) χωρίς να υποχρεούται να
πληρώσει αντίτιμο άδειας κυκλοφορίας στον αρχικό κάτοχο της πατέντας.
4. Το εμπορικό σήμα και το όνομα του φαρμάκου προστατεύονται επ’
αόριστον.
 • Ένα «ορφανό φάρμακο» είναι ένας φαρμακευτικός παράγοντας που έχει
αναπτυχθεί ειδικά για τη θεραπεία μιας σπάνιας ιατρικής κατάστασης, και η
κατάσταση αυτή από μόνη της πρέπει να αναφέρεται ως «ορφανή ασθένεια».
•Στις ΗΠΑ και την ΕΕ, είναι πιο εύκολο να κερδίσει κανείς την έγκριση κυκλοφορίας
για ένα ορφανό φάρμακο, και μπορεί να υπάρχουν και άλλα οικονομικά κίνητρα, όπως
παρατεταμένες περίοδοι αποκλειστικότητας, και όλα αυτά αποσκοπούν στο να
ενθαρρύνουν την ανάπτυξη φαρμάκων που διαφορετικά ίσως να μην έχουν το κέρδος
ως ένα επαρκές κίνητρο.
•Η ανακήρυξη μίας ιατρικής κατάστασης ως «ορφανής ασθένειας» και των φαρμάκων
που αναπτύχθηκαν για να την αντιμετωπίσουν ως «ορφανών» είναι ένα θέμα δημόσιας
πολιτικής σε πολλές χώρες, και έχει οδηγήσει σε ιατρικές ανακαλύψεις που μπορεί να
μην είχαν επιτευχθεί αλλιώς, λόγω των οικονομικών όρων που καθορίζουν και
επικρατούν στην έρευνα και ανάπτυξη των φαρμάκων.
 Περιγραφή ενός ορφανού φαρμάκου: Φάρμακα και Βιολογικά Προϊόντα

Ο νόμος για τα ορφανά φάρμακα (Orphan Drug Act (ODA) στις ΗΠΑ, προβλέπει
τη χορήγηση ειδικού καθεστώτος για ένα φάρμακο ή βιολογικό προϊόν
(«φάρμακο») για τη θεραπεία μιας σπάνιας ασθένειας ή πάθησης, κατόπιν
αιτήματος του αναδόχου.
Αυτή η κατάσταση αναφέρεται ως χαρακτηρισμός ορφανού (ή μερικές φορές «το
καθεστώς του ορφανού»).
Για να πληροί ένα φάρμακο τις προϋποθέσεις για το χαρακτηρισμό του ορφανού
τόσο το φάρμακο όσο και η ασθένεια ή η κατάσταση πρέπει να πληρούν ορισμένα
κριτήρια που καθορίζονται από το ODA και από την εφαρμογή των κανονισμών
του FDA κατά το 21 CFR Part 316.
Το καθεστώς του ορφανού δίνει το δικαίωμα στον χορηγό του φαρμάκου για την
παροχή διαφόρων κινήτρων ανάπτυξης από την ODA, συμπεριλαμβανομένης της
πιστώσεως φόρου για τις ειδικευμένες κλινικές δοκιμές. Η αίτηση κυκλοφορίας για
ένα προϊόν συνταγογραφούμενου φαρμάκου που έχει λάβει το καθεστώς του
ορφανού δεν υπόκειται στο τέλος χρήσης φαρμάκων, εκτός εάν η αίτηση
συμπεριλαμβάνει ένδειξη, ότι θα χρησιμοποιηθεί και εκτός των ορίων της σπάνιας
ασθένειας ή πάθησης για την οποία το φάρμακο χαρακτηρίστηκε ως ορφανό.
 http://www.scopus.com/

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What is the most promising treatment for Parkinsons disease: Genes, cells,
growth factors or none of the above?
Authors of Document Cummins, G., Barker, R.A.
Year the Document was Publish 2012
Source of the Document Regenerative Medicine