AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company Announce Updates to Prescribing Information for TRADJENTA® (linagliptin) Tablets and JENTADUETO® (linagliptin and metformin hydrochloride) Tablets

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Jun 232013
 

File:Linagliptin.png

linagliptin

June 20, 2013 /PRNewswire/ — Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company (NYSE: LLY) announce the U.S. Food and Drug Administration (FDA) has approved updates to the full U.S. Prescribing Information (PI) for TRADJENTA® (linagliptin) tablets and JENTADUETO® (linagliptin and metformin hydrochloride) tablets. These updates are part of ongoing efforts to update product labels to ensure physicians, pharmacists and patients have the information they need to use our medications appropriately. Information about pancreatitis was included in the adverse reactions sections of the original labels for these products; it is now displayed in additional sections of the PIs.1,2

read all at

http://www.pharmalive.com/tradjenta-jentadueto-get-label-updates-for-pancreatitis-risk

 

Linagliptin (BI-1356, trade names Tradjenta and Trajenta) is a DPP-4 inhibitordeveloped by Boehringer Ingelheim for treatment of type II diabetes.

Linagliptin (once-daily) was approved by the US FDA on 2 May 2011 for treatment of type II diabetes. It is being marketed by Boehringer Ingelheim and Lilly.

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Takeda Submits Vedolizumab BLA

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Jun 222013
 

Takeda Pharmaceuticals USA Inc. announced that a Biologics License Application (BLA) has been submitted to the United States (U.S.) Food and Drug Administration (FDA) for vedolizumab, an investigational humanized monoclonal antibody for the treatment of adults with moderately to severely active Crohn’s disease (CD) and ulcerative colitis (UC), the two most common types of inflammatory bowel disease (IBD).

http://www.dddmag.com/news/2013/06/takeda-submits-vedolizumab-bla

Vedolizumab is a monoclonal antibody being developed by Millennium Pharmaceuticals, Inc. for the treatment of ulcerative colitis and Crohn’s disease. It binds to integrin α4β7 (LPAM-1, lymphocyte Peyer’s patch adhesion molecule 1).

The cell line was discovered by Dr. Andrew Lazarovits and Dr. Robert Colvin as the murine MLN0002 homologue. Their discovery of the mouse equivalent of this antibody—originally applied to anti-rejection strategies in kidney transplantation—was published in the journal Nature, in 1996. The research was conducted at Massachusetts General Hospital in Boston, MA. Dr. Lazarovits and Dr. Colvin’s cell line was subsequently licensed to Millennium Pharmaceuticals of Boston for further development.

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Jun 212013
 

Why source drug substances from China?
Large markets, economies of scale and cheaper labor;An industrial ecosystem supplying raw materials and equipment;Developed infrastructure and industry friendly policies;About 5,000 manufacturers;

Thousands of chemists and students across China looking for novel synthesis routes for generic drug substances and intermediates.

read all at

http://www.pewhealth.org/uploadedFiles/PHG/Content_Level_Pages/Events/DSP_AfterHeparinAndre.pdf

 

 

 

 

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HOW ICH IS CHANGING DRUG DEVELOPMENT,REG STARTING MATERIALS AND BIG IDEAS

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Jun 212013
 

 

The desire for a dramatic increase in process understanding over
the past eight years has left industry leaders and Global Health
Agencies searching for a more relevant model for developing process and
drug substance understanding. Most recently, the Internationa l Conference on
Harmonization (ICH) has been drafting the ICH guideline q11 on the development and manufacture of drug substances, which takes a considerable step forward, offering sponsors greater flexibility in the definition and selection of Regulatory Starting Materials (RSM).

http://www.triphasepharmasolutions.com/Regulatory%20API%20Starting%20Materials%20Article.pdf

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EMA clears Roche’s polyarticular juvenile idiopathic arthritis drug

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Jun 212013
 
EMA clears Roche’s polyarticular juvenile idiopathic arthritis drug
The European Medicines Agency has cleared Roche’s RoACTEMRA for the treatment of a rare form of arthritis, polyarticular juvenile idiopathic arthritis (PJIA), in children aged two years and above…

read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/ema-clears-roches-polyarticular-juvenile-idiopathic-arthritis-drug-120613

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Japanese MHLW clears Roche’s Avastin as glioblastoma therapy

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Jun 212013
 
Japanese MHLW clears Roche’s Avastin as glioblastoma therapy
The Japanese Ministry of Health, Labour and Welfare (MHLW) has cleared Roche’s Avastin (bevacizumab) as a combination therapy and monotherapy to treat the aggressive form of brain cancer glioblastoma…

read all at

http://regulatoryaffairs.pharmaceutical-business-review.com/news/japanese-mhlw-clears-roches-avastin-as-glioblastoma-therapy-170613

 

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Jun 202013
 

Amgen In Focus
Seeking Alpha
According to Amgen, they have 45 drugs in development from Phase 1 to Phase 3. Conversely, Gilead has 32 drugs in development and Pfizer has 64. Meanwhile, Gilead only has 8 drugs in Phase 3, Pfizer has 25, and Amgen has 14. 7 of those Phase 3 

http://seekingalpha.com/article/1510002-amgen-in-focus?source=google_news

Amgen has the second deepest pipeline of drugs of the three large cap biotechs. According to Amgen, they have 45 drugs in development from Phase 1 to Phase 3. Conversely, Gilead has 32 drugs in development and Pfizer has 64. Meanwhile, Gilead only has 8 drugs in Phase 3, Pfizer has 25, and Amgen has 14. 7 of those Phase 3 drugs are focused on cancer treatments for Amgen, more than either Pfizer or Gilead. Keep in mind that 12.4 million people learn they have cancer each year, while 7.6 million people lose that battle each year. The CDC predicts that the global number of cancer related deaths will increase by 80% by 2030. It doesn’t take a rocket scientist to know that cancer treating drugs presents the largest opportunity for any drug maker considering those statistics. Amgen has the inside track versus Gilead and Pfizer as far as quantity of drugs in late stage development.

 

Pipeline

This information is current as of February 11, 2013. Amgen’s product pipeline will change over time as molecules move through the drug development process, including progressing to market or failing in clinical trials, due to the nature of the development process. This description contains forward-looking statements that involve significant risks and uncertainties, including those discussed in Amgen’s most recent Form 10-K and in Amgen’s periodic reports on Form 10-Q and Form 8-K, and actual results may vary materially. Amgen is providing this information as of the date above and does not undertake any obligation to update any forward-looking statements contained in this table as a result of new information, future events or otherwise.


Phase 1
Cancer Immunotherapy
Various cancer types
AMG 110 is an anti-EpCAM (epithelial cell adhesion molecule) x anti-CD3 (BiTE®) bispecific antibody. It is being investigated as a cancer treatment.
Antibody
Inflammatory diseases
AMG 139 is a human monoclonal antibody. It is being investigated as a treatment for Crohn’s disease. AMG 139 is being jointly developed in collaboration with AstraZeneca.
Antibody
Asthma
AMG 157 is a human monoclonal antibody that inhibits the action of thymic stromal lymphopoietin (TSLP). It is being investigated as a treatment for asthma. AMG 157 is being jointly developed in collaboration with AstraZeneca.
Antibody
Bone-related conditions
AMG 167 is a humanized monoclonal antibody that inhibits the action of sclerostin. AMG 167 is being developed in collaboration with UCB for bone-related conditions.
Other
Modality
Various cancer types
AMG 172 is a human anti-CD27L antibody drug conjugate. It is being investigated as a cancer treatment.
Oral/Small Molecule
Various cancer types
AMG 208 is a small molecule inhibitor of MET. It is being investigated as a cancer treatment.
Oral/Small Molecule
Various cancer types
AMG 232 is a small molecule. It is being investigated as a cancer treatment.
Oral/Small Molecule
Hematologic malignancies
AMG 319 is a small molecule inhibitor of PI3 Kinase delta. It is being investigated as a cancer treatment.
Antibody
Migraine
AMG 334 is a human monoclonal antibody that inhibits the receptor for Calcitonin Gene-Related Peptide (CGRP). It is being investigated for the prevention of migraine.
Oral/Small Molecule
Various cancer types
AMG 337 is a small molecule inhibitor of MET. It is being investigated as a cancer treatment.
Oral/Small Molecule
Autoimmune diseases
AMG 357 is a small molecule. It is being investigated as a treatment for autoimmune diseases.
Antibody
Systemic lupus erythematosus
AMG 557 is a human monoclonal antibody that inhibits the action of B7 related protein (B7RP-1). It is being investigated as a treatment for systemic lupus erythematosus. AMG 557 is being jointly developed in collaboration with AstraZeneca.
Other
Modality
Glioblastoma
AMG 595 is a human anti-EGFRvIII (epidermal growth factor receptor) antibody drug conjugate. It is being investigated as a treatment for glioblastoma.
Antibody
Autoimmune diseases
AMG 729 is a humanized monoclonal antibody that targets CD19 and CD32b to inhibit B cell. It is being investigated as a treatment for systemic lupus erythematosus and rheumatoid arthritis.
Antibody
Various cancer types
AMG 780 is a human anti-angiopoietin antibody that inhibits the interaction between the endothelial cell-selective Tie2 receptor and its ligands Ang1 and Ang2. It is being investigated as a cancer treatment.
Antibody
Systemic lupus erythematosus
AMG 811 is a human monoclonal antibody that inhibits interferon gamma. It is being investigated as a treatment for systemic lupus erythematosus.
Antibody
Various cancer types
AMG 820 is a human monoclonal antibody that inhibits c-fms and decreases tumor associated macrophage (TAM) function. It is being investigated as a cancer treatment.
Protein/Peptibody
Type 2 diabetes
AMG 876 is a fusion protein. It is being investigated as a treatment for type 2 diabetes.
Oral/Small Molecule
Various cancer types
AMG 900 is a small molecule inhibitor of Aurora kinases A, B, and C. It is being investigated as a cancer treatment.

Phase 2
Oral/Small Molecule
Type 2 diabetes
AMG 151 is a small molecule glucokinase activator. It is being investigated as a treatment for type 2 diabetes.
Antibody
Inflammatory bowel disease
AMG 181 is a human monoclonal antibody that inhibits the action of alpha4/beta7. It is being investigated as a treatment for ulcerative colitis and Crohn’s disease. AMG 181 is being jointly developed in collaboration with AstraZeneca.
Other
Modality
Secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis
AMG 416 is a peptide agonist of the human cell surface calcium-sensing receptor (CaSR). It is being investigated as a treatment for secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis.
Oral/Small Molecule
Schizophrenia
AMG 747 is a small molecule inhibitor of glycine transporter type-1 (GlyT-1). It is being investigated as a treatment for negative symptoms and cognitive deficits associated with schizophrenia.
Cancer Immunotherapy
Acute lymphoblastic leukemia
Blinatumumab is an anti-CD19 x anti-CD3 (BiTE®) bispecific antibody. It is being investigated as a cancer treatment.
Cancer Immunotherapy
Non-Hodgkin’s Lymphoma
Blinatumumab is an anti-CD19 x anti-CD3 (BiTE®) bispecific antibody. It is being investigated as a cancer treatment.
Antibody
Inflammatory diseases
Brodalumab is a human monoclonal antibody that inhibits the interleukin-17 receptor. It is being investigated as a treatment for a variety of inflammatory diseases. Brodalumab is being jointly developed in collaboration with AstraZeneca.
Oral/Small Molecule
Heart failure
Omecamtiv mecarbil is a small molecule activator of cardiac myosin. It is being investigated for the treatment of heart failure. We are developing this product in collaboration with Cytokinetics, Inc.
Antibody
Rheumatoid arthritis
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Protein/Peptibody
Various cancer types
Trebananib is a peptibody that inhibits the interaction between the endothelial cell-selective Tie2 receptor and its ligands Ang1 and Ang2. It is being investigated as a cancer treatment.
Antibody
Squamous cell head and neck cancer
Vectibix® is a human monoclonal antibody antagonist of the epidermal growth factor receptor (EGFr) pathway. It is being investigated as a cancer treatment.
Antibody
Giant cell tumor of the bone
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Antibody
Hypercalcemia of malignancy
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.

Phase 3
Antibody
Hyperlipidemia
AMG 145 is a human monoclonal antibody that inhibits Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). It is being investigated as a treatment for hyperlipidemia.
Protein/Peptibody
Myelodysplastic syndromes
Aranesp® is a recombinant human protein agonist of the erythropoietin receptor.
Brodalumab is a human monoclonal antibody that inhibits the interleukin-17 receptor. It is being investigated as a treatment for a variety of inflammatory diseases. Brodalumab is being jointly developed in collaboration with AstraZeneca.
Antibody
Glucocorticoid-induced osteoporosis
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Antibody
Male osteoporosis (EU)
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Antibody
Gastric cancer
Rilotumumab is a human monoclonal antibody that inhibits the action of hepatocyte growth factor/scatter factor. It is being investigated as a cancer treatment.
Antibody
Postmenopausal osteoporosis
Romosozumab is a humanized monoclonal antibody that inhibits the action of sclerostin. It is being developed in collaboration with UCB for the treatment of postmenopausal osteoporosis.
Sensipar®/Mimpara® is an orally-administered small molecule that lowers parathyroid hormone (PTH) levels in blood by increasing sensitivity of the calcium-sensing receptor (CaSR) to extracellular calcium. It is being evaluated in post renal transplant patients.
Talimogene laherparepvec is an oncolytic immunotherapy derived from HSV-1. It is being investigated as a cancer treatment.
Protein/Peptibody
Ovarian cancer
Trebananib is a peptibody that inhibits the interaction between the endothelial cell-selective Tie2 receptor and its ligands Ang1 and Ang2. It is being investigated as a cancer treatment.
Antibody
First- and second-line colorectal cancer (U.S.)
Vectibix® is a human monoclonal antibody antagonist of the epidermal growth factor receptor (EGFr) pathway. It is being investigated as a cancer treatment.
Antibody
Cancer-related bone damage (skeletal-related events) in patients with multiple myeloma
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Antibody
Delay or prevention of bone metastases in breast cancer
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.
Antibody
Delay or prevention of bone metastases in prostate cancer (EU)
Denosumab is a human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. It is being investigated across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis and numerous tumor types across the spectrum of cancer-related bone diseases, including hypercalcemia of malignancy.

Phase 1 clinical trials investigate safety and proper dose ranges of a product candidate in a small number of human subjects.Phase 2 clinical trials investigate side effect profiles and efficacy of a product candidate in a large number of patients who have the disease or condition under study.Phase 3 clinical trials investigate the safety and efficacy of a product candidate in a large number of patients who have the disease or condition under study.

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MEDICINE IN ANCIENT GREECE

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Jun 192013
 

 

Homer

 

 

Medicine In Homer 

The earliest source of Greek medical knowledge and descriptions of ancient Greek medical practices is Homer. The two epic poems attributed to Homer, the Iliad and the Odyssey, date to around the eighth century BCE. Of these two works the Iliad contains the more information concerning the treatment of injuries.

The Iliad chronicles part of the tenth and final year of the Trojan War. Within the text of this poem, Homer mentions nearly 150 different wounds. Most of these wounds are described with surprising anatomical accuracy. For instance, in the Iliad, Harpalion, a prince allied with the Trojans, is struck from behind by an enemy arrow. Homer explains that this was a fatal wound, for although the arrow entered near the right buttock, it sliced through the body, missed the pelvic and pubic bones, and hit the bladder (Il. XIII. 640-653). Wound after wound is described in a similar fashion in the Iliad. Spears and arrows strike specific internal organs according to their point of entry and trajectory. Homer also seems to have had an appreciation of which kinds of wounds were lethal. In the Iliad, wounds to the arms and legs are painful but not deadly (the story of Achilles’ and his famous heel is not mentioned in the poem). On the other hand, all of the 31 different head wounds were lethal.

Beyond the description of wounds, to a lesser extent Homer also recorded the care given to an injured warrior. Generally speaking, medical care focused on the comfort of the wounded man and not on treating the wound itself. Among the warriors, however, there were a few who were considered to be specialists in the art of healing through means of herbal remedies and bandaging. One of these doctors was Machaon, the son of the legendary healer Asclepius who later became deified. When Machaon was wounded himself, however, he was treated by being given a cup of hot wine sprinkled with grated goat cheese and barley (Iliad XI. 638). From these meager beginnings, Greek medicine rapidly developed over the course of the next several centuries.

THE DOCTORS AND THE PRESOCRATIC PHILOSOPHERS 

In order to give their new ideas a firmer foundation, and to be persuasive to their patients, many of the writers of the Hippocratic treatises turned to the writings of the Presocratic philosophers, men who sought to explain the nature of the cosmos and the things in it in terms of natural entities and non-personal forces (today we would call these men natural scientists).  Other Hippocratic writers vehemently opposed this trend, holding to what they saw as an uncompromising empiricism, based solely on experience, not on theory.  Their debate underlies many of the Hippocratic treatises, influencing not only content but also the form of argumentation, which makes it important to consider this philosophical background briefly.

In the following discussion, the fragments of the Presocratics are translated from the Greek text found in the standard source, H.Diels and W.Kranz, Die Fragmente der Vorsokratiker, 6th edition, 1954, and identified with their Diels-Kranz number, abbreviated as DK).  A useful source book for further background is G.S.Kirk, J.E.Raven and M. Schofield, The Presocratic Philosophers, 1983.

THALES OF MILETUS 

THALES OF MILETUS 

According to tradition, Thales, a native of the Ionian east Greek city of Miletus (in modern Turkey), was the first of the Presocratic philosophers.  Miletus was a large and cosmopolitan city, with long-standing trading connections with the states of the ancient Near East. He himself was probably of mixed ancestry (his family is said to have been originally Phoenician, and, like many Ionians, he probably also had an admixture of local Carians in his family tree).  He is reported to have assisted the Lydian king Croesus in his war against the Persians, and predicted an eclipse that put an end to a great battle in 585. Thus he was probably active not much before the beginning of the seventh century.

None of Thales’ own writings have survived, but later writers say that he held that the earth floats on water, which is in some way the source of all other things.  This may reflect Egyptian and other Near Eastern influences (Kirk, Raven and Schofield,  92).  Since our reports of his work come from a later period, it is possible that the idea of water as a source of all things was anachronistic, reflecting directions taken by later philosophers. Nonetheless, it seems reasonable to suppose that Thales’ was, as tradition holds, the first of these innovative thinkers who sought a new way of explaining the cosmos in natural terms.

ANAXIMANDER OF MILETUS 

Anaxamander of Miletus was said to have been the pupil of Thales.  If Thales in fact predicted the eclipse of 585, his pupil must have lived in the mid-sixth century (the presumption of a pupil-teacher series of philosophers was the basis of the ancient dating of their lives, which thus remains very uncertain).  He is the first of the Presocratics whose own words we have:

1. “The beginning of all things was the Apeiron [the unlimited, unbounded, undefined] … from which coming-to-be was for all things, and their destruction was of necessity into the same. For they suffer punishment and make reparation to each other for injustice according to the order of time.” (B1 DK)

2. “For this (the nature of the Apeiron) is everlasting and undying.” (B2 DK).

3.  A sort of evolutionary process was involved: “living creatures came to be from moisture evaporated by the sun. Man was like another creature, a fish, in the beginning.” (Frag. 11.6 DK)

Existing things were formed by a separation off from an undefined, undifferentiated being (the Apeiron), and over the course of time were balanced out so that no one form of being came to dominate the others, but all were bound to take their turns by a sort of natural justice.  Anaximander’s conception of a cosmic balance operating over time expressed an idea that was fundamental in the development of Greek medicine:  human beings are a part of the natural world, and the natural world tends toward a balance.

ANAXIMENES OF MILETUS 

The third of the Milesian monists (proponents of one elementary substance) was Anaximenes, who is traditionally considered to have been a pupil of Anaximander.  He identified the unlimited substance (the Apeiron of Anaximander) as Aer/Air.  He provided an analogical argument:

1. “Just as our soul, being air, holds us together, so also breath (pneuma) and air encompass the whole cosmos.” (B2 DK).

Anaximenes’ views were described by the second-century Roman church commentator Hippolytus:

2. “Anaximenes said that limitless (apeiron ) Aer (air) was the Arche (first principle), from which arise the things that are, and those that were, and those that will be, and gods and goddesses, and the rest arises from these.  The form of Aer is the following: whenever it is most uniform it is invisible to the sight, but it is revealed by cold, heat, moisture, and movement.  It is always moving, for nothing that changes changes if it is not moved. Through becoming denser or rarer, it becomes different. For whenever it is changed into the rarer, it becomes fire; when condensed, it becomes winds; when condensed further (felted), it becomes clouds; becoming yet more condensed, it changes into water; and still more, earth; and, when thickest of all, stone.  So that the most effective elements of generation are opposites, cold and hot.” (B7 DK)

In the fifth century, the theory of Aer seems to have become rather popular.  Another philosopher, Diogenes of Apollonia, adopted it as his first principle (see below), and it is attributed to the character representing the philosopher Socrates in Aristophanes’ comedy, the Clouds. The author of the Hippocratic treatise, On Breaths, also adopted the Aer theory.

HERACLITUS OF EPHESUS 

Another Ionian philosopher whose ideas influenced the Hippocratic writers was Heraclitus, a native of the city of Ephesus, not far from Miletus.  He is sometimes classified as a monist whose first principle was fire, but it is not clear whether he meant this to be taken literally or metaphorically.  His style was intentionally enigmatic and obscure, intriguing his audience by  paradoxes and leading them into fresh ways of thinking. Heraclitus’ obscure style found some imitators among the Hippocratic authors.

1. “Nature loves to hide.” (B123 DK) “The lord to whom belongs the oracle at Delphi neither speaks out nor hides his meaning, but gives a sign.” (B93 DK)

2.  “The way up and the way down are one and the same.” (B60 DK)

3.  “Sea water is the purest and foulest. For fish it is drinkable and life-preserving, for men it is undrinable and deadly.” (B61 DK)

4.  “It is not possible to step into the same river twice.” (B91 DK)

5.  “And good and evil are the same. For doctors, cutting and burning and torturing sick men in every way, still complain that they do not receive as much pay as they deserve from the sick, producing the same things, goods and sicknesses.” (B58 DK).
Some fragments suggest that Heraclitus saw Fire is the first principle of all things, in much the same way that Anaximenes saw Aer::

6. “This cosmos is the same for all, neither any of the gods nor of men made it, but it ever was and is and shall be everliving Fire, kindled by measures and extinguished by measures.” (B30 DK)

7. “The forms of Fire are, first sea; half of sea is earth, and half is thunderbolt.” (B31 DK)

8.  “All things are exchanged for Fire and Fire for all things, as goods for gold and gold for goods.” (B90 DK)

9.  “Fire lives the death of Air, and Air the death of Fire: Water lives the death of earth, and Earth of Water.” (B76 DK)

10. “A man when he is drunk is led by an ungrown boy, stumbling, not knowing where he is going, having a wet soul.” (B117 DK)

11. “A dry soul is the wisest and best.” (B118 DK)

Yet fire also encompasses the nature of strife and opposition, and may be a metaphor to convey the inexpressible nature of the changing world:

12.  “All things come into being by conflict of opposites, and the sum of things flows like a stream . . . . Of the opposites that which tends to birth or creation is called war and strife, and that which tends to destruction by fire is called concord and peace.” (Diogenes Laertes, On the Lives of Philosophers, 4.9.9-12)

PARMENIDES OF ELEA AND THE PROBLEM OF CHANGE 

Parmenides of Elea, a Greek colony in Southern Italy, took Monism to its logical conclusion when he argued that only being could be:

1. “For this is impossible to maintain, that not-being is” (Fr.7 DK)

2. “It [being] never ever was nor will it be, since it is now, all together, one, continuous. For what birth will you find for it? In what way, and from what, did it grow?” (Fr.8 DK)

3. “Nor is it divided, since it is all alike; nor is any part of it greater,  which would make it constrained, nor any part stronger, but it all is filled full of being, the whole of it is continuous: for being draws near to being.” (B8 DK)

Since only being exists, the world of change and difference that we perceive through the senses must be an illusion, or so Parmenides held.  Others followed his lead, either accepting his arguments (Zeno, with his paradoxes; Melissus), or finding some way to accommodate them while still maintaining the reality of the perceived world of change.  The solutions offered all posited a plurality of Parmenidean beings, each one unchanging and everlasting, by whose interchange and intermixture the perceptible world could arise.

EMPEDOCLES 

Empedocles of Akragas in Sicily was especially important in the development of medical thinking, in fart, perhaps, because he himself practiced medicine (but not exactly of the Hippocratic type). He described the cosmic processes as the operation of four eternal and unchangeable elements or Roots: earth, air, water,  and fire:

1.  “For hear first the four roots of all things: bright Zeus, and lifegiving Hera, and Hades, and Nestis, who moistens with her tears the springs of mortals (fire, air, earth and water).” (B6 DK)

The four elements were brought together and separated in great cycles of change by the cosmic forces of Love and Strife, thus alternatively creating and destroying the world that we perceive:

2. “But I tell you another thing: there is no birth of all mortal beings, nor any end in baneful death, but only mixture and separation of what is mixed, but mortals call this birth.” (B8 DK)

We see the influence of Parmenidean reasoning in one of his arguments:

3. “All these things are equal and of the same age, and each gives heed to the privilege of the other, and each has its own character, and they rule in turn as time revolves.  And in addition to them, nothing comes into being or passes away. For if they perished utterly, they would no longer be. Why would this whole cease to be? and from whence would it come? Into what would it be destroyed, since nothing is empty of these things?  But these things are all there is, and through exchanging places they become at once different and (yet) continuously alike.” (B 17 DK, 27-35)

Like Anaximander, Empedocles reasoned that the beings of this world evolved.  He posited a sort of “preservation of the fittest,” since things that were brought into contact in the eternal coming-together and separating-off sometimes didn’t “work”:

4. “But many came into being with double faces and double chests, human-headed ox-creatures, and others again ox-headed with human bodies, and creatures with male and female natures mingled, fashioned with unclear parts.” (B 61 DK)

Empedocles composed his works in epic meter, which has survived only in fragments.  Most of what has survived belonged to two poems, On Nature and Purifications, but there are some fragments of a lost work on medicine, in which we see empirical interests similar to those of the Hippocratics:

5. “[The heart] is turned in a sea of surging blood, in which that which is called thought by men exists, for the blood about the heart is thought for men.” (B105 DK)

6. “Thus all things breath in and out; in all things bloodless pipes of flesh are stretched to the uttermost body, and upon their openings at the periphery of skin they are pierced through with close-packed slits so that the blood is kept concealed and easy-flowing passages are cut for air. Thence whenever smooth blood rushes down, air bubbles in in a raging swell, and whenever blood rebounds, air breaths back out again, just as when a child plays with a klepsydra of shining metal….” (B100 DK)

7. “Empedocles holds that seed coming into a warm womb becomes male, that into a cold female, and that the cause of heat and cold is the flow of the menses, being hotter or colder, older or more recent.” (A81 DK)

Overview of Hippocratic Epidemics 

The treatise Epidemics consists of seven books which record the observations made by their doctor-authors during the course of their travels as itinerant physicians in northern Greece — Thessaly, Thrace, and the island of Thasos — at the end of the fifth and in the first half of the fourth centuries. The meaning of the title, “Epidemics,” is ambiguous; it could mean either “of the people (demos),” or “sojourning in a place (deme)”; thus its subject could be either the illnesses occurring in a given place and time, or the doctor’s visits in an area. The non-Athenian context, in addition to the fact that these cases are, at least in origin, non-literary texts, makes them especially valuable as sources for social history, since much of our other evidence is thoroughly Athenocentric and literary.

In addition to the case histories, each book of the Epidemics contains two other types of material: constitutions and generalizations (aphorisms, prognostic indications, lists of things to consider, various notes). The constitutions are summary accounts of the climatic conditions and the illnesses encountered by the doctor in a particular locality over a specific period of time, usually a year. These were probably derived by generalization from the doctor’s notes in case histories, but only in a few instances can a patient named in a constitution be identified with one in a case history. (One such patient is Philiscus, who is mentioned by name in the third constitution of Book I and discussed in detail in the first case history.) The constitutions are sometimes carefully crafted literary pieces, which suggests that they were intended for publication, either to students or to the general public. This impression is reinforced by their similarity to Thucydides’ description of the plague in his history of the Peloponnesian War, (Thuc. 2.47-54; Thucydides spent a long exile in the north where he would have had ample opportunity to come into contact with Hippocratic doctors,) and by the presence in the Hippocratic collection of other treatises in which the doctor-author directs his efforts at a lay audience.

The first childbirth case referred to in the Epidemics occurs in one of the constitutions of Book I in a passage that gives a good general idea of the style of the constitutions: (Hipp Epid. I 8, tr. Jones.)

“Though many women fell ill, they were fewer than the men and less frequently died. But the great majority had difficult childbirth, and after giving birth they would fall ill, and these especially died, as did the daughter of Telebulus on the sixth day after delivery. Now menstruation appeared during the fevers in most cases, and with many maidens it occurred then for the first time. Some bled from the nose. Sometimes both epistaxis (nosebleed) and menstruation appeared together; for example, the maiden daughter of Daitharses had her first menstruation during fever and also a violent discharge from the nose. I know of no woman who died if any of these symptoms showed themselves properly, but all to my knowledge had abortions if they chanced to fall ill when with child.

Each book of the Epidemics has its own idiosyncratic character, and on the basis of these differences scholars have noted “family resemblances” between books that have allowed them to define and date three main groups of books: I and III, dated 410-400; II, IV, and VI, dated 400-375; and V and VI, dated 375/360-350.

Books I and III of the Epidemics stand out from the other books in their polished form. They contain four complete and finished constitutions (three in Book I, and one in Book III), whose conclusions contain the sole aphoristic material in these books. The case histories, of which Book I contains four- teen and Book III two sets of twelve and sixteen, are organized chronologically according to the days of the illness. They consist mostly of lists of symptoms; only rarely is allusion made to treatment, and then only when it elicits symptoms useful in prognosis. Books I and III have been the most admired books of the Epidemics from antiquity, and scholars agree that they form a single work that is the oldest part of the treatise, dating to ca. 410- 400. They appear as representative of the Epidemics in most modern selections from the Hippocratic treatises, yet, from the standpoint of narrative interest, as sources for social history, and as evidence for the development of medical thinking, the other books are an equally valuable resource.

Books II, IV, and VI were grouped together from antiquity and attributed to Thessalus, the son of Hippocrates, who was said by Galen (7.854) to have edited and published them from notes made by his father. Thus ancient scholars gave them the status of Hippocratic at one remove. Book II contains 24 brief cases that give the impression of being rough notes taken at the bedside; it also contains four fragmentary constitutions, none as thoroughly worked out as those of I-III. The main interest of the author seems to have been in medical theory and treatment, which he presents in the form of general statements that are not incorporated into either the constitutions or the cases. The book includes a miscellaneous chapter devoted to gynecological information as well as several other chapters dealing with gynecological conditions and the development of the fetus. It has the highest percentage of female patients (55%) of any of the books of the Epidemics.

Book VI shares many characteristics with Book II. It too contains only a few case histories, 19 in all, and, like Book II, it gives a good deal of attention to didactic theoretical expositions and to treatment. In contrast to Book II, however, only 32% of its patients are female, and there is only one pregnancy-related case. Book VI is probably best known for the constitution usually called “the Cough of Perinthus,” which is the product of an accomplished literary writer. The philosophical allusions that characterize this book suggest that its author was highly educated: some aphorisms bear a stylistic resemblance to the work of the philosopher Heraclitus, while a methodological statement (Epid.VI 3.12) is reminiscent of the method of Collection and Division propounded by Plato, who was probably a contemporary of the author (Plato. Sophist. 253bff.; Politicus 260eff.; Phaedrus 263bff.) A.Nikitas, who has done a detailed study of II-IV-VI, has suggested that the author of II and VI had a fundamentally didactic aim; these books might even have served as lecture notes for a medical course. Wesley Smith stresses the author’s active, invasive approach to treatment: if nature makes a mistake, the doctor must intervene.

In contrast to Books II and VI, the third member of this middle group, Book IV, has few aphoristic or theoretical passages but reports on a large number — over 90 — cases, with many chapters including multiple cases. The book contains two constitutions that make numerous references to individual patients; neither is a polished literary piece. When theory appears in IV, it is modest and often placed within the case histories, a procedure unique to this book. In general, the book lacks the attention to therapy and diet, and the didactic tone, which are characteristic of Books II and VI.

The differences between IV and II-VI suggest that two authors were responsible for these books. Nikitas, who characterizes the author of II-VI as a well-educated medical theorist, probably a professor, assigns IV to a slightly later author. He describes him as a practical, working physician who had long been active in the area and had many patients, some of whom he visited several times; in some families he seems to have functioned as a sort of “house physician.” Nikitas’ study of the names and relationships of the patients involved in these three books demonstrates that they all belonged to a single generation, which he placed in the first quarter of the fourth century.

Books V and VII have also been grouped together since antiquity and their close interconnection is marked by considerable overlapping of material. Even in antiquity these books were considered to be post-Hippocratic: Galen remarked that everyone agreed that VII was spurious. V.Langholf analyzed V into three parts: the first part, A, consists of 31 case histories and appears to be the record of a doctor traveling from the Peloponnesus through Athens to Thessaly and Thrace. The second part, B, consisting of chapters 32-50, is clearly different in content and style from A but similar to the third part, C, which consists of chapters 51-106. All of the chapters in part C, with the single exception of chapter 86, also appear in Book VII, but in a different order, sometimes with minor changes in language, and sometimes augmented. Langholf argued that the two versions of C derived independently from a common source, which he identified as the archives of the Hippocratic school on the island of Cos. Modern scholars agree that V-VII are later than II-IV-VI and date them between 375 and 350. In particular, the fact that three of the patients were identified as residents of the city of Olynthus requires a date before 348, when that city was totally destroyed.

Hippocrates

Books V and VII both contain relatively large numbers of cases. Each of the fifty chapters included in VA-B describes a case. The chapters of VC contain, in addition to cases, a few general comments on treatment, and two mini-constitutions. Book VII contains 82 cases not included in Book V. Both V and VII pay special attention to treatment; prognosis appears to have fallen into the background, and numbered days have lost some of their fascination. On the other hand, narrative interest is higher in these books than in the earlier ones, and the writer is attracted to unusual cases. For example, V 86 (the only case in VC without a parallel in VII) recounts the illness of a young man who overindulged in wine, fell asleep on his back in a tent, found a snake in his mouth, bit it, and, seized with pain and convulsions, died. This case (except for its unfortunate conclusion) bears a striking resemblance to the procedure of dormition cure used in the temples of Asclepius: patients slept overnight in the temple and during their dreams they were visited by the god who either prescribed for them or treated them; sometimes the companions of the god, a snake or dog, healed the patient by licking. Was the story of V 86 perhaps intended to suggest that those who resorted to the god Asclepius and his snake for a cure might find death instead? Perhaps, but if we consider it in the context of some of the other cases in V-VII, it seems rather to be a case of inversion, possibly reflecting further influence of the philosopher Heraclitus, which we first noted in Book VI, where it was limited to aphoristic style.

The other cases that exhibit the trait of inversion follow a pattern in which the same object has opposite effects, as illustrated by the Heraclitean dictum: The bow is both life (bios = life) and death (bios = bow) (Heraclitus, DK 22 B48.). For example, in V 9, the case of the man who found a cure for itching in the baths at Melos, and then died of hydropsy, the same element, water, was both life/cure and death; and in V 74/VII 36, the patient was a ship’s cargo director for whom an anchor, an instrument of life/livelihood, became an instrument of death.

Still another of these odd cases seems to involve a mocking or inversion of taboos: VII 78, the man who urinated into the sea as part of a cure. Among the numerous admonitions in Hesiod’s Works and Days are two that involve the pollution of water by urination: one forbids urinating into a stream that flows into the sea, and the other forbids urinating into a spring.

An interesting point is the number of cases in which baths are indicted as the cause of illness: VII 11, chill after bath; VII 24, relapse after bath; VII 50, fever after warming in vapor bath; and V 9, the fatal baths of Melos. (On the other hand, in VII 102, a patient was saved because she vomited up a poisonous mushroom in the bath.) The author of Sacred Disease, in his condemnation of the religious charlatans who interpret epilepsy as divine possession, says that a prohibition on baths is part of their treatment. It was also a Heraclitean dictum that it is death for the soul to become wet (Heraclitus, DK 22 B36, B77, B117, B118). On a more pedestrian level, however, these cases documenting the deleterious effects of baths may simply indicate experience with malarial relapses brought on by a chill suffered during bathing.

Finally, a possible incursion of magic appears in V 25, in which a woman, barren all her life, at the age of 60 suffered labor-like pains after eating raw leaks; she was cured when another woman extracted a stone from the mouth of her womb. While probably reflecting the results of dietary indiscretion, this odd story fits the pattern of shamanistic cure by the removal of a foreign object. (A student has suggested that perhaps the stone was being used as a IUD.) Whatever the explanation, the case typifies the womb-centered approach that is apparent in the later books of the Epidemics.

An especially interesting feature of the case histories in the later two groups of books is the frequency with which medical mistakes are acknowledged. This is most noteworthy in Book V, whose author reports over-strong or ill-timed purgatives, badly done cauterization, inadequate or late trepanning, and the application of irritating medicine to a wound. One of these unfortunate cases involved a pregnant woman who died as a result of an over- dose of a purgative (V 18). Most of these references to mistakes appear in VA, although one occurs in VB, and one in VC, and thus also in Book VII. F.Robert has argued that these critical comments, some of which appear to refer to the acts of others, reveal that their author worked as a member of a medical team. Robert also identified three passages in Book VII that do not appear in Book V in which the form of expression (but not explicit criticism of mistakes) suggests a group-practice. Similarly, the author of Book VI (2.15) criticizes the treatment of a patient who was given an emetic when a steam bath was called for, and Smith sees this as evidence that he was working in a community of doctors. Again, the author of II 1.7 criticizes the treatment given in IV 26 to the niece of Temenes, who had an insufficient apostasis to the thumb after suffering fever and a distended hypochondrium — the doctor remarks that did not know if she was also pregnant. The mistake was fatal.

CONCLUSION

We have seen that the books of the Epidemics form a series that covers the period between 410 and 350 and that they have at least three different authors, and probably more. The earlier books are more rigorously prognostic, with few indications of treatment and a strict concentration on the description of symptoms. In the later books the course of the illness is less often followed in detail and indications of treatment are more frequent. Interest in theory in the different books varies probably more in accordance with the interests of the individual authors than in accordance with any general shift in direction over time, but there does seem to be an increase in Heraclitean thinking and possibly even the appearance of shamanistic practices in the latest books. Given these differences, we can expect that these variations may reflect changes in the thinking of the society as a whole over this period of time, as well as changes in medical thinking and practice.

REFERENCES:

Langholf, V. – Die parallelen Texte in Epidemien V und VII, Corpus Hippocraticum. Actes du Colloque Hippocratique de Mons (22-26 septembre 1975), Mons, Universite de Mons, 264-74, 1977
Nikitas, A., – Untersuchungen zu den Epidemienbuchern II IV VI des Corpus Hippocraticum, dissertation, Hamburg, 1968.
Robert, F. – “Medecine d’équipe dans les Épidemies V,” Die  hippokratischen Epidemien. Theorie – Praxis – Tradition. Verhandlungen des V Colloque international Hippocratique., Stuttgart, 1989.
Smith, Wesley D. – “Generic form in Epidemics I to VII,” in Die Hippokratischen Epidemien: Theorie – Praxis – Tradition. Verhandlungen des V Colloque International Hippocratique, eds. G.Badder and R.Winau, Stuttgart, 1989: 144-58.

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London University discovers vital clue to how cancer spreads

 new drugs  Comments Off on London University discovers vital clue to how cancer spreads
Jun 182013
 
Cancer cell

Researchers at University College London have made a key discovery about how cancer spreads through the body, which could lead to drugs being developed to halt the process.

Scientists at the university carried out experiments on frog and zebrafish embryos and discovered a mechanism called ‘chase and run’ that showed how diseased and healthy cells follow each other around the body, reports The Telegraph.

http://www.pharmaceutical-technology.com/news/newslondon-university-discovers-vital-clue-to-how-cancer-spreads?WT.mc_id=DN_News

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Double strike against cancer

 cancer, drugs  Comments Off on Double strike against cancer
Jun 172013
 
Double strike against cancer
13.06.2013 – German researchers have found a way to circumvent chemotherapy resistance in cancer cells.

A new therapeutic approach can take advantage of cancer cells’ need to repair double-strand breaks in DNA, in order to overcome the tumour’s resistance to chemotherapy (Science Transl. Medicine). According to the research group headed by Hans Christian from University Cologne, mutations in the ATM gene protect cancer cells from cell death during chemotherapy. ATM  is instrumental in initiating DNA repair and inducing cell death when repair is not possible in curse of the so-called DNA damage response (DDR).  http://www.eurobiotechnews.eu/news/news/2013-02/double-strike-against-cancer.html

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