Econstudentlog

The Second World War (II)

Here’s my first post about Churchill’s book(s). In this post I’ll add some further observations and data; I’m roughly two-thirds through the book(s) at this point.

“a significant proportion of our whole war effort had to be devoted to combating the mine. A vast output of material and money was diverted from other tasks, and many thousands of men risked their lives night and day in the minesweepers alone. The peak figure was reached in June 1944, when nearly sixty thousand were thus employed.”

“On January 10, 1940, anxieties about the Western Front received confirmation. A German staff major of the 7th Air Division had been ordered to take some documents to headquarters in Cologne. He missed his train and decided to fly. His machine overshot the mark and made a forced landing in Belgium, where Belgian troops arrested him and impounded his papers, which he tried desperately to destroy. These contained the entire and actual scheme for the invasion of Belgium, Holland, and France on which Hitler had resolved. […] I was told about all this at the time […] It was argued in all three countries concerned that probably it was a plant. But this could not be true. There could be no sense in the Germans trying to make the Belgians believe that they were going to attack them in the near future. This might make them do the very last thing the Germans wanted, namely, make a plan with the French and British Armies […] I therefore believed in the impending attack. We appealed to Belgium, but the Belgian King and his Army staff merely waited, hoping that all would turn out well. […] no further action of any kind was taken by the Allies or the threatened States. […] Hitler, […] ordered, after venting his anger, new variants [of the invasion plans] to be prepared.”

“until July 1944 Britain and her Empire had a substantially larger number of divisions in contact with the enemy than the United States. This general figure includes not only the European and African spheres but also all the war in Asia against Japan. […] Out of 781 German and 85 Italian U-boats destroyed in the European theatre, the Atlantic and Indian Oceans, 594 were accounted for by British sea and air forces […] of shipping losses by enemy action suffered by all nations throughout the war […] 80 per cent. were suffered in the Atlantic Ocean, including British coastal waters and the North Sea. Only 5 per cent. were lost in the Pacific. […] Up till the end of 1943 the British discharge of bombs upon Germany had in the aggregate exceeded by eight tons to one those cast from American machines”

“My relations with the President [Roosevelt – US] gradually became so close that the chief business between our two countries was virtually conducted by […] personal interchanges between him and me. […] In all I sent him nine hundred and fifty messages, and received about eight hundred in reply.”

“Altogether there came to the rescue of the Army under the ceaseless air bombardment of the enemy about eight hundred and sixty vessels […] at 2.23 p.m. on June 4 the Admiralty, in agreement with the French, announced that Operation “Dynamo” was now completed. More than 338,000 British and Allied troops had been landed in England. […] On June 17 it was announced that the Pétain Government had asked for an armistice, ordering all French forces to cease fighting, without even communicating this information to our troops. General Brooke was consequently told to come away with all men he could embark and any equipment he could save. We repeated now on a considerable scale, though with larger vessels, the Dunkirk evacuation. Over twenty thousand Polish troops who refused to capitulate cut their way to the sea and were carried by our ships to Britain. […] In all there were evacuated from all French harbours 136,000 British troops and 310 guns; a total, with the Poles, of 156,000 men.”

“Hitler and Stalin had much in common as totalitarians, and their systems of government were akin. […] On June 14, the day Paris fell, Moscow sent an ultimatum to Lithuania accusing her and the other Baltic States of military conspiracy against the U.S.S.R. and demanding radical changes of government and military concessions. On June 15 Red Army troops invaded the country. Latvia and Estonia were exposed to the same treatment. […] A Russian ultimatum to Roumania was delivered to the Roumanian Minister in Moscow at 10 p.m. on June 26. The cession of Bessarabia and the norther part of the province of Bukovina was demanded […] On June 27 Roumanian troops were withdrawn from the two provinces concerned, and the territories passed into Russian hands. […] On August 3-6 the pretence of pro-Soviet friendly and democratic Governments [in the Baltic] was swept away, and the Kremlin annexed the Baltic States to the Soviet Union.”

“From September 7 to November 3 an average of two hundred German bombers attacked London every night. […] The night raids were accompanied by more or less continuous daylight attacks by small groups or even single enemy planes, and the sirens often sounded at brief intervals throughout the whole twenty-four hours. To this curious existence the seven million inhabitants of London accustomed themselves. […] We did not know how long it would last. We had no reason to suppose that it would not go on getting worse. […] In the twelve months from June 1940 to June 1941 our civilian casualties were 43,381 killed and 40,856 seriously injured, a total of 94,237.”

“The only thing that ever really frightened me during the war was the U-boat peril. […] we poised and pondered together on this problem. It did not take the form of flaring battles and glittering achievements. It manifested itself through statistics, diagrams, and curves unknown to the nation, incomprehensible to the public. […] At the outset the Admiralty naturally thought first of bringing the ships safely to port, and judged their success by a minimum of sinkings. But now this was no longer the test. We all realised that the life and war effort of the country depended equally upon the weight of imports safely landed. In the week ending June 8, during the height of the battle in France, we had brought into the country about a million and a quarter tons of cargo, exclusive of oil. From this peak figure imports had declined at the end of July to less than 750,000 tons a week. […] I became increasingly concerned about this ominous fall in imports. “I see,” I minuted to the First Lord in the middle of February, 1941, “that entrances of ships with cargo in January were less than half of what they were last January.” The very magnitude and refinement of our protective measures – convoy, diversion, degaussing [a method employed to counteract magnetic mines – US], mine-clearance, the avoidance of the Mediterranean – the lengthening of most voyages in time and distance and the delays at the ports through bombing and the black-out, all reduced the operative fertility of our shipping to an extent even more serious than the actual losses. […] To the U-boat scourge was soon added air attack far out on the ocean by long-range aircraft. […] Powerful German cruisers were active. […] formidable vessels compelled the employment on convoy duty of nearly every available British capital ship. At one period the Commander-in-Chief of the Home Fleet had only one battleship in hand.”

“In the three months ending with May [1941] U-boats alone sank 142 ships, of 818,000 tons, of which 99 were British. […] in the same three months of March, April, and May 179 ships, of 545,000 tons, were sunk by air attack, mainly in the coastal regions. […] In the Atlantic [1942] proved the toughest [year] of the whole war. […] By the end of January [1942] thirty-one ships, of nearly 200,000 tons, had been sunk off the coast off the United States and Canadian coast. […] In February they destroyed seventy-one ships, of 384,000 tons, in the Atlantic, of which all but two were sunk in the American zone. […] The American Army Air Force, which controlled almost all military shore-based aircraft, had no training in anti-submarine warfare, whereas the Navy, equipped with float-planes and amphibians, had no means to carry it out, and in these crucial months an effective American defence system was only achieved with painful, halting steps. […] It was not until the end of the year that a complete interlocking convoy system covering all [the] immense areas [involved] became fully effective. […] In seven months the Allied losses in the Atlantic from U-boats alone amounted to over three million tons, which included 181 British ships of 1,130,000 tons. Less than one-tenth occurred in convoys. All this cost the enemy up to July no more than fourteen U-boats sunk throughout the Atlantic and Arctic Oceans, and of these kills only six were in North American waters. […] during [August] U-boats sank 108 vessels […] Between January and October 1942 the number of U-boats had more than doubled. 196 were operational […] All our escorts had to be cut to the bone for the sake of our main operations in Africa, and in November our losses at sea were the heaviest of the whole war, including 117 ships, of over 700,000 tons, by U-boats alone, another 100,000 from other causes.”

April 19, 2016 Posted by | Books, History | Leave a comment

Einstein quotes

“Einstein emerges from this collection of quotes, drawn from many different sources, as a complete and fully rounded human being […] Knowledge of the darker side of Einstein’s life makes his achievement in science and in public affairs even more miraculous. This book shows him as he was – not a superhuman genius but a human genius, and all the greater for being human.”

I’ve recently read The Ultimate Quotable Einstein, from the foreword of which the above quote is taken, which contains roughly 1600 quotes by or about Albert Einstein; most of the quotes are by Einstein himself, but the book also includes more than 50 pages towards the end of the book containing quotes by others about him. I was probably not in the main target group, but I do like good quote collections and I figured there might be enough good quotes in the book for it to make sense for me to give it a try. On the other hand after having read the foreword by Freeman Dyson I knew there would probably be a lot of quotes in the book which I probably wouldn’t find too interesting; I’m not really sure why I should give a crap if/why a guy who died more than 60 years ago and whom I have never met and never will was having an affair during the early 1920s, or why I should care what Einstein thought about his mother or his ex-wife, but if that kind of stuff interests you the book has stuff about those kinds of things as well. My own interest in Einstein, such as it is, is mainly in ‘Einstein the scientist’ (and perhaps also in this particular context ‘Einstein the aphorist’), not ‘Einstein the father’ or ‘Einstein the husband’. I also don’t find the political views which he held to be very interesting, but again if you want to know what Einstein thought about things like Zionism, pacifism, and world government the book includes quotes about such topics as well.

Overall I should say that I was a little underwhelmed by the book and the quotes it includes, but I would also note that people who are interested in knowing more about Einstein will likely find a lot of valuable source material here, and that I did give the book 3 stars on goodreads. I did learn a lot of new things about Einstein by reading the book, but this is not surprising given how little I knew about him before I started reading the book; for example I had no idea that he was offered the presidency of Israel a few years before his death. I noticed only two quotes which were included more than once (a quote on pages 187-188 was repeated on page 453, and a quote on page 295 was repeated on page 455), and although I cannot guarantee that there aren’t any other repeats almost all quotes included in the book are unique, in the sense that they’re only included once in the coverage. However it should also be mentioned in this context that there are a few quotes on specific themes which are very similar to other quotes included elsewhere in the coverage. I do consider this unavoidable considering the number of quotes included, though.

I have included some sample quotes from the book below – I have tried to include quotes on a wide variety of topics. All quotes without a source below are sourced quotes by Einstein (the book also contains a small collection of quotes ‘attributed to Einstein’, many of which are either not sourced or sourced in such a manner that Calaprice did not feel convinced that the quote was actually by Einstein – none of the quotes from that part of the book’s coverage are included below).

“When a blind beetle crawls over the surface of a curved branch, it doesn’t notice that the track it has covered is indeed curved. I was lucky enough to notice what the beetle didn’t notice.” (“in answer to his son Eduard’s question about why he is so famous, 1922.”)

“The most valuable thing a teacher can impart to children is not knowledge and understanding per se but a longing for knowledge and understanding” (see on a related note also Susan Engel’s book – US)

“Teaching should be such that what is offered is perceived as a valuable gift and not as a hard duty.”

“I am not prepared to accept all his conclusions, but I consider his work an immensely valuable contribution to the science of human behavior.” (Einstein said this about Sigmund Freud during an interview. Yeah…)

“I consider him the best of the living writers.” (on Bertrand Russell. Russell incidentally also admired Einstein immensely – the last part of the book, including quotes by others about Einstein, includes this one by him: “Of all the public figures that I have known, Einstein was the one who commanded my most wholehearted admiration.”)

“I cannot understand the passive response of the whole civilized world to this modern barbarism. Doesn’t the world see that Hitler is aiming for war?” (1933. Related link.)

“Children don’t heed the life experience of their parents, and nations ignore history. Bad lessons always have to be learned anew.”

“Few people are capable of expressing with equanimity opinions that differ from the prejudices of their social environment. Most people are even incapable of forming such opinions.”

“Sometimes one pays most for things one gets for nothing.”

“Thanks to my fortunate idea of introducing the relativity principle into physics, you (and others) now enormously overrate my scientific abilities, to the point where this makes me quite uncomfortable.” (To Arnold Sommerfeld, 1908)

“No fairer destiny could be allotted to any physical theory than that it should of itself point out the way to the introduction of a more comprehensive theory, in which it lives on as a limiting case.”

“Mother nature, or more precisely an experiment, is a resolute and seldom friendly referee […]. She never says “yes” to a theory; but only “maybe” under the best of circumstances, and in most cases simply “no”.”

“The aim of science is, on the one hand, a comprehension, as complete as possible, of the connection between the sense experiences in their totality, and, on the other hand, the accomplishment of this aim by the use of a minimum of primary concepts and relations.” A related quote from the book: “Although it is true that it is the goal of science to discover rules which permit the association and foretelling of facts, this is not its only aim. It also seeks to reduce the connections discovered to the smallest possible number of mutually independent conceptual elements. It is in this striving after the rational unification of the manifold that it encounters its greatest successes.”

“According to general relativity, the concept of space detached from any physical content does not exist. The physical reality of space is represented by a field whose components are continuous functions of four independent variables – the coordinates of space and time.”

“One thing I have learned in a long life: that all our science, measured against reality, is primitive and childlike – and yet it is the most precious thing we have.”

“”Why should I? Everybody knows me there” (upon being told by his wife to dress properly when going to the office). “Why should I? No one knows me there” (upon being told to dress properly for his first big conference).”

“Marriage is but slavery made to appear civilized.”

“Nothing is more destructive of respect for the government and the law of the land than passing laws that cannot be enforced.”

“Einstein would be one of the greatest theoretical physicists of all time even if he had not written a single line on relativity.” (Max Born)

“Einstein’s [violin] playing is excellent, but he does not deserve his world fame; there are many others just as good.” (“A music critic on an early 1920s performance, unaware that Einstein’s fame derived from physics, not music. Quoted in Reiser, Albert Einstein, 202-203″)

April 12, 2016 Posted by | Books, History, Physics, Quotes/aphorisms, Science | Leave a comment

Quotes

i. “Only half of writing is saying what you mean. The other half is preventing people from reading what they expected you to mean.” (James Richardson)

ii. “How often feelings are circular. How embarrassing to be embarrassed. How annoying to be annoyed.” (-ll-)

iii. “I worked so hard to understand it that it must be true.” (-ll-)

iv. “Always tell the Truth: where it is not loved, it is respected and feared.” (Thomas Fuller)

v. “the wise Man that holds his Tongue, says more than the Fool who speaks.” (-ll-)

vi. “‘Tis better for thee to be wise and not seem so, than to seem wise and not be so: Yet Men, for the most Part, desire and endeavor the contrary.” (-ll-)

vii. “If any one giveth thee excessive Praises more than can handsomely belong to thee, thou art to think of him, that he taketh thee for vain and credulous, and easy to be deceived, and effectually a Fool.” (-ll-)

viii. “When thou shewest Respect to any one, see that thy Submissions be proportionable to the Homage thou owest him. There is Stupidity and Pride in doing too little; but in over acting of it, there is Abjection and Hypocrisy.” (-ll-)

ix. “The Way to think we have enough, is not to desire to have too much.” (-ll-)

x. “A Friend to all, is a Friend to none.” (-ll-)

xi. “One needs time to free oneself of wrong convictions. If it happens too suddenly, they go on festering.” (Elias Canetti)

xii. “Duty largely consists of pretending that the trivial is critical.” (John Fowles)

xiii. “You have not converted a man, because you have silenced him.” (John Morley)

xiv. “It is a test of true theories not only to account for but to predict phenomena.” (William Whewell)

xv. “Personally, I find the concept of a “final theory,” or a “theory of everything,” rather limiting. The fun of discovery will most likely last as long as the human race continues.” (F. J. Duarte)

xvi. “There is no meaning to space that is independent of the relationships among real things of the world. …Space is nothing apart from the things that exist. …If we take out all the words we are not left with an empty sentence, we are left with nothing.” (Lee Smolin)

xvii. “One should never forget, that society would rather be amused than instructed.” (Adolph Freiherr Knigge)

xviii. “Clearly, a civilization that feels guilty for everything it is and does will lack the energy and conviction to defend itself.” (Jean-François Revel; quoted by Jeane Kirkpatrick during a speech she gave in 1984).

xix. “Democratic civilization is the first in history to blame itself because another power is working to destroy it.” (Jean-François Revel, 1983)

xx. “The only excuse for God is that He does not exist.” (Stendhal)

 

 

April 9, 2016 Posted by | Quotes/aphorisms | Leave a comment

Human Drug Metabolism (I)

“It has been said that if a drug has no side effects, then it is unlikely to work. Drug therapy labours under the fundamental problem that usually every single cell in the body has to be treated just to exert a beneficial effect on a small group of cells, perhaps in one tissue. Although drug-targeting technology is improving rapidly, most of us who take an oral dose are still faced with the problem that the vast majority of our cells are being unnecessarily exposed to an agent that at best will have no effect, but at worst will exert many unwanted effects. Essentially, all drug treatment is really a compromise between positive and negative effects in the patient. […] This book is intended to provide a basic grounding in human drug metabolism, although it is useful if the reader has some knowledge of biochemistry, physiology and pharmacology from other sources. In addition, a qualitative understanding of chemistry can illuminate many facets of drug metabolism and toxicity. Although chemistry can be intimidating, I have tried to make the chemical aspects of drug metabolism as user-friendly as possible.”

I’m currently reading this book. To say that it is ‘useful if the reader has some knowledge’ of the topics mentioned is putting it mildly; I’d say it’s mandatory – my advice would be to stay far away from this book if you know nothing of pharmacology, biochem, and physiology. I know enough to follow most of the coverage, at least in terms of the big picture stuff, but some of the biochemistry details I frankly have been unable to follow; I think I could probably understand all of it if I were willing to look up all the words and concepts with which I’m unfamiliar, but I’m not willing to spend the time to do that. In this context it should also be mentioned that the book is very well written, in the sense that it is perfectly possible to read the book and follow the basic outline of what’s going on without necessarily understanding all details, so I don’t feel that the coverage in any way discourages me from reading the book the way I am – the significance of that hydrogen bond in the diagram will probably become apparent to you later, and even if it doesn’t you’ll probably manage.

In terms of general remarks about the book, a key point to be mentioned early on is also that the book is very dense and has a lot of interesting stuff. I find it hard at the moment to justify devoting time to blogging, but if that were not the case I’d probably feel tempted to cover this book in a lot of detail, with multiple posts delving into specific fascinating aspects of the coverage. Despite this being a book where I don’t really understand everything that’s going on all the time, I’m definitely at a five star rating at the moment, and I’ve read close to two-thirds of it at this point.

A few quotes:

“The process of drug development weeds out agents [or at least tries to weed out agents… – US] that have seriously negative actions and usually releases onto the market drugs that may have a profile of side effects, but these are relatively minor within a set concentration range where the drug’s pharmacological action is most effective. This range, or ‘therapeutic window’ is rather variable, but it will give some indication of the most ‘efficient’ drug concentration. This effectively means the most beneficial pharmacodynamic effects for the minimum side effects.”

If the dose is too low, you have a case of drug failure, where the drug doesn’t work. If the dose is too high, you experience toxicity. Both outcomes are problematic, but they manifest in different ways. Drug failure is usually a gradual process (days – “Therapeutic drug failure is usually a gradual process, where the time frame may be days before the problem is detected”), whereas toxicity may be of very rapid onset (hours).

“To some extent, every patient has a unique therapeutic window for each drug they take, as there is such huge variation in our pharmacodynamic drug sensitivities. This book is concerned with what systems influence how long a drug stays in our bodies. […] [The therapeutic index] has been defined as the ratio between the lethal or toxic dose and the effective dose that shows the normal range of pharmacological effect. In practice, a drug […] is listed as having a narrow TI if there is less than a twofold difference between the lethal and effective doses, or a twofold difference in the minimum toxic and minimum effective concentrations. Back in the 1960s, many drugs in common use had narrow TIs […] that could be toxic at relatively low levels. Over the last 30 years, the drug industry has aimed to replace this type of drug with agents with much higher TIs. […] However, there are many drugs […] which remain in use that have narrow or relatively narrow TIs”.

“metabolites are usually removed from the cell faster than the parent drug”

“The kidneys are mostly responsible for […] removal, known as elimination. The kidneys cannot filter large chemical entities like proteins, but they can remove the majority of smaller chemicals, depending on size, charge and water solubility. […] the kidney is a lipophilic (oil-loving) organ […] So the kidney is not efficient at eliminating lipophilic chemicals. One of the major roles of the liver is to use biotransforming enzymes to ensure that lipophilic agents are made water soluble enough to be cleared by the kidney. So the liver has an essential but indirect role in clearance, in that it must extract the drug from the circulation, biotransform (metabolize) it, then return the water-soluble product to the blood for the kidney to remove. The liver can also actively clear or physically remove its metabolic products from the circulation by excreting them in bile, where they travel through the gut to be eliminated in faeces.”

“Cell structures eventually settled around the format we see now, a largely aqueous cytoplasm bounded by a predominantly lipophilic protective membrane. Although the membrane does prevent entry and exit of many potential toxins, it is no barrier to other lipophilic molecules. If these molecules are highly lipophilic, they will passively diffuse into and become trapped in the membrane. If they are slightly less lipophilic, they will pass through it into the organism. So aside from ‘ housekeeping ’ enzyme systems, some enzymatic protection would have been needed against invading molecules from the immediate environment. […] the majority of living organisms including ourselves now possess some form of effective biotransformational enzyme capability which can detoxify and eliminate most hydrocarbons and related molecules. This capability has been effectively ‘stolen’ from bacteria over millions of years. The main biotransformational protection against aromatic hydrocarbons is a series of enzymes so named as they absorb UV light at 450 nm when reduced and bound to carbon monoxide. These specialized enzymes were termed cytochrome P450 monooxygenases or sometimes oxido-reductases. They are often referred to as ‘CYPs’ or ‘P450s’. […] All the CYPs accomplish their functions using the same basic mechanism, but each enzyme is adapted to dismantle particular groups of chemical structures. It is a testament to millions of years of ‘ research and development ’ in the evolution of CYPs, that perhaps 50,000 or more man-made chemical entities enter the environment for the first time every year and the vast majority can be oxidized by at least one form of CYP. […] To date, nearly 60 human CYPs have been identified […] It is likely that hundreds more CYP-mediated endogenous functions remain to be discovered. […] CYPs belong to a group of enzymes which all have similar core structures and modes of operation. […] Their importance to us is underlined by their key role in more than 75 per cent of all drug biotransformations.”

I would add a note here that a very large proportion of this book is, perhaps unsurprisingly in view of the above, about those CYPs; how they work, what exactly it is that they do, which different kinds there are and what roles they play in the metabolism of specific drugs and chemical compounds, variation in gene expression across individuals and across populations in the context of specific CYPs and how such variation may relate to differences in drug metabolism, etc.

“Drugs often parallel endogenous molecules in their oil solubility, although many are considerably more lipophilic than these molecules. Generally, drugs, and xenobiotic compounds, have to be fairly oil soluble or they would not be absorbed from the GI tract. Once absorbed these molecules could change both the structure and function of living systems and their oil solubility makes these molecules rather ‘elusive’, in the sense that they can enter and leave cells according to their concentration and are temporarily beyond the control of the living system. This problem is compounded by the difficulty encountered by living systems in the removal of lipophilic molecules. […] even after the kidney removes them from blood by filtering them, the lipophilicity of drugs, toxins and endogenous steroids means that as soon as they enter the collecting tubules, they can immediately return to the tissue of the tubules, as this is more oil-rich than the aqueous urine. So the majority of lipophilic molecules can be filtered dozens of times and only low levels are actually excreted. In addition, very high lipophilicity molecules like some insecticides and fire retardants might never leave adipose tissue at all […] This means that for lipophilic agents:
*the more lipophilic they are, the more these agents are trapped in membranes, affecting fluidity and causing disruption at high levels;
* if they are hormones, they can exert an irreversible effect on tissues that is outside normal physiological control;
*if they are toxic, they can potentially damage endogenous structures;
* if they are drugs, they are also free to cause any pharmacological effect for a considerable period of time.”

“A sculptor was once asked how he would go about sculpting an elephant from a block of stone. His response was ‘knock off all the bits that did not look like an elephant’. Similarly, drug-metabolizing CYPs have one main imperative, to make molecules more water-soluble. Every aspect of their structure and function, their position in the liver, their initial selection of substrate, binding, substrate orientation and catalytic cycling, is intended to accomplish this deceptively simple aim.”

“The use of therapeutic drugs is a constant battle to pharmacologically influence a system that is actively undermining the drugs’ effects by removing them as fast as possible. The processes of oxidative and conjugative metabolism, in concert with efflux pump systems, act to clear a variety of chemicals from the body into the urine or faeces, in the most rapid and efficient manner. The systems that manage these processes also sense and detect increases in certain lipophilic substances and this boosts the metabolic capability to respond to the increased load.”

“The aim of drug therapy is to provide a stable, predictable pharmacological effect that can be adjusted to the needs of the individual patient for as long is deemed clinically necessary. The physician may start drug therapy at a dosage that is decided on the basis of previous clinical experience and standard recommendations. At some point, the dosage might be increased if the desired effects were not forthcoming, or reduced if side effects are intolerable to the patient. This adjustment of dosage can be much easier in drugs that have a directly measurable response, such as a change in clotting time. However, in some drugs, this adjustment process can take longer to achieve than others, as the pharmacological effect, once attained, is gradually lost over a period of days. The dosage must be escalated to regain the original effect, sometimes several times, until the patient is stable on the dosage. In some cases, after some weeks of taking the drug, the initial pharmacological effect seen in the first few days now requires up to eight times the initial dosage to reproduce. It thus takes a significant period of time to create a stable pharmacological effect on a constant dose. In the same patients, if another drug is added to the regimen, it may not have any effect at all. In other patients, sudden withdrawal of perhaps only one drug in a regimen might lead to a gradual but serious intensification of the other drug’s side effects.”

“acceleration of drug metabolism as a response to the presence of certain drugs is known as ‘enzyme induction’ and drugs which cause it are often referred to as ‘inducers’ of drug metabolism. The process can be defined as: ‘An adaptive increase in the metabolizing capacity of a tissue’; this means that a drug or chemical is capable of inducing an increase in the transcription and translation of specific CYP isoforms, which are often (although not always) the most efficient metabolizers of that chemical. […] A new drug is generally regarded as an inducer if it produces a change in drug clearance which is equal to or greater than 40 per cent of an established potent inducer, usually taken as rifampicin. […] inducers are usually (but not always) lipophilic, contain aromatic groups and consequently, if they were not oxidized, they would be very persistent in living systems. CYP enzymes have evolved to oxidize this very type of agent; indeed, an elaborate and very effective system has also evolved to modulate the degree of CYP oxidation of these agents, so it is clear that living systems regard inducers as a particular threat among lipophilic agents in general. The process of induction is dynamic and closely controlled. The adaptive increase is constantly matched to the level of exposure to the drug, from very minor almost undetectable increases in CYP protein synthesis, all the way to a maximum enzyme synthesis that leads to the clearance of grammes of a chemical per day. Once exposure to the drug or toxin ceases, the adaptive increase in metabolizing capacity will subside gradually to the previous low level, usually within a time period of a few days. This varies according to the individual and the drug. […] it is clear there is almost limitless capacity for variation in terms of the basic pre-set responsiveness of the system as well as its susceptibility to different inducers and groups of inducers. Indeed, induction in different patients has been observed to differ by more than 20-fold.”

This one I added mostly because I didn’t know this and I thought it was worth including it here because it would make it easier for me to remember later (i.e., not because I figured other people might find this interesting):

CYP2E1 is very sensitive to diet, even becoming induced by high fat/low carbohydrate intakes. Surprisingly, starvation and diabetes also promote CYP2E1 functionality. Insulin levels fall during diet restriction, starvation and in diabetes and the formation of functional 2E1 is suppressed by insulin, so these conditions promote the increase of 2E1 metabolic capability. One of the consequences of diabetes and starvation is the major shift from glucose to fatty acid/tryglyceride oxidation, of which some of the by-products are small, hydrophilic and potentially toxic ‘ketone bodies’. These agents can cause a CNS intoxicating effect which is seen in diabetics who are very hypoglycaemic, they may appear ‘drunk’ and their breath will smell as if they had been drinking.”

A more general related point which may be of more interest to other people reading along here is that this is far from the only CYP which is sensitive to diet, and that diet-mediated effects may be very significant. I may go into this in more detail in a later post. Note that grapefruit is a major potentially problematic dietary component in many drug contexts:

“Although patients have been heroically consuming grapefruit juice for their health for decades, it took until the late 1980s before its effects on drug clearance were noted and several more years before it was realized that there could be a major problem with drug interactions […] The most noteworthy feature of the effect of grapefruit juice is its potency from a single ‘dose’ which coincides with a typical single breakfast intake of the juice, say around 200–300 ml. Studies with CYP3A substrates such as midazolam have shown that it can take up to three days before the effects wear off, which is consistent with the synthesis of new enzyme. […] there are a number of drugs that are subject to a very high gut wall component to their ‘first-pass’ metabolism […]; these include midazolam, terfenadine, lovastatin, simvastatin and astemizole. Their gut CYP clearance is so high that if the juice inhibits it, the concentration reaching the liver can increase six- or sevenfold. If the liver normally only extracts a relatively minor proportion of the parent agent, then plasma levels of such drugs increase dramatically towards toxicity […] the inhibitor effects of grapefruit juice in high first – pass drugs is particularly clinically relevant as it can occur after one exposure of the juice.”

It may sound funny, but there are two pages in this book about the effects of grapefruit juice, including a list of ‘Drugs that should not be taken with grapefruit juice’. Grapefruit is a well-known so-called mechanism-based inhibitor, and it may impact the metabolism of a lot of different drugs. It is far from the only known dietary component which may cause problems in a drug metabolism context – for example “cranberry juice has been known for some time as an inhibitor of warfarin metabolism”. On a general note the author remarks that: “There are hundreds of fruit preparations available that have been specifically marketed for their […] antioxidant capacities, such as purple grape, pomegranate, blueberry and acai juices. […] As they all contain large numbers of diverse phenolics and are pharmacologically active, they should be consumed with some caution during drug therapy.”

April 7, 2016 Posted by | Biology, Books, Medicine, Microbiology, Pharmacology | Leave a comment

The Second World War (I?)

“I am perhaps the only man who has passed through both the two supreme cataclysms of recorded history in high executive office. Whereas […] in the First World War I filled responsible but subordinate posts, I was in this second struggle with Germany for more than five years the head of His Majesty’s Government. I write therefore from a different standpoint and with more authority than was possible in my earlier books. I do not describe it as history, for that belongs to another generation. But I claim with confidence that it is a contribution to history which will be of service to the future.”

“Let no one look down on those honourable, well-meaning men whose actions are chronicled in these pages without searching his own heart, reviewing his own discharge of public duty, and applying the lessons of the past to his future conduct.”

I am currently reading this book, which is really an abridgement of 6 different volumes written by Churchill. All of the stuff included is Churchill’s own stuff; the only thing that has been done is that some stuff has been left out, and some of the remaining stuff has been rearranged. Which means that you in this book get four books/subsections, rather than six. The titles of these are: Milestones to disaster (1919-May 10, 1940), Alone (May 10, 1940-June 22, 1941), The Grand Alliance (Sunday, December 7, 1941 and onwards), and Triumph and Tragedy (1943-1945). I have by now finished Book 1 (the Milestones to Disaster part), and I’ve read close to 100 pages of Book 2. It’s great stuff, and very detailed. In this post I have included quotes from roughly the first 150 pages of the book’s coverage, all of which belong to the ‘Milestones to disaster’ part.

“When Marshall Foch heard of the signing of the Peace Treaty of Versailles he observed with singular accuracy: “This is not peace. It is an Armistice for twenty years.””

[In the context of the reparations:] “whereas about £1,000 millions of German assets were appropriated by the victorious Powers, more than £1,500 millions were lent a few years later to Germany, principally by the United States and Great Britain […] until 1931 the victors, and particularly the United States, concentrated their efforts upon extorting by vexatious foreign controls their annual reparations from Germany. The fact that these payments were made only from far larger American loans reduced the whole process to the absurd. Nothing was reaped except ill-will. […] History will characterize all these transactions as insane. […] All this is a sad story of complicated idiocy”

“Deliberate extermination of whole populations was contemplated and pursued by both Germany and Russia in the Eastern war.”

“”We are apparently finished and done with economic cycles as we have known them,” said the President of the New York Stock Exchange in September.” [That would be September, 1929. Talk about bad timing… – US]

“The opinions of the Press and public were in no way founded upon reality […] delight in smooth-sounding platitudes, refusal to face unpleasant facts, desire for popularity and electoral success irrespective of the vital interests of the State, genuine love of peace and pathetic belief that love can be its sole foundation, obvious lack of intellectual vigour […] marked ignorance […] the utter devotion […] to sentiment apart from reality […]: all these constituted a picture of British fatuity and fecklessness which, though devoid of guile, was not devoid of guilt, and, though free from wickedness or evil design, played a definite part in the unleashing upon the world of horrors and miseries which, even so far as they have unfolded, are already beyond comparison in human experience. […] It is difficult to find a parallel to the unwisdom of the British and weakness of the French Governments, who none the less reflected the opinion of their Parliaments in this disastrous period” [the period in question being the early thirties – US].

“Several visitors of consequence came to me from Germany and poured their hearts out in their bitter distress. Most of these were executed by Hitler during the war.”

“It would be wrong in judging the policy of the British Government not to remember the passionate desire for peace which animated the uninformed, misinformed majority of the British people, and seemed to threaten with political extinction any party or politician who dared to take any other line. This, of course, is no excuse for political leaders who fall short of their duty. It is much better for parties or politicians to be turned out of office than to imperil the life of the nation. […] To be so entirely convinced and vindicated in a matter of life and death to one’s country, and not to be able to make Parliament and the nation heed the warning, or bow to the proof by taking action, was an experience most painful.”

“the number of Germans under regular military training in 1936 was 1,511,000 men. The effective strength of the French Army, apart from reserves, in the same year was 623,000 men, of whom only 407,000 were in France.”

Abyssinia [see also this] was a member of the League of Nations. By a curious inversion it was Italy who had in 1923 pressed for her inclusion, and Britain who had opposed it. The British view was that the character of the Ethiopian Government and the conditions prevailing in that wild land of tyranny, slavery, and tribal war were not consonant with membership of the League. But the Italians had had their way” [incidentally if you want an update on how things are going in that part of the world, apropos all those migrants coming to Europe from that region these days, here’s some updated information: “Eritrea is a one-party state in which national legislative elections have been repeatedly postponed.[111] According to Human Rights Watch, the government’s human rights record is considered among the worst in the world. […] In June 2015, a 500-page United Nations Human Rights Council report accused Eritrea’s government of extrajudicial executions, torture, indefinitely prolonged national service and forced labour, and indicated that sexual harassment, rape and sexual servitude by state officials are also widespread.” (wikipedia)]

“One day in 1937 I had a meeting with Herr von Ribbentrop, German ambassador to Britain. […] he had asked Hitler to let him come over to London in order to make the full case for an Anglo-German entente or even alliance. […] What was required was that Britain should give Germany a free hand in the East of Europe. She must have her Lebensraum […] All that was asked of the British Commonwealth and Empire was not to interfere. There was a large map on the wall, and the Ambassador several times led me to it to illustrate his projects. After hearing all this I said at once that I was sure the British Government would not agree to give Germany a free hand in Eastern Europe. […] Ribbentrop turned abruptly away. He then said, “In that case, war is inevitable. There is no way out. The Fuehrer is resolved. Nothing will stop him and nothing will stop us.” We then returned to our chairs.” [At this time Churchill was just an MP, so Ribbentrop was not asking Churchill himself to consent to the proposed scheme and ‘make a deal’; he was trying to figure out if there was any deal to be made. The year after, on July 26, 1938, Lord Halifax, the British Foreign Minister, incidentally stated in Parliament that: “I do not believe that those responsible for the Government of any country in Europe to-day want war.” – US]

“On the day of the march of the German armies into Austria we heard that Goering had given a solemn assurance to the Czech Minister in Berlin that Germany had “no evil intentions towards Czechoslovakia” […] On the evening of the 26th [of September, 1938 – US] Hitler spoke in Berlin. […] He said categorically that the Czechs must clear out of the Sudetenland, but once this was settled he had no more interest in what happened to Czechoslovakia. “This is the last territorial claim I have to make in Europe.” […] Chamberlain returned to England [after signing the agreement – US]. […] from the windows of Downing Street he waved his piece of paper again and used these words, “This is the second time in our history that there has come back from Germany to Downing Street peace with honour. I believe it is peace for our time.”

“In 1938-39 British military expenditure of all kinds reached £304 millions,* and German was at least £1,500 millions. It is probable that in the last year before the outbreak Germany manufactured at least double, and possibly treble, the munitions of Britain and France put together […] in the single year 1938 Hitler had annexed to the Reich and brought under his absolute rule […] a total of over ten millions of subjects, toilers, and soldiers. […] The German armies were not capable of defeating the French in 1938 or 1939. The vast tank production with which they broke the French front did not come into existence till 1940”

“if you will not fight for the right when you can easily win without bloodshed, if you will not fight when your victory will be sure and not too costly, you may come to the moment when you will have to fight with all the odds against you and only a precarious chance of survival. There may even be a worse case. You may have to fight when there is no hope of victory, because it is better to perish than live as slaves.”

“At the Kremlin in August 1942 Stalin, in the early hours of the morning, gave me one aspect of the Soviet position. “We formed the impression,” said Stalin, “that the British and French governments were not resolved to go to war if Poland were attacked, but that they hoped the diplomatic line-up of Britain, France, and Russia would deter Hitler. We were sure it would not.””

“There were known to be twenty thousand organised German Nazis in England at this time [at the end of August, 1939US], and it would only have been in accord with their procedure in other friendly countries that the outbreak of war should be preceded by a sharp prelude of sabotage and murder. I had at that time no official protection, and I did not wish to ask for any; but I thought myself sufficiently prominent to take precautions. I had enough information to convince me that Hitler recognised me as a foe. My former Scotland Yard detective, Inspector Thompson, was in retirement. I told him to come along and bring his pistol with him. I got out my own weapons, which were good. While one slept the other watched.”

 

April 6, 2016 Posted by | Books, History | Leave a comment