E2Medicine

Nexium is a brand name for S-omeprazole, a drug that reduces gastric acid secretion, of the British-Swedish firm AstraZeneca. It is used to treat peptic ulcers, duodenal ulcers, and to relieve acid reflux (heartburn) symptoms, such as erosive esophagitis. It is a proton pump inhibitor, which works by decreasing stomach acid secretion.

AstraZeneca already had an omeprazole product in the market, namely Prilosec, and its competetors sold omeprazole analogues. Now, the analogues of omeprazole itself are not more or less effective, and there is no reason to choose one over omeprazole, so no company had an edge over other.

But, omeprazole is an chiral compound. That is, there is an atom, called chiral center, with four different substituents on it. This makes it necessarily asymmetric. If you change the places of two substituents, it will no longer be the same molecule, but its mirror image, or another enantiomer. This may not seem like a big deal, but in the human body, the places where the molecule binds to are similarly asymmetric. One enantiomer of omeprazole, namely the S-enantiomer, works. The other, namely the R-enantiomer, just sits there, and contributes to the side effects, so it's not actually just inert, but counterproductive. It also forces the manufacturer to waste half of the precursor chemicals, since without special steps, both S-, and R-forms are produced equally, which is called a racemic mixture.

So, the people at AstraZeneca figured out, if you selectively produce only S-omeprazole, you can give twice the dose "for free", without twice everything else. More importantly, the omeprazole patent was into expiring in 2000, so they could re-patent, re-market and re-set prices for the same omeprazole by developing an enantiopure product. And that they did. The enantiomer was patented, "The new Purple Pill" campaign was launched in the USA to encourage people to switch from the racemic Prilosec to the enantiopure Nexium, and the price was set considerably higher. A course of Nexium (40 mg) costs a bit over 2 € per day. (Someone could provide a dollar figure.)

Nexium is more effective than its racemic competetitors only by a thin margin, and even the existence of this margin has been "controversialized", although individual patients say there is an improvement. A curiosity of marketing is that they also renamed the S-enantiopure omeprazole to "esomeprazole", which sounds like a different chemical, while it's only a purer form of the same chemical. Yet it's a baseless claim to say that AstraZeneca is just "ripping off", since the ability to double the dose "for free" is an improvement.

Nexium is in pills, which absorb water and burst open soon after being wetted in acid, to release tiny enteric coated pellets. Although there is no proof that this is better than simply coating the entire pill, it does reduce the annoyance of swallowing pills. It appears to me that the disintegration is catalytic in acid: plain water does not work, but adding few drops of apple juice will do the trick in seconds. The released pellets, about half a millimeter in size, are stable in the acidic stomach, but disintegrate in the non-acidic small intestine to release the omeprazole. Enteric coating is needed, because omeprazole converts to its insoluble form in acid, and is thus incapacitated.

The patient should not take antacids (chemicals that neutralize acid) with Nexium, because the neutral-to-basic environment dissolves the enteric coated pellets, and when stomach acid is secreted again, the omeprazole is incapacitated. On the other hand, the Nexium course is not a contraindication to antacids, since after the omeprazole has absorbed, antacids can be taken again, and omeprazole absorbs and does its trick in a matter of hours.

Its mechanism of action is proton pump inhibition. The cells which secrete stomach acid do it by pumping protons (acid ions) to the stomach. In their cell membranes, they have enzyme proteins called proton pumps, which pump the protons (that is, the acidity) to the stomach. These are ideal targets for medication, because they are ultimately responsible for the secretion of stomach acid. S-omeprazole irreversibly and specifically binds to these pumps, incapacitating them. It takes very long, about 24 hours, for the cells to synthesize new pumps. This is why a single pill a day can be effective. This is also the reason one should take the pill about one hour before the first meal: when one begins eating and thus starts the secretion of stomach acid, the maximum number of pumps are incapacitated and secretion minimized.

Because omeprazole does not act directly, but indirectly by inhibiting proton pumps, its full effect of inhibition doesn't kick in immediately with the first dose. Rather, it takes a couple of days to pile up. Its effective utility is only 64% first, but if repeated, it rises to 89%. Omeprazole is absorbed fast, and it achieves its peak concentration in blood in 1-2 hours. Its half-life is only 1.3 hours in the blood, and it is completely eliminated from the body each day. Its metabolism takes place in the liver, which converts it to a form that is excreted in urine. As already noted, the short retention time does not make a difference, because it is specifically bound to the proton pumps until new ones are synthesized. It is not necessary to continuously maintain its concentration in blood, as with histamine receptor inhibitors such as ranitidine (Ranimex) or famotidine (Pepcid).

The dose is 40 mg per day for acute, serious peptic ulcers. Paradoxically, the same dose but divided in 20 mg twice a day is used for maintenance treatment of chronic disease.

The form the drug is given is inactive, but it is soluble to lipids (fats), and it can easily go through cell membranes, which are made of lipid (phospholipids, exactly). When it reaches an acidic environment inside the cell, it is protonated and rearranged into its active form. This form binds covalently to the proton pump (by an irreversible chemical reaction, that is). Should you break the enteric coating in the capsules, you expose the drug to acid, which protonates it and disables it from passing through the cell membrane.

Since it's for reducing stomach acidity, any drugs that depend on stomach acidity for absorption don't absorb well. Since it is metabolized by a specific enzyme in the liver, namely CYP2C19, drugs that depend on it for elimination, such as benzodiazepam, are retained longer, and a smaller dose of these drugs is needed. Liver insuffiency causes longer retention times for Nexium, but it is not necessary to change the dose, since it will be completely eliminated anyway if taken once a day.

Side effects are rare, found only in 10-1% or less of patients. These include upset stomach (abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation) and headache. Less common effects are rash, itch, vertigo, dry mouth, and urticaria. Rare symptoms are severe allergic reactions and symptoms of the nervous system, such as tactile hallucinations, lethargy, vertigo and insomnia. Other such effects are confusion, anxiety, aggression, depression and hallucinations, which are typical of severely ill patients. The effects of aggression and anxiety are particularly problematic, if the ulcers are stress-induced, since the stress response includes an increase in stomach acid secretion.

Chemically, omeprazole is moderately complex, but not very complex. It consists of substituted pyridinyl and benzimidazole groups bound at a chiral sulfinyl, also known as sulfoxide. Sulfinyl is sulfur with oxygen double bonded to it, and it takes two substituents. The "chiral" bit means that it is center of asymmetry; changing the places of the substituents makes S-omeprazole into R-omeprazole, and vice versa, and that in this preparation, it is exclusively the S-enantiomer. The pyridine ring or a pyridinyl group is an six-membered aromatic ring like benzene, except with one nitrogen atom instead of a carbon in the ring. In omeprazole, this nitrogen is at the ortho position (next to the sulfinyl bond). On the other side of the ring with respect to the nitrogen, there are three substituents: two methyls (-CH3) at the ortho and para positions, and a methoxy group (-OCH3) at the meta position between them. An imidazole group has a carbon in the center, and two nitrogens connected to it (-C(=N-)(-NH-)). One is by a double bond, one by a single bond; the single-bonded nitrogen has also a proton. Benzimidazole is an imidazole connected to a benzene ring by both of these nitrogens, giving a five-membered ring fused with the six-membered benzene. In omeprazole, the benzene ring has a methoxy substituent at the para position with respect to the single-bonded nitrogen.

Here is an ASCII art attempt at the chemical structure. The rings inside the rings denote an aromatic system. Notice that the sulfinyl has a 3-D chiral configuration that can't be drawn in 2-D ASCII art. The pyridinyl should be facing away from the viewer, while the electron pair (denoted with ':') out from the plane.

:         OMe     methoxy (OCH3) at meta
:         |
:    Me   C   Me  methyls (CH3) at para, ortho
:      \ / \ /
:       C _ C
:       |(_)|     pyridinyl ring
:       C   C
:        \ / \
:         N  :S=O sulfinyl
:            /
: imide   N=C     \
:        /  |     |
:       C   NH    |-imidazole part of benzimidazole
:      / \ /      /
:     C _ C
:     |(_)|       benzene ring of benzimidazole
:     C   C
:    / \ /
: MeO   C

Nexium does not offer immediate help, and it does not cure you, since peptic ulcers are only a symptom of something else. But, it stops your body from aggravating the symptoms, and allows you to heal. If the formation of peptic ulcers is induced by stress (and not as a side effect of a NSAID painkiller, for example), one should find out and eradicate the behaviors leading to anxiety. A self-supporting positive feedback loop can form, when anxiety causes heightened sensitivity to pain, which increases the stress response to the stomach pain, which causes more anxiety, which causes more excessive acid secretion.

Disclaimer: This text is not written by a medical professional. Seek treatment from and follow the directions of a medical doctor should any symptoms occur.

E2 Medical Disclaimer

I thought it was a joke the first time I read the word. Like sexalicious or sextastic. Then, I found out that sexsomnia was real. Not just because google confirmed it (and google is the arbiter of reality these days), but because I suddenly remembered that I had been a party to it. Many times, in fact. I had simply forgotten it, like gossamer lube from a libidinous dream. But I tease.

What is it?

Sexsomnia is sleepsex. Like sleepwalking, but, you know, sex. It is also called SBS, for Sexual Behavior during Sleep. It is one of several parasomnias that include the more familiar somnambulism, sleep eating, and sleep apnea. It is not as common as sleep violence.

The afflicted find themselves waking up in the middle of sexual activity. In benign forms the activity is harmless, such as masturbation when alone or in some sexual act with a bed partner. In extreme cases the behavior can be embarrassing or dangerous, such as the protracted shouting of sexual noises, engaging in violent masturbation (more common in men, who can awake with bruises), or in the worst cases sexual assault of a bed partner. Subjects are often more dominant in their behaviors than they are when doing the same things when awake. Subjects report complete amnesia of the events.

Some sufferers of the harmful variety also reported some common precipitating factors: alcohol abuse, polysubstance abuse, sleep deprivation, or psychophysiological stress. There's also evidence that it runs in families.

From a first person perspective I can say that being awakened by a benign sexsomnulist (sexsomniac?) can be at first wonderfully surprising. You think that you're dreaming a sexy dream, but then come out of it. Darn. It was just a dream. But wait, it not a dream at all! Hey-hey! It's only when you realize that your bed buddy isn't quite aware of what they're doing that it loses much of its sexiness. (Not all.) It is when your sleeping partner "loses interest" now that you're aroused and awake that it can become annoying. Especially if they get grumpy when you try to awake them. Especially if it occurs repeatedly. Especially.

It has been only recently identified by the psychological community. The earliest paper that I could find citing the problem was as recent as 1996. It is not yet recognized in the most widely used classification of such things, the American Academy of Sleep Medicine's International Classification of Sleep Disorders. Still, the topic is reaching the layperson, as evidenced by Cosmopolitan magazine's 2002 article "Her Boyfriend Did a Shocking Thing in His Sleep. Could Yours?"

The topic only took 9 years to reach the courts. Canadian defense lawyers cited sexomnia in defense of their client, a Toronto man accused of sexually assaulting a woman sleeping on his couch after they had met at a party. She reported that, "During the entire altercation, when someone touches you, you can feel their body heat. He had no body heat. His arms were very limp." He was acquitted of the charges. Women's rights activists were very upset at the court's ruling, fearing that this added another excuse by which men could justify sexual assault.

What causes it?

Well, I'd like to think sex appeal, thank you very much. But that's just me "suffering" from the benign type. Sleep scientists say it is a problem with the arousal mechanism, which means the biological processes by which an individual is roused from deep sleep to wakefulness. But in the harmful kind, it may signal a deeper problem.

Sleep researchers at Stanford University did a study on harmful-sexomnia sufferers and ascribed much of it (not all) to feelings of guilt, shame, and depression about sex while awake. It is notable that none were diagnosed with dissociative disorders. (The authors of the Stanford study suspect that some sufferers in the world will be diagnosed as such.) Sufferers also displayed some other stuff I don't yet understand: sleep-disordered breathing, stage 3 to 4 non-rapid eye movement sleep parasomnias, and REM sleep behavior disorder, all of which, are apparently concurrent with morning amnesia. Because of the general taboo of the subject and the sufferers' feelings in particular, partners often tolerated harmful varieties of the behavior for many months before seeking help.

What cures it?

If you know of someone who has the harmful variety, they should seek counseling, which helped most patients in the study. A low-level step you can take in the meantime is simply to sleep apart from each other to avoid the physical contact that may partially initiate the arousal mechanism. Also, if you notice a correlation with any precipitating factors (see above), avoid those things. In extreme cases, treatment of psychiatric disorders are needed, including prescriptions of Clonazepam (trade name: Klonopin) or other antiepileptic or antidepressant drugs. These were the minority.

To learn more, head to http://www.sleepsex.org/ and read up. You can share your stories and if you're suffering from the harmful kind read up on steps you can take. This is important, as sufferers may be at risk, like the Toronto guy, of being accused of sexual assault. If you'd rather read, one book has been published to date, with the perhaps-inapprioriately double-entendred title Sleepsex: Uncovered.

---

sources:
my bed
http://www.sleepsex.org/
http://www.menstuff.org/issues/byissue/sleepsex.html
http://www.local6.com/news/5441888/detail.html
http://www.psychosomaticmedicine.org/cgi/content/full/64/2/328
(this last contains an excellent set of references.)

Fighting against all illnesses - even injustice.

Médecins du Monde (Doctors of the World) is an international medical organization founded in 1980 by Bernard Kouchner and a group of doctors who had been part of Médecins Sans Frontières. MdM broke away from the larger organization on acrimonious terms in the late 1970s due to a disagreement about helping Vietnamese boat people. While MSF went on to win the Nobel Peace Prize in 1999, MdM is relatively unknown, despite its good work all over the world.

Prehistory of Médecins du Monde

Kouchner was born in 1939 in Avignon to a Jewish father and a Protestant mother. When the Nazis came, his family fled Paris, only to return when they could find nowhere to live. His grandparents were sent to Auschwitz and gassed. Although he is obviously unable to remember these early years, they left an indelible mark on him. At age fourteen he joined the French Communist Party, a thing that was not unusual to do at a time when the Party had huge support in France. He participated as a teenager in street battles against right-wingers and anarchists when Soviet troops rolled into Hungary in 1956. He was, for a while, Communist through and through.

But by the time Kouchner came to found MSF in 1971, his views had changed hugely. Having been involved in the student movement in Paris in 1968, and having visited Cuba, Kouchner's views began to change. At a time when his friends in the student movement were starting to form terrorist groups in Europe, or going to Latin America to engage in the revolutionary struggle there, Kouchner had different ideas. By now a doctor, he set about applying the spirit of 1968 to his own field.

Kouchner spent the last two years of the 1960s in Biafra in Nigeria with the Red Cross. In Kouchner's estimation, there was a genocide going on in Biafra, co-ordinated by the Nigeran government: a situation not too different to our own problem in Darfur today. He and his team provided medical help, and then returned to Paris. When he got back, he was highly frustrated by Red Cross policy that its agents never pass judgement on a situation they had been in. They were not supposed to ascribe blame, or describe what they had seen: they were supposed to do nothing.

This angered Kouchner, and so he rushed to press with what he had seen in Biafra. Then, he rushed to form his own small organization that would do exactly the opposite. He conceived a humanitarian organization that would be composed of people with the spirit of 1968 - willing to risk death in dangerous places to help others, but through providing medical aid and not through revolutionary struggle. The organization would not be afraid to speak out against atrocities, expose the criminals behind them, and bring the pressure of the international community to bear on the perpetrators. He considered such activity much more worthwhile than trying to help Marxist guerrilla movements, who in his opinion ended up causing more destruction than anything. MSF was born.

MdM is born

The first few missions of MSF were apolitical, taking the form of disaster relief efforts. It went to the aid of victims of an earthquake in Nicaragua and a hurricane in Honduras. In 1975, they went to the Thai border to help refugees who were fleeing the genocidal Khmer Rouge regime in Cambodia. Few in the West believed the atrocity stories coming from within Cambodia. The left didn't want to admit their precious "agrarian reformers" were capable of such things, and the right didn't want to think about the moral implications of not intervening. However, MSF were there, with the horror before their eyes and humanitarian packs on their backs. They remained there four years later when the Khmero-Vietnamese war drove yet more refugees over the border.

Yet in that same year, MSF was torn apart. In 1979, the Vietnamese Communists had embarked on a new program of repression, as well as starting a war with the Khmer Rouge.¹ Refugees duly poured in poorly-constructed boats into the South China Sea. Kouchner, founder of MSF, wanted to set off in a French boat, the Isle of Light, and pick up some of the refugees so they could be taken to a safe country. Simple enough, and one would have thought, uncontroversial enough. But this was not so.

It must be remember that this was only a few years after the Vietnam War had ended, and most on the left (and MSF was made up of those on the left) saw the Vietnamese regime as something great. It was a new vanguard of socialism in the world, a finger in the eye to the American imperialists. To help those who were enemies of this regime was no humanitarianism at all, they said. It was short-sighted. The only real humanitarianism was to support the enemies of Western imperialism, and declare solidarity with the Communist movements of Asia.

This was all compounded by Kouchner's legendary capacity for self-promotion, which led to numerous clashes within the organization. Many people saw the boat expedition as an attempt by him to boost his popularity, a motive hardly likely to gain him much sympathy. And so, Kouchner went off and did it anyway, without MSF. And then, a year later, about one fifth of MSF broke off and formed Médecins du Monde.

Médecins du Monde was based on the idea that the humanitarian organization had a right to "intervene" (note the quasi-military language) anywhere. They formally announced this doctrine in 1987 as "le droit d'ingérence". The organization proclaimed its goal was to "make health a human right". And human rights, unlike civil rights, know no borders: hence Médecins du Monde claims the right (Kouchner calls it a "duty") to intervene anywhere people are suffering, regardless of the existence of a sovereign nation state or the ideology of that state.

Since the creation

I'd like to add a note on the Vietnamese boat people, and what subsequently happened to Bernard Kouchner. Kouchner went on to occupy places in the French government, and went on to be the U.N. administrator in Kosovo. Interestingly, this former Communist went on to support the U.S. war against Iraq in 2003.

The Isle of Light managed to help some Vietnamese refugees, which was all well and good. But then, President Carter decided to send the Sixth Fleet of the U.S. Navy to perform the same task. Naturally, this Fleet was able to get substantially more done than one boat. To Kouchner, it became obvious that enlisting power in the support of humanitarian intervention was the only way of really getting things done. Hence, he was the natural choice for U.N. administrator in Kosovo. While there, he went around saying things like "The fascists must be beaten" - an odd thing to say in the former Yugoslavia, you might think. But really not so odd at all, if you consider the similarities between the Nazis and Milesovic's regime. Similarities that also extended to the Iraqi Ba'ath. Here was a man who represented liberal anti-totalitarianism, and hence his support for the war on Iraq. He soon, however, became disillusioned with the United States' poor handling of the post-war situation.

Kouchner ceased to be director of MdM in 1982, but the organization went on. In 2003, it had a global budget of 436 million Euros and delegations in twelve countries. Its primary mission to provide healthcare wherever it is needed, but also to vigorously report situations where healthcare is denied along with other basic human rights. It continues to respond to all crises, be they disasters or man-made.

Kouchner and Médecins du Monde have much to teach us. In a world of increasing dogmatism, their outlook on the world allows them to do the maximum amount of good, even more so than the apolitical Red Cross. For the Red Cross can never tackle the root causes of problems, despite the huge amount of good humanitarian work it does. While it can be argued that MdM's strategy of condemnation makes it likely to be ejected from nations, it is vital that organizations exist which continue to denounce and publicize human rights abuses on the globe.

Secondly, we can learn something from Kouchner himself. Kouchner realized that the extreme left is just as inclined toward totalitarianism as the extreme right, and soon abandoned his romance with Che Guevara and Third World revolutionaries. The organizations he went on to create oppose state power brutally wielded in all its forms, without excusing a country because of its ideology. This seems to me the standpoint that everyone in Western nations, the liberals, the conservatives, and the government - oh, especially the governments - should go on to adopt. This will lead to true progress. Idealistic, yes, but maybe, 37 years after 1968, we need a touch more idealism in our societies.

1. A war, however, that we can hardly be sorry was fought. Interestingly, as well as hoping to stop the pesky meddling of the Khmer Rouge in Vietnam, the Vietnamese also hoped they would get credit from the West for overthrowing the vicious regime. The Americans, demonstrating the way common sense and humanity can take a back seat when local conditions are not sufficiently understood (and possibly demonstrating a touch of hatred at their former enemy), continued to support the Khmer Rouge for years afterwards.

Sources:

The interpretation of Kouchner and the political outlook of MdM is explicated in Paul Berman, Power and the Idealists: Or, the Passion of Joschka Fischer and Its Aftermath (Brooklyn, N.Y.: 2005).

On Cambodia, see Samantha Power, "A Problem From Hell": America and the Age of Genocide (Perenniel, 2002)

"LIFESAVER HERO: BERNARD KOUCHNER", http://myhero.com/myhero/hero.asp?hero=kouchner_fredericksburg_04

Médecins du Monde UK, http://www.medecinsdumonde.org.uk/

Läkare i Världen (MdM Sweden), http://www.lakareivarlden.org/sidor/om_liv_en.htm