A safe NSAID for RNY?

On January 7, 2010, in Uncategorized, by Andrea

There’s a new NSAID that’s being tested.. and what’s neat is that it’s less toxic for the GI system.  While this info is more about the blood pressure aspect — as that’s one of the key problems for many people taking NSAIDs these days, this clearly states that this new derivative is less toxic.  So maybe a new drug that we could take?  It’s something to keep an eye out for.

From Medscape:

Best Evidence Interview: CINODs — The NSAID Holy Grail?

Linda Brookes Good, MSc

A Best Evidence Interview With William White, MD

The Best Evidence Study

William B. White, MD, is the lead author of the following study:

White WB; Schnitzer TJ; Fleming R; et al. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol. 2009;104):840-845.

This study was selected as the subject of this interview because of its high ranking in Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, clinicians who used this system ranked this study as 6 for relevance and 7 for newsworthiness.

About the Interviewee: William White, MD

William B. White, MD, is Professor and Chief of the Division of Hypertension & Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center, University of Connecticut School of Medicine, in Farmington. Dr. White is a fellow of the American College of Physicians, the Council for High Blood Pressure Research of the American Heart Association, and the International Society for Hypertension in Blacks, and a charter member of the American Society of Hypertension. He is also chair of the study section for the Catherine and Patrick Donaghue Medical Research Foundation in Hartford, Connecticut.

Dr. White has a long-standing interest in clinical hypertension and pharmacology, particularly in the areas of ambulatory blood pressure monitoring, clinical trials of antihypertensive drugs, and the impact of cyclooxygenase (COX)-2 inhibitors in cardiovascular disorders. He is the author or coauthor of over 300 articles and book chapters in the field of hypertension and clinical pharmacology. Dr. White’s recently published books include Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics and Hypertension and Related Disorders. He is editor in chief of the journal Blood Pressure Monitoring, and he serves on numerous other editorial boards, including the American Journal of Hypertension, American Journal of Cardiology, American Journal of Medicine, Clinical Pharmacology and Therapeutics, Ethnicity and Diseases, Journal of Human Hypertension, Journal of Clinical Hypertension, and Hypertension.

Introduction to the Interview

Nonsteroidal anti-inflammatory drugs (NSAIDs) are universally used in the treatment of conditions that cause chronic pain, such as osteoarthritis (OA). However, their use is limited by their safety profiles, particularly gastrointestinal side effects and adverse effects on the cardiovascular system. Traditional NSAIDs such as ibuprofen and naproxen, which act by blocking the COX-1 and -2 enzymes, and COX-2 selective inhibitors, such as celecoxib, are associated with the destabilization of blood pressure control. This effect is particularly marked in hypertensive patients treated with blockers of the renin-angiotensin system (RAS).

Naproxcinod, a nitric oxide (NO) derivative of naproxen, is an investigational drug and the first of a class of NSAIDs known as COX-inhibiting NO donors. It is being developed by NicOx S.A. (Sophia Antipolis, France). Naproxcinod has been studied in a clinical phase 3 program in patients with OA of the knee and hip, and, on the basis of the results of these studies, it is currently under regulatory review for approval for treatment of OA in the United States. As of the date of this interview, a regulatory submission is also planned in Europe for late 2009. In preclinical studies, naproxcinod had similar anti-inflammatory and analgesic activity to naproxen but caused less gastric injury. Phase 2 and 3 trials showed that naproxcinod is an effective analgesic agent with reduced gastrointestinal toxicity compared with naproxen, and in contrast to naproxen, it reduces systemic blood pressure by 2-3 mm Hg. On the basis of these findings, naproxcinod may represent an alternative to traditional NSAIDs or COX-2 inhibitors in patients who have or are at risk for cardiovascular disease.

In the best evidence study discussed in this interview, the effects of naproxcinod on blood pressure in patients with OA were compared with those of naproxen and placebo over 13 weeks in a phase 3, randomized clinical trial carried out at the University of Connecticut, Farmington, and Northwestern University, Chicago, Illinois. The results of the trial, which were first presented at US and European rheumatology and cardiology conferences,[1,2] were published recently in the American Journal of Cardiology.[3] The trial randomly assigned a total of 916 patients with OA, with or without a history of hypertension, to treatment twice daily with either naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo. Reductions in systolic blood pressure (SBP) with naproxcinod 750 mg were larger and significantly different from those with naproxen 500 mg at 2, 6, and 13 weeks (P < .05). The difference in mean change from baseline between these 2 groups was -2.9 mm Hg (P = .015). The 2 doses of naproxcinod showed reductions from baseline in diastolic blood pressure relative to naproxen (P < .04) and similar changes compared with placebo. The proportion of patients in the overall population with SBP increases > 10 mm Hg was greater with naproxen 500 mg (22%) compared with naproxcinod 750 mg (14%; P = .04), naproxcinod 375 mg (14%; P = .055), and placebo (15.6%; P = .155).

Separate analysis of a subgroup of 207 patients with hypertension treated with RAS-blocking agents alone or with diuretics showed a difference in mean change from baseline in SBP between naproxen 500 mg and naproxcinod 750 mg of -6.5 mm Hg in favor of naproxcinod (P = .011). Analysis of 73 patients being treated with antihypertensive drugs that did not include a RAS blocker did not show any statistically significant differences from baseline in SBP within or between groups.

The study authors concluded that naproxcinod is likely to destabilize the control of SBP compared with naproxen in patients with OA and behaves in a similar fashion to placebo overall as well as in patients treated with antihypertensive therapies involving blockade of the RAS. They suggested that the hypertensive burden induced by traditional NSAIDs in patients with OA and hypertension could be reduced by an NO-donating agent such as naproxcinod.

Lead author William B. White, MD, spoke with Linda Brookes, MSc, for Medscape Cardiology, to discuss some of the implications of this study for Medscape’s readers.

The Interview

Medscape: This study was the first, large-scale randomized clinical trial to investigate whether naproxcinod caused blood pressure destabilization in patients with OA that used standardized blood pressure measurements. What had earlier studies with naproxcinod shown with respect to its effect on blood pressure?

Dr. White: The phase 1 and 2 studies were very small, mostly in patients with OA, but one looked at hypertensives without OA, and they demonstrated a definite difference in blood pressure effect between naproxcinod and naproxen.[4-8] The pharmacodynamics of that were related to the time of dose, ie, the biggest blood pressure difference between naproxcinod and naproxen occurred during the first 8 hours after the dose of naproxcinod or naproxen was administered. Subsequently, there was a study done that compared naproxcinod, ibuprofen, and naproxen with placebo, and in that study, ibuprofen caused the greatest increase in blood pressure, naproxen the second largest, and naproxcinod and placebo were basically neutral.[9] So, those data predicted what we were expecting to see in this much larger clinical trial.

Medscape: The trial included a majority (about 70%) of women, and the mean age was 61 years, with one third of the patients aged 65 years or older. Was this cohort typical of the population that presents with OA?

Dr. White: OA is a more common disorder in women. In OA clinical trials, sometimes 75% of the population is older women. Usually the mean age of participants in OA trials is in the late 60s.

Medscape: What is the prevalence of hypertension in patients with OA?

Dr. White: Most surveys show that about 40% of patients with OA are taking treatment for hypertension, but probably a higher percentage actually has hypertension. That is usually because in this age group, there is more systolic hypertension developing as arteries get stiffer, and there is the loss of estrogen that seems to have a vasodilating effect. Together, these increase the prevalence of hypertension. The prevalence of hypertension in the entire population is about 20%-25%, but it is much higher in the OA population due to age.

Medscape: Not all the patients in your study had hypertension.

Dr. White: No one was selected for whether he or she did or did not have hypertension, but about 50% of the population in the trial did have a medical diagnosis of hypertension and was treated with various antihypertensive drugs.

Medscape: Most (more than 90%) of the 457 hypertensive patients in the trial were being treated with some form of antihypertensive therapy. About 23% were taking RAS agents. This subgroup group was also analyzed separately; why was that?

Dr. White: There was a hypothesis that we generated before we did this analysis, on the basis of earlier work that I and others did, showing that patients who were taking a RAS-blocking drug, which could be an angiotensin converting-enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a renin inhibitor, or even a beta-blocker (which also inhibits renin release), either alone or in combination with a thiazide-type diuretic, could be more predisposed to destabilization of blood pressure by NSAIDs.[10-12] This effect could arise by 2 mechanisms. One is that NSAIDs enhance salt and water retention, increasing plasma volume of the body and, by doing so, mitigate the effectiveness of the other drugs. The same will happen if you eat a high-salt diet in the presence of an ACE inhibitor or an ARB. The other mechanism is related to the way in which ACE inhibitors lower blood pressure by increasing the amount of bradykinin in the circulation. Bradykinin, a weak vasodilator, works in part by stimulating prostacyclin production. So, taking a conventional NSAID that impairs the generation of prostacyclin and subsequent NO release will have an impact on the mechanism of action of an ACE inhibitor. I think, then, that it was probably that interplay that was responsible for the different responses in the treatment groups that we studied. We also looked at the hypertensive group that was being treated with non-RAS blocker therapy, but we did not see any statistical significant differences from baseline in SBP within or between groups in this small subset.

Medscape: Would the mechanism of action of naproxcinod that prevents blood pressure rise in normotensive patients be the same as that in hypertensive patients controlled on a RAS blocker?

Dr. White: I think that it is all part of the same thing. My general thought is that among the population at large with OA, if you take a large group, half of whom are normotensive and half are hypertensive, the more impressive effect will be seen in the hypertensive than in the normotensive individuals. That is, if you give a conventional NSAID, such as ibuprofen or naproxen, a fairly substantial minority of those patients, maybe 15%-30%, will have a further increase in blood pressure, but it will be much less in the normotensives than it would be in the treated hypertensive population because it is not very easy to make a normotensive hypertensive by causing salt and water retention unless he or she has underlying renal disease. So, there is a small increase, and that would be less likely to occur with the NO donation of naproxcinod. Then, in the hypertensive population, whether or not it is on a RAS blocker vs another agent, it is more likely to have a rise in blood pressure on a conventional NSAID than its normotensive counterpart. But again, NO donation seems to prevent that from happening. It does not necessarily lower its blood pressure compared with baseline, but it keeps it from rising any more than with a placebo. The population of treated hypertensives that is on RAS blockers has the biggest benefit in terms of the difference in blood pressure increases on a conventional NSAID vs the lack of increase on an NO donating drug like naproxcinod. So, I think that that we are going to get most of the clinical benefit in treated hypertensive patients on antihypertensive drugs like ACE inhibitors, ARBs, diuretics, and beta-blockers, which is actually almost all of them because sooner or later, hypertensive patients will end up on one of those classes of drugs.

Medscape: Presumably they are likely to be on combination therapy with at least 2 or more drugs of different classes; what effects would naproxcinod have on blood pressure in these patients with OA?

Dr. White: Patients with OA on combination antihypertensive treatment will be more complicated to treat because if a patient is on an ACE inhibitor and a calcium channel blocker, which is quite likely nowadays, we cannot be completely sure what the effect of a COX-inhibiting NO donor will be. There will be a heterogeneous impact of the NSAID on the one hand; in the ACE inhibitor situation, it is going to raise the pressure, but with the calcium channel blocker, it is going to have very little effect. So, that might actually attenuate to some extent the rise in blood pressure seen with an NSAID compared with an ACE inhibitor alone. But this has not been a very well-studied population, so we do not know very much about this.

Medscape: So, not much is known about the effects of even traditional NSAIDs in hypertensive patients on combination antihypertensive treatment?

Dr. White: No, we do not know very much about the traditional NSAIDs in the population taking combinations of antihypertensive drugs in general. However, I hope we will soon know a little more about patients taking combination antihypertensive drugs vs those taking an ACE inhibitor or an ARB alone because in the coming months, I will be looking at this in a very large database with naproxcinod that was prespecified in about 3000 patients from 3 large clinical trials. I would hope to present that analysis at US and European meetings and submit it for publication in 2010.

Medscape: Two doses of naproxcinod were evaluated in your study. Could you say something about the differences in effects seen with the 375 and the 750-mg doses?

Dr. White: A 375-mg dose of naproxcinod is equipotent to 250 mg of naproxen but with each molecule of naproxen having 1 NO molecule linked to it. When a patient takes 750 mg of naproxcinod, he or she is taking an equipotent dose of naproxen, which would be 500 mg, with 2 NO molecules linked. So, there is greater efficacy in treating OA with the 750-mg dose, and because there is more NO release for that dose, there is a larger change in blood pressure in the downward direction. So, naproxcinod 750 mg is more likely to not increase blood pressure relative to 375 mg. The 375-mg dose is not statistically different from placebo, but its effect on blood pressure numerically is about 1 mm Hg higher than the 750-mg dose.

Medscape: Five hundred milligrams of naproxen is the dose usually prescribed in OA?

Dr. White: Yes, very few patients take naproxen 250 mg twice a day for arthritis because it is not effective enough. I understand from my colleagues in rheumatology that 250 mg is used in more than 20% of all prescriptions for naproxen.

Medscape: One serious adverse cardiovascular event occurred with the 750-mg dose of naproxcinod in this trial, although this was in a patient who had cardiovascular disease at baseline. Is this consistent with other data?

Dr. White: There has been no increase in cardiovascular events seen in studies with naproxcinod, including the pooled data, although it should be kept in mind that the average duration of these studies was 13 weeks. However, the impact of relatively small increases in SBP on cardiac events in patients with hypertension and vascular disease has been demonstrated in a number of clinical trials. In addition, naproxen (as a molecule) has been studied in large clinical trials, and in contrast to other drugs — of course, we do not know against placebo, but at least against other NSAIDs — it looks to be better in terms of development of cardiovascular disease events. I would not consider those data definitive, but naproxen certainly looks better than ibuprofen and diclofenac, the other 2 widely used NSAIDs. So, most people in the cardiovascular community recognize naproxen as probably being the more cardiovascular friendly of the NSAIDs — not that it cannot increase blood pressure, and it can increase gastrointestinal events — but certainly it may not be prothrombotic because it has a long enough half-life and a long enough antiplatelet effect.

Medscape: Do you think that many physicians are aware of the hypertensive effects of NSAIDs?

Dr. White: I think that prescribing rheumatologists or internists usually know what other medications their patients are taking, but cardiologists know very little about NSAIDs, quite frankly. They may very often not recognize the fact that one of the mechanisms for hypertension is, in fact, the NSAID a patient is taking.

Medscape: So, do you think that cardiologists will eventually become more aware of this effect of NSAIDs? Maybe they need not be aware of it if patients are already taking a drug like naproxcinod, if that isn’t a too flippant way of looking at it?

Dr. White: I think from a public health perspective it is a good way of looking at it. Here is an NSAID that does not destabilize or increase the blood pressure, so it would have to have a greater potential for long-term safety in a population of treated hypertensives. That is a good thing. Whether that will ultimately translate into fewer strokes and development of less heart failure will, I think, require a registry study of some sort when it has become more widely available. You need to look at a population of hundreds or thousands to determine that rather than a clinical trial, which would not be feasible because it would be too expensive and too time consuming.

Medscape: Is there anything else that researchers should be looking at with naproxcinod in the meantime?

Dr. White: We should learn more about the effects of NO in the regional vasculature with this drug. For example, NO itself is vasoprotective; it improves renal blood flow and coronary blood flow. So, one of the questions we might ask is whether it might be safer to use this drug in populations that we might have avoided treating with NSAIDs until now, for instance, patients with mild renal dysfunction (stage II chronic kidney disease) or peripheral vascular disease. There should be a lot of interest in evaluating this further because those are populations who have arthritis, and they have pain, and yet they are currently denied these drugs because of that.

Where does it absorb?

On January 4, 2010, in Fat Solubles, Minerals, Vitamins, Water Solubles, by Andrea

Here’s something that shows where things are absorbed in the digestive tract.  While it’s not overly specific (ie beta-carotene rather than vitamin A in the duodenum) it’s still a good tool.

Please note that the shaded areas are bypassed in an RNY patient.  Thanks go to Vitalady for this graphic.  I like it better than the others that have been floating around since there are no misspellings…

(Want a larger view?  Click on it twice.)

RNY Malabsorption

Vitamins from A-Zinc — Vitamin A

On January 2, 2010, in Fat Solubles, Vitamins, by Andrea

Vitamin A

Vitamin A — What is it?

Vitamin A is a generic term that refers to compounds with the biological activity of retinol.  These compounds include the precursor, or provitamin A carotenoids – principally beta-carotene, alpha-carotene, and beta-cryptoxanthin, which are provided in the diet by green, yellow, or orange vegetables and by some fruits, and preformed vitamin A, namely retinyl esthers (such as retinyl palmitate and retinyl acetate) and retinol itself which are present in foods of animal origin – mainly in organ meats such as liver, other meats, eggs, and dairy products.

Rarely in research, you may come across connotations of vitamins A1 and A2.  Vitamin A1 is retinol as mentioned above, while vitamin A2 is dehydroretinol, an oily yellow alcohol found in some fish that is 40% less active in mammals.  These differentiations are rare in common usage – retinol is typically called as such rather than vitamin A1 and the other vitamin A analogues such as beta-carotene do not have such distinctions as they are not technically vitamin A – just precursors to the vitamin.

What is it good for?


Regulation of gene expression

Immunity – commonly known as the anti-infective vitamin, it is required for normal function of the immune system; plays a central role in development and differentiation of white blood cells

Growth and Development – essential for embryonic development; during fetal development, retinonic acid (RA) functions in limb development and formation of heart, eyes and ears; RA has been found to regulate expression of the gene for growth hormone

Red Blood Cell Production – stem cells are dependant on retinoids for differentiation into red blood cells; vitamin A appears to facilitate mobilization of iron from storage to developing red blood cells for incorporation into hemoglobin

Where do I get it?

As a fat-soluble compound, beta-carotene’s absorption in the GI tract depends on the fat content of the meal with which it is eaten.  It is less easily absorbed than retinol and must be converted to retinol and retinal by the body.  For this reason, a conversion factor has been created to represent this.  The most recent international standard of measure for vitamin A is Retinol Activity Equivalents (RAE) which represent vitamin A activity as retinol.

2 micrograms (mcg) of supplemental beta-carotene can be converted by the body into 1mcg of retinol, giving it an RAE ratio of 2:1.

1 mcg of dietary vitamin A     =     1mcg retinol     =     1:1 RAE ratio
1 mcg supplemental vitamin A     =     1mcg retinol     =     1:1 RAE ratio
2mcg supplemental beta-carotene     =     1mcg retinol     =     2:1 RAE ratio
12mcg dietary beta-carotene     =     1mcg retinol     =     12:1 RAE ratio
24 mcg dietary alpha-carotene     =     1mcg retinol     =     24:1 RAE ratio
24mcg dietary beta-crytoxanthin     =     1mcg retinol     =     24:1 RAE ratio

1 IU = 0.3mcg of retinol

Food Sources

Food Vitamin A (IU)* %DV**
Liver, beef, cooked, 3 ounces 27,185 545
Liver, chicken, cooked, 3 ounces 12,325 245
Milk, fortified skim, 1 cup 500 10
Cheese, cheddar, 1 ounce 284 6
Milk, whole (3.25% fat), 1 cup 249 5
Egg substitute, ¼ cup 226 5
Food Vitamin A (IU)* %DV**
Carrot juice, canned, ½ cup 22,567 450
Carrots, boiled, ½ cup slices 13,418 270
Spinach, frozen, boiled, ½ cup 11,458 230
Kale, frozen, boiled, ½ cup 9,558 190
Carrots, 1 raw (7½ inches) 8,666 175
Vegetable soup, canned, chunky, ready-to-serve, 1 cup 5,820 115
Cantaloupe, 1 cup cubes 5,411 110
Spinach, raw, 1 cup 2,813 55
Apricots with skin, juice pack, ½ cup 2,063 40
Apricot nectar, canned, ½ cup 1,651 35
Papaya, 1 cup cubes 1,532 30
Mango, 1 cup sliced 1,262 25
Oatmeal, instant, fortified, plain, prepared with water, 1 cup 1,252 25
Peas, frozen, boiled, ½ cup 1,050 20
Tomato juice, canned, 6 ounces 819 15
Peaches, canned, juice pack, ½ cup halves or slices 473 10
Peach, 1 medium 319 6
Pepper, sweet, red, raw, 1 ring (3 inches diameter by ¼ inch thick) 313 6

Vitamin Sources

Most multivitamins contain vitamin A as a combination of a retinyl esther and beta-carotene.  There have been some studies showing a higher risk of osteoporsis in older adults taking more than 5,000 IU of retinol per day, which has led many companies to reduce the retinol content in their multivitamin supplements to 750mcg (2,500 IU).  Additionally, there have been some studies showing supplemental beta-carotene as a pro-oxident, meaning it helps grow free radicals in the body rather than reduce them.  However, there has not been a push to reduce or limit beta-carotene from multivitamin supplements as of yet.  In fact, there are some experts that still believe a separate RDA should be set specifically for beta-carotene should be set — one that is set approximately 6x the current RDA for the entire vitamin A RDA is today.

The current RDA for vitamin A is:

(mcg RAE)
(mcg RAE)
(mcg RAE)
(mcg RAE)
(mcg RAE)
1-3 300
(1,000 IU)
4-8 400
(1,320 IU)
9-13 600
(2,000 IU)
14-18 900
(3,000 IU)
(2,310 IU)
(2,500 IU)
(4,000 IU)
19+ 900
(3,000 IU)
(2,310 IU)
(2,565 IU)
(4,300 IU)

Keep in mind that the RDA is the amount needed to avoid deficiency symptoms – not to achieve an optimum level.  Unfortunately, there have been no studies conducted to determine what the optimum vitamin A level is as of now.


Severe zinc deficiency often accompanies vitamin A deficiency.  Zinc is required to make retinol binding protein (RBP), which transports vitamin A, so a zinc deficiency limits the body’s ability to move vitamin A stores from the liver to body tissues where they are needed.  Zinc also helps to protect against potential toxicity of retinol.  Additionally, a zinc deficiency results in decreased activity of the enzyme that releases retinol from it’s storage form, retinyl palmitate, in the liver.  Zinc is also required for the enzyme that converts retinol into retinal.  Despite these well-documented associations between zinc and vitamin A, the health consequences of zinc deficiency on vitamin A nutrition status in humans is still unclear as of now.

Vitamin A deficiency may exacerbate iron deficiency anemia.  Vitamin A supplementation has beneficial effects on iron deficiency anemia and has been show to improve iron nutritional stores status among children and pregnant women.  A combination of supplemental vitamin A and iron seems to reduce anemia more effectively than supplemental iron or supplemental vitamin A alone.  Additionally, there have been some studies in which iron deficient anemia has been helped by supplemental vitamin A, even in the absence of a vitamin A deficiency.

Night blindness is one of the first symptoms of vitamin A deficiency.  Vitamin A deficiency contributes to blindness by making the cornea very dry, which damages it and the retina.

Deficiency in A also diminishes the body’s ability to fight infections.  In vitamin A deficient individuals, the cells lining the lungs lose the ability to remove disease-causing microorganisms.  This may contribute to a larger amount of pneumonia cases seen in vitamin A deficient individuals.

Keep in mind that a subclinical deficiency does not exhibit the signs and symptoms of a deficiency, but still may have the adverse effects of the deficiency.  A mild form of deficiency may increase the risk of developing respitory or diarrheal infections, decrease growth rate and slow bone development in children, and decrease the liklihood to survive a serious illness.

A vitamin A deficiency early in life could have adverse effects on neurologic and behavioral development and function later in life.  Some researchers even believe that schizophrenia may result from vitamin A deficiency.


Hypervitaminosis A refers to a high storage level of vitamin A in the body that can lead to toxic symptoms.  Severe cases may result in liver damage, hemmorrhage, and coma, and may generally only occur in individuals with long-term consumption in excess of 8,000-10,000 mcg/day or 25,000-33,000 IU/day.

Acute toxicity is relatively rare.  Symptoms include nausea, vomiting, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, cerebral edema, bone and joint pain, blurred vision, lack of muscular function, and abnormal liver function.

It is important to note a few things about vitamin A toxicity.  First, the Upper Limit (UL) does not apply to malnourished individuals receiving vitamin A either periodically or through fortification programs as a measure of preventing a vitamin A deficiency.  Additionally, beta-carotene and other carotenoids in foods, even when consumed in high levels have not produced toxicity; therefore, the UL does not include the carotenoids.

0-1 600
(2,000 IU)
1-3 600
(2,000 IU)
4-8 900
(3,000 IU)
9-13 1,700 (5610 IU)
14-18 2,800 (9,240 IU) 2,800 (9,240 IU) 2,800 (9,240 IU) 2,800 (9,240 IU)
19+ 3,000 (10,000 IU) 3,000 (10,000 IU) 3,000 (10,000 IU) 3,000 (10,000 IU)

There are some troubling concerns with the two major forms of vitamin A found in supplements today.

Intakes of retinol not far above the RDA, but well under the UL may reduce bone mineral density and increase the risk of osteoporatic disease and breaks.  It is speculated that perhaps retinol increases the bone resorption response or perhaps interferes with vitamin D in the maintenance of calcium within the bones.  This problem has only been found with the retinol form of vitamin A and not with beta-carotene, which has caused some multivitamin manufacturers to limit the amount of retinol in their product to 750mcg (2,500 IU).  In fact, my bottle of Centrum has a warning about taking too much vitamin A in the form of retinol on the label.

My bottle of Centrum...

The picture for beta-carotene isn’t a bed of roses, either.  Believing beta-carotene to be a powerful anti-oxidant, researchers gave patients supplements of both retinol and beta-carotene supplements to ascertain exactly how good it really was.  The findings of the Beta-Carotene and Retinol Efficacy Trial (CARET) shocked everyone.  Results suggest that high-dose supplementation of vitamin A and beta-carotene should be avoided in people at high risk of lung cancer.  One hypothesis had to do with the high amount of oxidation in the lung tissue – but there were no definative conclusions reached except the spike of lung cancers in high risk individuals who received the extra supplementation.  Despite this higher risk, there has been no push to remove or reduce beta-carotene from multivitamins.  However, a quick Google search will find a few tailor-made vitamins without beta-carotene for smokers, at a premium price of course.


Under conditions of vitamin A adequacy, most mammals, including humans, store more than 90% of their total vitamin A in their liver.

The safety of vitamin A is frequently questioned during pregnancy.  With vitamin A, there is such a thing as “too little” as well as “too much.”  Vitamin A is important in fetal development during cellular and tissue differentiation.  Excess retinol during pregnancy is known to cause birth defects.  There have been no birth defects observed at doses of preformed A from supplements below 3,000mcg (10,000 IU/day), but since foods are commonly supplemented, it is advised to stay under 5,000 IU/day.  It should be noted that vitamin A from beta-carotene is not known to increase the risk of birth defects.

WLS Concerns

Beta-carotene is a poor supplement of vitamin A for those who have had RNY, DS, and VSG.

To begin with, beta-carotene requires an acidic environment to absorb properly.  A study was conducted to measure the absorption of retinol, retinyl palmitate, and beta-carotene in an achlorhydriac, or low gastric acidic environment.  To test the supplements, subjects were given a proton pump inhibitor (PPI) to neutralize gastric acidity over a period of time, then tested with a gastric probe to ensure the pH level.  Once a low gastric level was reached, individuals were given supplements, then serum levels were checked.  Serum concentrations of beta-carotene were significantly greater at a low gastric pH (ie normal) than those at a high gastric pH (ie achlorhydria, or low gastric acid environment).  Serum concentrations of retinol and retinyl palmitate were not significantly different between the low gastric pH and high gastric pH.  Those with a lower acid content will not absorb beta-carotene fully, if at all.  It is also important to note that as we age, even those of normal stomachs will begin to neutralize their gastric acidity.  This was confirmed by a study published in the New England Journal of Medicine in reference to the breakdown of calcium citrate versus carbonate — but the problem of acidity remains the same.

Additionally, beta-carotene is absorbed in the duodenum, which is bypassed in the RNY and DS procedures.  Since this absorption site is bypassed completely, beta-carotene does little-to-no good to patients with either surgery – especially coupled with the lower gastric-acid component present in both surgeries as well.

Those with Adjustable Gastric Bands (AGB’s) should take note as well – beta-carotene absorbs better when eaten with some fat.  Those who have been extreme in removing fat from their diets should note this key interaction.

For post-WLS patients who become deficient in vitamin A, one can find dry-form, or water-miscible forms of the vitamin.  It should be noted that labs should be watched carefully, as always, when supplementing.  There is some evidence that water-miscible forms of retinol vitamins can be more toxic than their oil-based counterparts – but the study conducted was on non-bypassed individuals who had no level of malabsorption.  There are many rules in the nutrition world that simply do not apply to us – but I’m not going to be the one to say which ones are which.  Labs are really your only guide to know where you stand nutritionally and you should follow them accordingly.

Information compiled from:

Handbook of Vitamins, 4th Edition
Linus Pauling Institute
Advanced Health and Life

Office of Dietary Supplements
Gastric acidity influences the blood response to a beta-carotene dose in humans
Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations
NEJM — Calcium absorption and achlorhydria



On December 31, 2009, in Uncategorized, by Andrea

I’m all about the emotions today.

This is a study regarding adolescents undergoing RNY — specifically, it states that those with a lower BMI before surgery will have a lower BMI 1 year after surgery.  Those with a higher BMI prior to surgery (and they were looking at kids — and here’s where the sadness hits — with a BMI between 65 and 95) remain “extremely obese” one year post-op.

This is a limited study — only looking at a limited number of kids (61) and only follow them for one year.  We know that those that are super morbidly obese can continue to lose long past the year mark, so it is not as if the kids in the two groups with the larger BMIs (group 1 had BMIs between 40 and 54.9, group 2 had BMIs between 55 and 64.9, and group 3 had BMIs between 65 and 95) should be written off as “failures” by the medical community.  To do so would be extremely short-sighted and just plain incorrect.

For purposes of reading the study, nadir is defined as “the lowest point.”

From Medscape:

In Adolescents, Baseline BMI Predicts Nadir BMI After Gastric Bypass

NEW YORK (Reuters Health) Dec 29 – In adolescents undergoing gastric bypass surgery, baseline body mass index (BMI) predicts nadir BMI, a new study shows.

But regardless of baseline BMI, gastric bypass improves cardiovascular risk factors and brings BMI down by about 37% in all patients, the authors report in the January Journal of Pediatrics.

“This finding suggests that the timing of surgery for adolescent obesity is an important consideration, as ‘late’ referral for bariatric surgery at higher BMI values may preclude reversal of obesity or extreme obesity within the first post-operative year and may increase the risk of weight regain over the long term,” according to lead author Dr. Thomas H. Inge, of Cincinnati Children’s Hospital Medical Center, Ohio, and colleagues.

“The BMI spectrum for adolescents seeking surgery is broad, with values in the literature ranging from 35 to 95 kg/m squared, with average BMI values much higher than those seen in most adult surgical practices,” Dr. Inge and his co-authors point out.

To determine the effect of preoperative BMI status on outcomes in their younger patients, the investigators followed 61 adolescents for a year after laparoscopic Roux-en-Y gastric bypass. Nearly 70% were female, more than 80% were white, and their average age at surgery was 17.2 years.

In all cases, patients were left with a gastric pouch volume of 30 ml, and the jejunum was divided 15 to 20 cm from the ligament of Treitz.

Patients were stratified into three groups based on preoperative BMI (kg/m squared): Group 1, n = 23: BMI 40.0 to 54.9; Group 2, n = 21: BMI 55.0 to 64.9; and Group 3, n = 17: BMI 65.0 to 95.0.

The mean BMI in the overall cohort, which was 60.2 kg/m squared at baseline, fell by 37.4% at 1 year after surgery (p < 0.0001), with little variation in BMI reduction among the groups (37.2% in Group 1, 36.8% in Group 2, and 37.7% in Group 3).

The rate of change in absolute BMI units did vary significantly by group, however, with one-year nadir BMI (kg/m squared) reaching 31 in Group 1, 38 in Group 2, and 47 in Group 3.

Only 10 patients (17%) achieved a BMI of less than 30 kg/m squared at 1 year. Eight of these were from Group 1.

Systolic and diastolic blood pressures fell significantly after surgery by 8.8% and 13.5%, respectively, regardless of baseline BMI (P < 0.0001 for each). Surgery also reduced total cholesterol (by 16.8%; p = 0.0007), triglycerides (by 37.3%; p < 0.0001), and insulin (by 75.8%; p < 0.0001), no matter the baseline BMI.

Albumin levels did not change at 1 year despite the significant weight loss.

“In this investigation, we found that most adolescents within the highest ranges of baseline BMI…remained extremely obese…despite BMI reductions averaging nearly 40%,” the authors write.

Adolescents “who present at higher weights and BMI values lose more weight than those who present at lower weights but also plateau at a higher weight on average,” they add. “The biological and potentially behavioral reasons for this are unclear.”

J Pediatr 2010;156:103-108.

Bariatric surgery is safe? Who knew?!?

On December 31, 2009, in Uncategorized, by Andrea

Well.  I guess I did since I’m still breathing.

And my readers who had it do, since, well, they’re reading this.  Unless there’s broadband and Farkle and such in the hereafter — and in that case put me down for a comfy chair, free refills of my coffee, with my current 20MBPS FiOS connection when I pass over to the other side, kthanx.

From Medscape:

How Safe is Bariatric Surgery?

Jacob A. Greenberg; Malcolm K. Robinson


The use of bariatric surgery for the treatment of morbid obesity has increased dramatically over the past decade, which has raised concerns about safety, efficacy and cost-effectiveness. A new study by the Longitudinal Assessment of Bariatric Surgery consortium has assessed the safety of these increasingly frequent procedures.


Clinicians are still struggling to find a solution to the world’s growing weight problem. New diets, prescriptions pills and exercise videos become available every week. Unfortunately, however, these weight-loss strategies fail to produce substantial, durable weight reduction for the vast majority of patients with morbid obesity. As a consequence, patients and physicians have turned to a more drastic approach to weight loss: bariatric surgery. Despite the 10-fold rise in bariatric procedures in the US—from 16,200 surgeries in 1994 to 171,000 procedures in 2005—the safety and advisability of such an extremely invasive therapy is often questioned. The Longitudinal Assessment of Bariatric Surgery (LABS) consortium have published the results of their first study, LABS-1, in the New England Journal of Medicine, which indicate that the overall risk of adverse outcomes of bariatric surgical procedures is low and contingent on patient characteristics.[1]

LABS-1 was a prospective, multicenter, observational study, which measured the 30-day morbidity and mortality of 4,776 patients who underwent one of the three most frequent bariatric surgical procedures performed in the US. The investigators found an overall mortality rate of 0.3% and a major complication rate of 4.1%, both of which are comparable to other major abdominal surgical procedures. Furthermore, they noted that patients with obstructive sleep apnea, poor functional status (for example, the inability to walk more than 100 feet), or a history of prior thrombotic events had increased complication rates.

The procedures evaluated in this study included open and laparoscopic Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding. Roux-en-Y gastric bypass involves the creation of a small upper stomach pouch and its attachment to the jejunum, which results in bypass of the rest of the stomach and the duodenum. This bypass leads to weight loss by restriction of food intake, as well as through a variety of poorly understood neurohormonal changes that enhance satiety. During the procedure of laparoscopic gastric banding, a small stomach pouch is generated by placement of an adjustable band around the upper stomach. Weight loss predominantly occurs as a result of restricted food intake, although neurohormonal changes that enhance satiety can also occur with this procedure. The LABS-1 investigators found that the 30-day composite end point of death, major thrombotic complication, reintervention and prolonged hospitalization was 1.0% for laparoscopic adjustable gastric banding, 4.8% for laparoscopic Roux-en-Y gastric bypass surgery, and 7.8% for open Roux-en-Y gastric bypass surgery.

The literature is rife with data on both the short-term and the long-term outcomes of bariatric surgery; however, the LABS-1 study differs from previous studies in a variety of ways. Previous data on clinical outcomes of bariatric surgery cannot be generalized, as they are derived from retrospective studies published by individual surgeons or institutions.[2,3] Inclusion of data from centers that do not practice state-of-the-art care within a comprehensive bariatric program might have added to the perception of increased adverse outcomes after bariatric surgery compared with other abdominal surgical procedures.

By contrast, the LABS-1 researchers analyzed data from patients treated by 33 different surgeons at 10 different clinical sites. Pertinent data points such as the primary endpoint and the presence or absence of specific prior comorbidities, were clearly defined and the data were managed by trained data collectors. Some critics might argue that the LABS-1 data underestimates the true morbidity and mortality of bariatric surgery, as the procedures analyzed were performed by highly skilled surgeons at high-volume centers of excellence which perform more than 100 laparoscopic Roux-en-y gastric bypasses annually. Previous research, however, has revealed that outcomes of both high-volume and low-volume programs are similar between centers of excellence and centers without said designation.[4] The data analyzed in LABS-1, therefore, represents the current state of the art in bariatric surgery and the study provides both surgeons and patients with realistic expectations of postoperative safety of three different bariatric procedures.

What LABS-1 does not address is the efficacy of bariatric surgery. Clinicians must be careful not to recommend a type of bariatric surgery on the basis of safety data alone. For example, although laparoscopic adjustable gastric banding is currently considered the safest bariatric procedure, gastric bypass might be the best option for patients who require substantial and durable weight loss.[5] In addition, bariatric procedures vary not only in the time until weight loss is achieved or the mechanisms that effect weight reduction, but also in their effects on glycemic control. After placement of an adjustable gastric band, improvements in glycemic control are dependent on weight loss, and patients might not see appreciable improvements in blood glucose control for some time.[6] After Roux-en-Y gastric bypass, most patients see an improvement in their glycemic control before any weight loss occurs. Although the mechanisms behind these changes are complex and not entirely clear, an alteration in the release of gut peptides seems to improve glycemic control independent of weight loss.[7] These effects, coupled with safety and other factors, must all be taken into account when a bariatric procedure is recommended for an individual patient. The results of the long-term LABS-2 study, currently in progress, will hopefully shed light on these efficacy issues and treatment recommendations.

In light of the imminent health-care reform proposed by the Obama administration, questions of cost-effectiveness must be addressed for all treatments, and bariatric surgery is no exception. The long-term health benefits after bariatric surgery include improved cardiovascular-related and diabetes-related outcomes. These improvements in comorbidities are associated with a decrease in mortality that ranges from 24-40% compared to patients treated non-surgically, as indicated by two other important studies published in the New England Journal of Medicine.[2,5] Ameliorations in overall health can lead to compensatory decreases in cost, if patients require fewer medications and less frequent hospitalizations than previously. At this point, however, it remains to be determined whether these decreases in cost are equivalent to the upfront cost of surgery and perioperative care. Further research through long-term cost-benefit analyses is needed before these questions can be answered adequately.

The prevalence of obesity and obesity-related disorders is on the rise in young adults, adolescents, and even in the pediatric population. Hence, this problem is unlikely to be resolved in the near future. In a perfect world, primary prevention through diet and exercise would alleviate the need for any surgical intervention. Unfortunately, until we begin to see success with primary prevention or develop equally effective medical management, bariatric surgery will remain an important—and reasonably safe—tool in our armamentarium for the treatment of obesity.

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