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The Vitamin D Newsletter June/July 2006

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Is Vitamin D An Antibiotic?

Antimicrobial Peptides

Dr. Liu and colleagues at UCLA, publishing in this March's edition of the prestigious journal Science, showed that vitamin D might be, in effect, a potent antibiotic. Vitamin D increases the body's production of naturally occurring antibiotics: antimicrobial peptides. Antimicrobial peptides are produced in numerous cells in the human body where they directly and rapidly destroy the cell walls of viruses and bacteria, including tuberculosis. Furthermore, Liu showed that adding vitamin D to African American serum (African Americans have higher rates of TB) dramatically increased production of these naturally occurring antibiotics. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RLToll-like receptor triggering of a vitamin D-mediated human antimicrobial response.Science. 2006 Mar 24;311(5768):1770–3.

Plenty of you have e-mailed me that pharmacological doses (high doses) of vitamin D (1,000–2,000 units/kg per day for three days), taken at the first sign of influenza, effectively reduces the severity of symptoms. However, has anyone ever studied giving 100,000, 200,000, or 300,000 units a day for several days to see if vitamin D induces antimicrobial peptides to help fight other life-threatening infections? (By the way, doses up to 600,000 units as a single dose are routinely used in Europe as "Stoss" therapy to prevent vitamin D deficiency and have repeatedly been shown to be safe for short-term administration.) No, you say, studies of "Stoss" therapy in serious infections have never been studied or reported in reputable journals. Well, maybe such treatment has been studied—and reported in the best journals—by way of the weirdest medical invention ever patented in the USA.

Before I get into that, I want to compliment the English for their sense of fair play. Last month I pointed out that the English discovered activated vitamin D (calcitriol) before the Americans. It's important because I suspect the Nobel Committee will get around to awarding a Prize for vitamin D sometime in the next several decades, especially if vitamin D turns out to function like an antibiotic. Well, I got an email from an English scientist who pointed out that it was an American who first discovered calcitriol—but none of the ones I listed. He pointed out that Dr. Tony Norman was actually the first to discover calcitriol—in a series of experiments starting in 1968. Too often, we only think of Dr. DeLuca's and Dr. Holick's lab when we think of vitamin D, while Dr. Norman's lab at UC Riverside is overlooked. He has authored 486 papers to date about vitamin D beginning in 1963 when he was a student in Dr. DeLuca's lab (by the way, Dr. DeLuca also trained Dr. Holick as he has many vitamin D researchers). When a Nobel Prize is awarded, how will they choose? I don't know—perhaps they should all share it. I do know that I love the English sense of fair play. Haussler MR, Myrtle JF, Norman AW. The association of a metabolite of vitamin D3 with intestinal mucosa chromatin in vivo. J Biol Chem. 1968 Aug 10;243(15):4055–64. Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite. Proc Natl Acad Sci U S A. 1969 Jan;62(1):155–62. Myrtle JF, Haussler MR, Norman AW. Evidence for the biologically active form of cholecalciferol in the intestine. J Biol Chem. 1970 Mar 10;245(5):1190–6.

Before I get into this, be warned that what follows is bizarre. It might not make much sense in the beginning. However, if you'll bear with me, you'll see where I'm going. Remember how Professor Reinhold Vieth has written about the complete absence of studies using pharmacological doses of vitamin D (100,000 to 300,000 units a day for several days) in serious diseases. Are there frequently fatal illnesses, such as peritonitis (generalized infection in the abdominal cavity), septicemia (infection of the blood), pneumonia (the Captain of the Men of Death), etc, in which pharmacological doses of vitamin D may be clinically useful when added to conventional treatment?

We know that vitamin D has profound effects on human immunity. Quite recently, three independent groups have reported that vitamin D triggers the release of these powerful natural antibiotics called antimicrobial peptides. If you gave someone large doses of vitamin D, would their bodies make large amounts of antimicrobial peptides? Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand). 2003 Mar;49(2):277–300. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004 Sep 1;173(5):2909–12. Gombart AF, Borregaard N, Koeffler HP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005 Jul;19(9):1067–77. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006 Mar 24;311(5768):1770–3.

Blood Irradiation

My attempts to answer that question led me to some very strange research. Did you know that when some people get an infection, they go to an alternative health care provider and have their blood irradiated? I'm not kidding. About 300 cc of their blood is removed, irradiated with UVB and UVC, and then returned to their body. Today, alternative health practitioners call it "Photoluminescence Therapy". When results appeared in the best American medical journals, it was called the "Knott Technic"."e way, I'm not talking about "photopheresis", Dr. Richard Edelson's irradiation of some blood components to treat cutaneous T-cell lymphoma, used today in 150 medical centers around the country. I'm talking about Knott's irradiation of whole blood to treat life-threatening infections, used in hospitals around the country in the 1930s, '40s, and early '50s. In the 1940s, at least one prestigious American hospital even had a "Department of Blood Irradiation." Knott EK, Hancock VKIrradiated blood transfusion in treatment of infections.Northwest Med.1934; 33:200–204.

Sunlight and the Knott Technic

It began in the 1920s. Seattle scientist Emmett Knott knew that sunlight and UV light was being used to successfully treat infectious diseases. The 1903 Nobel Prize in Medicine was awarded to Dr. Niels Finsen for his discovery that artificial UV radiation of the skin cured tuberculosis of the skin. If skin infections could be treated by irradiating the skin, Dr. Knott thought blood infections might be cured by irradiating the blood! Knott built an apparatus that would remove about 5% of the blood volume, anti-coagulate it, expose it to UVB and UVC radiation, and then pump the irradiated blood back into the body. Depending on the patient's weight, about 300 cc of blood is removed and circulated in thin glass tubing while being irradiated by ultraviolet light. The blood is then returned to the patient and the process is repeated a number of times, depending on the seriousness of the condition being treated. Sound crazy? Knott EKDevelopment of ultraviolet blood irradiation.American Journal of Surgery 1948; 76(2):165–171.

However, a couple of things caught my eye. First, the "Knott Technic" didn't really work on test animals until Knott began using ultra-thin quartz glass tubing. (Regular glass blocks UV radiation but quartz glass does not.) Second, Knott added a series of baffles to ensure all the blood came in direct contact with the interior surface of the quartz tube. (The heme molecule would absorb UV light if the blood was not agitated). Third, according to a book by Dr. William Douglas, the procedure rapidly cured both rickets and tetany. (Of course, a common cause of rickets and tetany is vitamin D deficiency.) Fourth, according to Douglas, Knott's early animal studies showed this procedure could maintain serum calcium in animals whose parathyroid glands were surgically removed. (We used to use pharmacological doses of vitamin D in humans who have had their parathyroid glands removed in order to maintain serum calcium.) Finally, when Knott experimented on dogs, he found that irradiating 100% of their blood volume (10 sessions with 10% of the blood removed and irradiated each time) cured experimentally induced infections, but all the dogs died 5–7 days later with cardiac arrhythmia, low blood pressure, respiratory depression, loss of reflexes, loss of muscle tone, followed by coma and death (this is the clinical course in fatal hypercalcemia—the cause of death in severe vitamin D toxicity). If the "Knott Technic" cured rickets and tetany, maintained serum calcium in parathyroidectomized animals, and caused hypercalcemia with over-irradiation, it must have delivered pharmacological amounts of vitamin D into the circulation. See where I'm heading? Douglass, William Campbell. Into the Light, Tomorrow's Medicine Today. 2003; Rhino Entertainment.

Pharmacological Doses of Vitamin D

Some of you may know that many substances develop vitamin D activity when irradiated. Milk used to be irradiated to fortify it with vitamin D, now the vitamin D is just added. The famous Harry Steenbock of the University of Wisconsin, found many things develop vitamin D activity when irradiated, including olive oil, cereal products, orange juice, and egg yolk. (He patented the procedure of irradiating things, including ergosterol to make ergocalciferol or vitamin D2, and gave the proceeds—which were enormous—to the University of Wisconsin.) However, I couldn't locate a study that sought to discover if human blood makes vitamin D when it is irradiated. To find out, I looked in what must be the first vitamin D textbook ever published in English (Blunt and Cowan, 1930). I learned two interesting things. One: wavelengths between 250–280 nm (UVC) were more effective in curing rachitic rats than was the UVB range (pp. 74). Two: recrystalized red blood cells made lots of vitamin D when irradiated (pp. 135). However, to my knowledge, no one has ever directly tested the theory that irradiating blood delivers vitamin D to the circulation. The entire idea is so weird, who would ever do that? Blunt K, Cowan R. Ultraviolet Light and Vitamin D Nutrition. 1930; University of Chicago Press, Chicago Illinois.

About now, you may be wondering if I've lost my mind. Why would anyone care if irradiating blood triggers vitamin D production when vitamin D supplements will do the trick? The reason it's important is that hundreds of studies have been published, many in the best journals, describing clear-cut antibiotic-like actions following blood irradiation. Remember when I said Dr. Reinhold Vieth has complained that pharmacological doses of vitamin D have never been tested in clinical trials. Well, maybe they have, and on lots of frequently fatal infections—but no one knew blood irradiation was actually delivering hundreds of thousands of units of vitamin D to desperately ill patients. That is, no one knew it was pharmacological doses of vitamin D actually being tested.

I'll concentrate on just a few of the published studies. In 1942, Professor George Miley at Hahnemann Hospital in Philadelphia reported using the "Knott Technic" on 103 patients with life-threatening infections. Remember, all they had at the time was sulfa drugs so most of these patients usually died. He classified the patients as early, moderately advanced, and moribund (close to death). The diagnosis included sepsis, septic abortion, peritonitis, pneumonia, appendicle abscess, pelvic abscess, wound infection, septicemia, and similar conditions. He treated all of them with ultraviolet blood irradiation and reported that all 20 of the early patients, 46 of 47 of the moderately advanced patients, and 17 of 36 moribund patients fully recovered—such results were unheard of at the time. Miley GP. The Knott Technic of Ultraviolet Blood Irradiation in Acute Pyogenic Infections. New York State Journal of Medicine. 1942;42(1):38–46.

Miley and Christensen went on to report what might be the largest case series ever published by The American Journal of Surgery. They reported treating 445 patients with a variety of life-threatening infections over six years. All of the early, 98% of moderately advanced, and 45% of moribund patients recovered after treatment with Knott hemo-irradiation—results that would rival those obtained today. The only side effect noted was a curious flushing of the skin that occurred in most treated patients and lasted up to 30 days. They also noted that treatment of staph aureus septicemia with sulfa drugs reduced effectiveness of hemo-irradiation. Miley GP, Christensen JA. Ultraviolet blood irradiation therapy: further studies in acute infections. American Journal of Surgery 1947; 73:486–493.

Miley and Rebbeck also reported on 40 patients with generalized peritonitis (a usually fatal infection of the abdominal cavity). All 23 moderately advanced patients and 9 of 17 moribund patients recovered after blood irradiation. Miley GP, Rebbeck EW. The Knott Technic of Ultraviolet Blood Irradiation as a Control of Infection in Peritonitis. Review of Gastroenterology. 1943;10:1.

In 1948, Miley and Christensen reported the technique had near miraculous results on viral pneumonia, including influenza. Within a few days of one treatment, fever disappeared and symptoms abated. For those of you who haven't tried it, 1,000–2,000 units/kg per day of vitamin D, early in the course of influenza or influenza-like illnesses, has very similar effects. Miley GP, Christensen JA. Ultraviolet blood irradiation therapy in acute virus-like infections. Review of Gastroenterology 1948; 15; 271–277.

Dr. Rebbeck, from the "Department of Blood Irradiation", at Shadyside Hospital in Pittsburgh went on to independently confirm Miley's reports of successful treatments in acute peritonitis, puerperal (childbirth) sepsis, post-abortion sepsis—even 6 of 8 patients survived E-coli septicemia, a routinely lethal infection. Of interest, the two patients who died from E-coli septicemia had autopsies: one had a sterile bloodstream and the other showed the E-coli was gone but staph aureus was present. Rebbeck EW. Ultraviolet Irradiation of Auto-transfused Blood in the Treatment of Escherichia coli Septicemia. Archives of Physical Therapy. 1943;24:158–67. Rebbeck EW. Ultraviolet Irradiation of Auto-transfused Blood in the Treatment of Acute Peritonitis, General. The Hahnemannian Monthly, April, 1941. Rebbeck EW. Ultraviolet Irradiation of Auto-transfused Blood in the Treatment of Puerperal Sepsis. American Journal of Surgery. 1941;54:691. Rebbeck EW. Ultraviolet Irradiation of Auto-transfused Blood in the Treatment of Postabortional Sepsis. American Journal of Surgery. 1942;55:476–86. Rebbeck EW. Further studies with ultraviolet blood irradiation therapy (Knott technic) in septic abortions. Am J Surg. 1951 Dec;82(6):736–40. Rebbeck EW. Use of ultraviolet blood irradiation (Knott technic) in biliary tract surgery. Am J Surg. 1950 Jul;80(1):108–12.

In the late '40s and '50s, articles in the American Journal of Surgery reported that the technique was useful in a variety of ailments. Olney reported that viral hepatitis responded. Miley GP, Dunning PM. Ultraviolet blood irradiation therapy (Knott technic) in thrombophlebitis. Am J Surg. 1949 Dec;78(6):892. Neff FE, Anderson CM. Use of ultraviolet blood irradiation in the treatment of bursitis and tendinitis calcarea. Am J Surg. 1951 Jun;81(6):622–8. Schultz IT. Use of the Knott technic of blood irradiation therapy in cases of threatened and inevitable abortion. Am J Surg. 1954 Sep;88(3):421–4. Olney RC. Treatment of viral hepatitis with the Knott technic of blood irradiation. Am J Surg. 1955 Sep;90(3):402–9.

Vitamin D As Broad-Spectrum Antibiotic

Let me say again, I'm not advocating blood irradiation. I'm only interested in the research because it may mean pharmacological doses of vitamin D acts as a broad-spectrum antibiotic by ramping up production of the body's own antimicrobial peptides. If the "Knott Technic" creates pharmacological amounts of vitamin D, then maybe that's its mechanism of action. If so, thousands of desperately ill patients with life-threatening infections in ICUs all over the world might be saved if short pharmacological courses of vitamin D were added to standard treatment with conventional antibiotics.

So what ended research on ultraviolet blood irradiation in the United States? First, more antibiotics became available, with much improved results (that was before many bacteria developed resistance to antibiotics). Second, Knott's proposed mechanism of action—directly killing bacteria in the irradiated blood or sterilization of the blood—was proven wrong. When you think about Knott's reasoning, it never made any sense. Only a small portion of the blood volume is irradiated so bacteria in the un-irradiated blood would be free to reproduce inside the body. No, direct sterilization of the blood was never a reasonable mechanism of action. However, without a viable mechanism of action, the procedure was doomed, at least in America. Blundell GP, Ere LA, Jones HW, Hoban RT. Observations on the Effect of Ultra Violet Irradiation (Knott Technic) on Bacteria and Their Toxins Suspended in Human Blood and Appropriate Diluents. J Bacteriol. 1944 Jan;47(1):85–96. Archives of Physical Medicine 1948;19:358–65.

Another critical study was funded in part by the American Medical Association and appeared in its journal. Again, they found that blood irradiation didn't sterilize the blood. They also administered Knott hemo-irradiation to 68 patients with a wide range of diseases and found it safe, but ineffective, although none of the treated patients died. Although the JAMA article was its death knell in the USA, the authors concluded with the sentence, "A longer and more extensive program of study is warranted before in vivo ultraviolet irradiation of blood can be finally either accepted or rejected." Schwartz SO, Kaplan SR, Stengle J, Stevenson FL, Vincenti M. Ultraviolet irradiation of blood in man; studies of sixty-eight patients. J Am Med Assoc. 1952 Jul 26;149(13):1180–3.

After its death in the USA the Germans revived it, followed by the Russians. One of the German studies was exceptionally well controlled, finding ultraviolet blood irradiation compared favorably to infrared and sham ultraviolet blood irradiation as well as whole-body skin irradiation—which will produce physiological amounts of vitamin D. Therefore, if it works by a vitamin D mechanism, it is producing pharmacological amounts of vitamin D. To this day, it remains a treatment modality in Russia where it is often added to standard treatment of severe infections. Russian scientists have reported it helps improve standard treatment of numerous infections including tuberculosis, just what the UCLA group recently suggested about vitamin D. At the bottom of this page is a list of the few Russian studies with abstracts; hundreds more have been published without abstracts, so many my wife refuses to read anymore of them to me.

Vitamin D—Safe and Effective

Perhaps I've lost my mind and need to see one of my psychiatric colleagues. Another possibility is that pharmacological doses of vitamin D (via hemo-irradiation) have been tested in life-threatening infections and found to be safe and remarkably effective, first in the USA, then in Germany and finally in Russia. We will never know until the Food and Nutrition Board starts living in the 21st Century. Their Upper Limit of 2,000 units a day effectively prevents vitamin D researchers from testing pharmacological doses of vitamin D, while drug manufacturers test pharmacological doses of vitamin D analogs all the time.

What we really need are some intrepid volunteers, some readers interested in donating their body to science. The study would be simple. Just contact an Alternative Health Care Provider that practices Photoluminescence Therapy and see if they use the German-made Euphoton EN 600 NT hemo-irradiator. If so, arrange for a course of ultraviolet blood irradiation. But have your 25(OH)D levels checked the day before you begin treatment and again about a week after the course of treatment is finished. Then we will know if Dr. Knott was—and Dr. Cannell is—out of their minds. Actually, if I had a serious infection, I wouldn't hesitate to take 200,000 units of vitamin D a day for 3 days, but I wouldn't have my blood irradiated on a bet.

Russian Studies with Abstracts

Hemosorption and ultraviolet irradiation of the blood in the treatment of acute septicemia.
Kariakin AM, Kucher VV, Susla PA, Kofman BL. Vestn Khir Im I I Grek. 1983 Apr;130(4):109–12.
Ultraviolet irradiation of the blood.
Petukhov VA, Perekokin NN, Gorelenko AG, Koloda AS. Vestn Khir Im I I Grek. 1987 Jan;138(1):66–7.
Ultraviolet irradiation of the blood in the complex treatment of suppurative-inflammatory diseases.
Butylin LP, Volobuev NN, Tikhonov KS, Sinani MB. Klin Khir. 1989;(1):27–9.
Serial infrared and ultraviolet whole body irradiation and placebo and ultraviolet irradiation of autologous venous blood in peripheral arterial occlusive disease. 1. Treadmill ergometry, metabolic, rheologic and hemodynamic parameters.
Scherf HP, Baumler H, Meffert H, Turowski A, Schmidt HH, et al. Z Gesamte Inn Med. 1989 Apr 1;44(7):201–7.
Hemosorption and ultraviolet irradiation of the blood in the complex treatment of peritonitis.
Riabtsev VG, Gorbovitskii EB, Myslovatyi BS, Masiukevich AV, Ronami VG. Vestn Khir Im I I Grek. 1989 Apr;142(4):84–7.
The ultraviolet irradiation of autologous blood and endolymphatic antibiotic therapy in treating pneumonia in patients with craniocerebral trauma] Zh Vopr Neirokhir Im N N Burdenko.
Kibirev AB, Kochulanov AN, Strelets BM, Grebenkina LA. 1990 May–Jun;(3):11–4.
Hemosorption and ultraviolet irradiation of blood in the complex treatment of suppurative and septic diseases in children.
Zalesnyi SA, Khankoev IM, Grechishkin AI, Krasnopol'skii IS, Sitnik SD. Vestn Khir Im I I Grek. 1990 Jun;144(6):79–81.
Ultraviolet irradiation of blood in surgery.
Piksin IN, Atiasov NI, Kiseleva RE, Romanov MD, Dorofeeva LS, et al. Khirurgiia (Mosk). 1990 Nov;(11):100–4.
Ultraviolet irradiation of the blood in the treatment of pyo-inflammatory complications in patients with terminal renal failure.Vestn Akad Med Nauk SSSR. 1991;(3):15–20.
Paleev NR, Cherniakov VL, Vetchinnikova ON. Vestn Akad Med Nauk SSSR. 1991;(3):15–20.
Ultraviolet irradiation of blood in patients with pulmonary tuberculosis.
Sukhodub LF, Tertyshnyi NG, Duzhyi ID, Pliskachev VM. Probl Tuberk. 1991;(7):65–8.
Autotransfusion of ultraviolet-irradiated blood in destructive pneumonia of young children.
Kalinkin VN, Mezentsev GD, Kashuba EA, Konovalova LA, Shatilovich LN. Khirurgiia (Mosk). 1991 Aug;(8):14–20.
Extracorporeal methods for detoxification in the combined treatment of gunshot peritonitis.
Sychev MD, Manucharov NK, Tomaev KB, Litvin AA. Voen Med Zh. 1992 Jan;(1):44–5.
The efficacy of the ultraviolet irradiation of the blood in the combined treatment of erysipelatous inflammation.
Potashov LV, Reshetov AV, Tone RV, Vismont VG. Vestn Khir Im I I Grek. 1992 Jul–Aug;149(7–8):84–8.
Effectiveness of chemotherapy in combination with electrophoresis and ultraviolet irradiation of blood in newly diagnosed patients with destructive pulmonary tuberculosis.
Zhadnov VZ, Mishanov RF, Kuznetsov AA, Shprykov AS, Ryzhakova TM. Probl Tuberk. 1995;(3):20–2.
Effectiveness of extracorporeal ultraviolet blood irradiation in treatment of chronic obstructive bronchitis in pulmonary tuberculosis.
Kuvshinchikova VN, Shmelev EI, Mishin VIu. Probl Tuberk. 1998;(3):48–50.
Extracorporeal ultraviolet irradiation of blood in combined treatment of patients with peritonitis.
Kravets VP, Kravets AV. Klin Khir. 2002 Jul;(7):19–20.

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