Bookmark and Share  

MELATONIN

The NIH study spurred other scientists to look more closely at melatonin as an anticancer agent. Several researchers undertook to investigate whether melatonin could impede the growth of breast cancer tumors. In one study, researchers found that blind women who typically have higher levels of melatonin than normal, have a lower risk of developing breast cancer. Another study, performed by Steven M. Hill and David E. Blask at the University of Arizona, tested the effect of melatonin on a tissue culture of an estrogen-sensitive human breast cell tumor identified as MCF-7. They found that melatonin did indeed inhibit the growth of these cells by up to 78 percent. Other test tube studies have confirmed that melatonin can inhibit the growth of other kinds of tumor cells as well.

Melatonin not only inhibits the growth of tumor cells in test tubes. It also has been shown to block the growth of breast tumors in laboratory animals, which is significant because cancer grows and spreads in animals as it does in humans. In order to assess the effectiveness of a particular substance against cancer, one commonly used technique is to first administer a known carcinogen to an animal, and then administer the potential antidote. In several studies, researchers administered carcinogens known to produce mammary tumors in mice, rats, and hamsters. Then they administered melatonin. In most cases, melatonin either prevented the onset of cancer or significantly slowed down its growth.

Sleeping with a light on diminish melatonin levels?
http://tinyurl.com/l6ose5

As we mentioned earlier, prostate cancer is one of the leading causes of death among men over the age of fifty. The deaths due to prostate cancer of several prominent men in recent years, including Warner Communications CEO Steven Ross, and actors Telly Savalas and Bill Bixby, have called the attention to this often lethal disease. As in the case of breast cancer, the growth of prostate tumors may be accelerated by male hormone testosterone. Although there is no known cure for prostate cancer, it appears as if melatonin can slow down the progression of this disease. In a study conducted at the University of Texas Medical School, researchers found that melatonin could reduce by 50 percent rate of prostate tumors in rats, If melatonin works as well on human prostatic cancers, it could make a significant difference in the progression of this disease.

Melatonin may thwart the growth of hormone-sensitive tumors by normalizing the production of sex hormones; that, however, is not all it does. Melatonin attacks cancer cells in many different ways. One of the most potent ways to combat cancer is to black the process of cell division, thus nipping the troublesome cells in the bud. When a cell divides, it must undergo a complex sequence of events, one of which is the formation of what scientist’s call a spindle poisons. They prevent cells from forming a spindle and thereby prevent them from dividing. These drugs include Taxol, originally derived from the bark of the Pacific yew tree, which is used to treat lymphomas. Melatonin also interferes with spindle formation, thereby potentially inhibiting cell division. Thus it may prove to be another important weapon in our chemotherapy arsenal, but one that does not cause the unpleasant side effects that other chemotherapy drugs do.

There’s yet another intriguing way in which melatonin may be useful in the treatment of cancer. Studies have shown that melatonin can increase the number of estrogen receptors on human breast cancer cells. Receptors are cells that carry messages from hormones to cells; the hormone gives instructions to the cells via the receptors. Paradoxically, an increase in the number of estrogen receptors on breast cancer cells should promote the growth of breast tumors, and yet, for reasons unknown, in melatonin’s case it doesn’t. The capacity to increase estrogen receptors, however, can have some genuine therapeutic value. Tamoxifen, one of the most effective and commonly used drugs in the treatment of breast cancer, works by binding with estrogen receptors and inhibiting their effect on cell growth. About 60 percent of all breast tumors are estrogen-sensitive, and many women with these tumors do well on tamoxifen. However, over time, tamoxifen’s effectiveness can wear off, and other treatment options are limited. We propose that it may be possible to give melatonin to women who do not have estrogen-sensitive cancers to induce the growth of estrogen receptors so that these women can also respond to tamoxifen. Given the epidemic of breast cancer in the West, these ideas warrant further investigation.

Melatonin may also prevent the initiation of cancer by inhibiting the action of the initiators, the substances that inflict the initial cell damage that causes cells to mutate and become malignant. At the Third Strombli Conference on Aging and Cancer, noted pineal expert Dr. Russell Reiter reported that melatonin is a highly7 potent free-radical scavenger. Free radicals are unstable forms of oxygen molecules that can combine at random with components of healthy cells and interfere with normal growth. As we mentioned earlier, healthy cells divide in a methodical fashion. Healthy cells are programmed to know precisely to stop dividing. When the nucleus of a cell is injured, however, it loses its memory and begins to behave erratically. Cancer occurs when cells begin to grow out of control in a random fashion. The cellular damage inflicted by these free radicals can damage the cell nucleus, and thus promote many different forms of cancer. Free-radical scavengers are molecules that gobble up free radicals before they do any harm. Dr. Reiter’s observations and studies have revealed that melatonin appears to have an affinity for the nucleus of the cell where the DNA is stored. In other words, when melatonin passes through the cell, it finds its way to this important location. This has led some researchers, most notably Dr. Reiter, to speculate that melatonin’s specific task may be to protect DNA from the free –radical damage that can cause cancer. Although we find Dr. Reiter’s theory to be interesting, we feel that is probably overstates this particular aspect of melatonin. Some of the most innovative work on melatonin and cancer is being done outside the United States, in places such as San Gerardo hospital in Monza, Italy. There, our friend Dr. Paoli Lissoni, one of the most creative researchers in the field of cancer, has conducted some particularly promising studies involving melatonin. We think you should know about them. Lissoni’s group has used melatonin alone as a cancer treatment, and in combination with other forms of chemotherapy. In both cases, the results have been very encouraging. In one study, Lissoni gave only melatonin to patients with a variety of cancers that has already spread from other parts of the body to form inoperable brain tumors. These patients had little hope of recovery. However, those receiving melatonin along with supportive care fared significantly better than those just receiving supportive care. Specifically, those patients on melatonin lived longer and showed slower tumor progression that the untreated patients. In other studies, Lissoni and his co-workers have combined melatonin with interleukin-2 (IL-2), a natural disease-fighting compound produced by the immune system. In the 1980s, IL-2 was touted as a potential breakthrough in the treatment of certain types of cancers, and it is approved by the FDA for treatment of renal cancer in the United States. However, the side effects of IL-2 are nothing short of terrible. This Drug, which is quite toxic, can produce high fevers, chills water retention, swelling and other problems. IL-2 may do a good job of wiping out cancer cells, but few patients can tolerate its side effects. Lissoni, however, devised an ingenious approach. HE used a lower and less toxic dose of IL-2 and combined it with melatonin. He administered Il-2/melatonin to patients with a wide variety of cancers, including kidney, stomach and liver cancer and even melanoma. Once again, these were patients who had little hope of long term survival. After the IL-2/melatonin program, many of these patients showed marked improvement, their tumors regressed, their appetites returned, and they seemed to be generally doing better. A handful of patients even appeared to experience partial remission. Moreover, the melatonin was able to virtually eliminate the severe side effects of IL-2, making the immunotherapy treatment more tolerable. Follow-up studies have showed that although the IL-2/melatonin regimen did not result in any miracle cures, it did appear to extend the lives of many patients, and perhaps, more importantly, to improve the quality of their lives.

One of Lissoni’s most interesting studies established a link between melatonin levels and patient response to cancer therapy. In his study of forty-two chemotherapy patients, Lissoni tested their melatonin levels before chemotherapy and also four weeks after the end of their treatment . Lissoni found a direct correlation between patient improvement and a rise in melatonin levels. Out of the sixteen patents who had shown a rise in melatonin levels, tumors shrank in twelve and did not progress in the rest. Out of the twenty-six patients who had shown a rise in melatonin levels, tumors shrank in twelve and did not progress in the rest. Out of the twenty-six patients who had shown a continuous fall in melatonin, only two showed any improvement. Melatonin levels may indeed be a marker that can help doctors predict the prognosis of their cancer patients.

In addition to Lissoni’s work, there are other examples of how melatonin may enhance the effect of traditional chemotherapy, while sparing patients some of its horrendous side effects. Under the direction of Dr. Bruno Neri, researchers at the University of Florence in Italy tested the effect of melatonin combined with another anticancer drug, human lymphoblastoid intereron (HLI). HLI is a natural protein that can kill viruses and cancer cells, but also causes miserable side effects, including fever, chills, and muscle aches. In Neri’s study, twenty-one patients with progressive renal cell carcinoma – a particularly insidious form of kidney cancer that can spread quickly, and is often unresponsive to chemotherapy – were given HLI and melatonin. In past studies, HLI had been shown to be only mildly effective against this cancer. When combined with melatonin, however, the HLI appeared to work better, and the side effects were lessened. In fact, in three patients the tumors disappeared completely, although only follow-up studies will show if this is a true and lasting cure. Four patients showed partial remissions. As of this writing, Neri is conducting a larger study to determine if HLI and melatonin will prove to be an effective treatment for this potentially deadly form of cancer.

The studies that we’ve just described show that melatonin, when combined with traditional chemotherapy, not only can improve the performance of anticancer drugs, but can also lessen the severity of side effects, and actually makes the patients feel better. This makes perfect sense given what we know about melatonin. Our studies have shown that melatonin works in combination with the natural opiates or painkillers produced in our bodies. When we’re sick and under a great deal of stress, or in pain due to an injury, our bodies produce chemical compounds called endorphins, which help relieve pain. The immune system is instrumental in the release of certain endorphins, and in fact, these hormones may also play a role in healing. Such studies suggest that melatonin may work in tandem with these natural opiates, and may enhance their action. Perhaps this is why the cancer patients felt better when taking melatonin. In fact, it’s also possible that when melatonin is combined with other narcotics or tranquilizers, there might be a synergistic effect, that is, the two combined may be stronger than the effect of any one alone. In this respect, melatonin may be beneficial for cancer patients, or any patients suffering pain, since it decreases the need for narcotics and minimizes negative side effects.

One o the problems with many of the most effective forms of chemotherapy is that the cure is almost as bad as the disease itself in terms of the harm it can inflict on the body. By necessity, chemotherapy drugs must be strong enough to knock out cancer cells, and very often they also destroy healthy cells in the process. For example, some anticancer drugs can destroy the blood-forming cells in the bone marrow, which can result in severe anemia, and can inflict untold damage on the immune system. We investigated whether melatonin might actually protect the bone marrow from this kind of damage. With Vladimir Lesnikov in St. Petersburg, we tested the toxicity of several chemotherapy agents on the bone marrow cells suffered far less damage. This is yet another aspect of melatonin that is worthy of further investigation.

Our findings are consistent with those of other researchers who have shown that chemotherapy is often more effective and less toxic when given at night, presumably because melatonin levels are at their peak. In fact, many chemotherapy patients are now given intravenous pumps with timers that automatically pulse anticancer drugs into their bodies while they sleep. Thanks to this innovation, many of these patients are now able to get their chemotherapy treatments in the comfort of their own home, which is a much more natural and relaxing setting than a hospital. This also means that the treatment does not disrupt normal sleep patterns – and nighttime melatonin production which can be disturbed by the bright lights and noise of a busy hospital.

Melatonin as biological response modifier in cancer patients

Neri B, de Leonardis V, Gemelli MT, di Loro F, Mottola A, Ponchietti R, Raugei A, Cini G

Oncological Day Hospital, Department of Internal Medicine, University of Florence, Italy

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis.
At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes.
The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months).
We obtained blood samples just before the start of MLT administration and after 30 days of therapy.
Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN).
We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05).
After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment.
Nineteen patients (61%) showed disease progression.
The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels.
These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types.
Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

PMID: 9615811 [PubMed - indexed for MEDLINE]

Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9615811&dopt=Abstract

Side Effects, Toxicity and Interactions:
Melatonin may increase the frequency of seizures in certain types of seizure disorders.

Large doses of melatonin may interfere with ovarian function. Definite interference with sexual development has been demonstrated in animals given supplements of melatonin.

Avoid driving or operating machinery for several hours after taking melatonin. The natural secretion of melatonin is possibly affected by stimulants, including coffee, late night exercise, late night snacks and light in the bedroom.

There are no known significant food or drug interactions.

Melatonin pdf

Sources

Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53:43-46.

Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23:15-19.

. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5:126-129.

Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.

Neri B, de Leornardis V, Gemelli MT. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.

Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-released melatonin. Lancet. 1995;346:541-544.

Haimov I, et al. Sleep disorders and melatonin thythms in elderly people. BMJ. 1994;309:167.

Lissoni P, Tancini G, Barni S. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5:126-129.

Waterhouse J, et al. Jet lag. Lancet. 1997;350:1611-1616.

References[ - ]
1. Jan JE, Hamilton D, Seward N, et al. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res. 2000;29:34-39.

2. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth. 1999;82:875-880.

3. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg. 2000;91:473-479.

4. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53:43-46.

5. Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23:15-19.

6. Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.

7. Fauteck JD, Schmidt H, Lerchl A, et al. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept. 1999;8:105-110.

8. Rasmussen DD, Boldt BM, Wilkinson CW, et al. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology. 1999;140:1009-1012.

9. Cagnacci A. Melatonin in relation to physiology in adult humans. J Pineal Res. 1996;21:200-213.

10. Nelson RJ, Demas GE. Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res Bull. 1997;44:423-430.

11. Oaknin-Bendahan S, Anis Y, Nir I, et al. Effects of long-term administration of melatonin and a putative antagonist on the aging rat. Neuroreport. 1995;6:785-788.

12. Suhner A, Schlagenhauf P, Johnson R, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int. 1998;15:655-666.

13. Arendt J, Skene DJ, Middleton B, et al. Efficacy of melatonin in jet lag, shift work and blindness. J Biol Rhythms. 1997;12:604-617.

14. Garfinkel D, Laudon M, Nof D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541-544.

15. Chase JE, Gidal BE. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother. 1997;31:1218-1226.

16. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18:598-603.

17. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep. 1998;21:52-68.

18. Garfinkel D, Laudon M, Zisapel N. Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs. Arch Gerontol Geriatr. 1997;24:223-231.

19. Folkard S, Arendt J, Clark M. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int. 1993;10:315-320.

20. Dawson D, Encel N, Lushington K. Improving adaptation to simulated night shift: timed exposure to bright light versus daytime melatonin administration. Sleep. 1995;18:11-21.

21. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001;86:4727-4730.

22. Smits MG, Nagtegaal EE, van der Heijden J, et al. Melatonin for chronic sleep onset insomnia in children: a randomized placebo-controlled trial. J Child Neurol. 2001;16:86-92.

23. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol. 2001;16:581-584.

24. Yang CM, Spielman AJ, D'Ambrosio P, et al. A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern. Sleep. 2001;24:272-281.

25. Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int. 2000;17:71-76.

26. Garfinkel D, Wainstein J, Halabe A, et al. Beneficial effect of controlled release melatonin on sleep quality and hemoglobin A1C in type 2 diabetic patients. Presented at: World Congress of Gerontology; July 1-6, 2001; Vancouver, Canada.

27. Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry. 2000;61:373-377.

28. Sack RL, Brandes RW, Kendall AR, et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med. 2000;343:1070-1077.

29. Kayumov L, Brown G, Jindal R, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63:40-48.

30. Garfinkel D, Zisapel N, Wainstein J, et al. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med. 1999;159:2456-2460.

31. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. Br J Anaesth. 1999;82:875-880.

32. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg. 2000;91:473-479.

33. Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology. 1996;53:43-46.

34. Lissoni P, Paolorossi F, Ardizzoia A, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res. 1997;23:15-19.

35. Lissoni P, Tancini G, Barni S, et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer. 1997;5:126-129.

36. Neri B, de Leonardis V, Gemelli MT, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res. 1998;18:1329-1332.

37. de Lourdes M, Seabra V, Bignotto M, et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193-200.

38. Graw P, Werth E, Krauchi K, et al. Early morning melatonin administration impairs psychomotor vigilance. Behav Brain Res. 2001;121:167-172.

39. Fraschini F, Cesarani A, Alpini D, et al. Melatonin influences human balance. Biol Signals Recept. 1999;8:111-119.

40. Cagnacci A, Arangino S, Renzi A, et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxford). 2001;54:339-346.

41. Garfinkel D, Wainstein J, Halabe A, et al. Beneficial effect of controlled release melatonin on sleep quality and hemoglobin A1C in type 2 diabetic patients. Presented at: World Congress of Gerontology; July 1-6, 2001; Vancouver, Canada.

42. Sharkey KM, Fogg LF, Eastman CI. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001;10:181-192.

43. James M, Tremea MO, Jones JS, et al. Can melatonin improve adaptation to night shift? Am J Emerg Med. 1998;16:367-370.

44. Paul MA, Brown G, Buguet A, et al. Melatonin and zopiclone as pharmacologic aids to facilitate crew rest. Aviat Space Environ Med. 2001;72:974-984.

45. Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry. 2001;58:1049-1052.

46. Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cochrane Database Syst Rev. 2001;CD001520.

47. Chazot G, Claustrat B, Brun J, et al. A chronobiological study of melatonin, cortisol, growth hormone, and prolactin secretion in cluster headache. Cephalalgia. 1984;4:213-220.

48. Leone M, Lucini V, D’Amico D, et al. Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia. 1998;18:664-667.

49. Leone M, Lucini V, D’Amico D, et al. Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache. Cephalalgia. 1995;15:224-229.

50. Waldenlind E, Gustafsson SA, Ekbom KA, Wetterberg L. Circadian secretion of cortisol and melatonin during active cluster periods and remission. J Neurol Neurosurg Psychiatry. 1987;50:207-213.

51. Cos S, Fernández R, Güézmes A, Sánchez-Barceló EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998;58:4383-4390.

52. Lissoni P, Barmo S. Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995;71:854-856.

53. Lissoni P, Cazzanga M, Tancini G, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol. 1997;31:178-181.

54. Lockwood K, Moesgaard S, Hanioka T, Folkers K. Apparent partial remission of breast cancer in ‘high risk’ patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Molec Aspects Med Suppl. 1994;5:S231-S240.

55. Lockwood K., Moesgaard S., Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q 10. Biochem Biophys Res Comm. 1994;199:1504-1508.

56. Lockwood K., Moesgaard S., Yamamoto T., Folkers K. Progress on therapy of breast cancer with vitamin Q 10 and the regression of metastases. Biochem Biophys Res Comm. 1995;212:172-177.

57. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing. 2003;32:164-170.

58. Cardinali DP, Gvozdenovich E, Kaplan MR, et al. A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Neuroendocrinol Lett. 2002;23:55-60.

59. Leone M, D’Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996;16:494-496.

60. Karadottir R, Axelsson J. Melatonin secretion in SAD patients and healthy subjects matched with respect to age and sex. Int J Circumpolar Health. 2001;60:548-551.

61. Rosenthal NE, Sack DA, Jacobsen FM, et al. Melatonin in seasonal affective disorder and phototherapy. J Neural Transm. 1986;21(Suppl):257-267.

62. Lewy AJ, Bauer VK, Cutler NL, Sack RL. Melatonin treatment of winter depression: a pilot study. Psychiatry Res. 1998;77:57-61.

63. Wirz-Justice A, Graw P, Krauchi K, et al. Morning or night-time melatonin is ineffective in seasonal affective disorder. J Psychiatr Res. 1990;24:129-137.

64. Nave R, Iani C, Herer P, et al. Residual effects of daytime administration of melatonin on performance relevant to flight. Behav Brain Res. 2002;131:87-95.

65. Zeitzer J, Daniels J, Duffy J, et al. Do plasma melatonin concentrations decline with age? Am J Med. 1999;107:432-436.

66. Luboshitzky R, Shen-Orr Z, Nave R, et al. Melatonin administration alters semen quality in healthy men. J Androl. 2002;23:572-578.

67. Scheer FA, Van Montfrans GA, Van Someren EJ, et al. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004 Jan 19. [Epub ahead of print]

68. Nelson LA, McGuire JM, Hausafus SN. Melatonin for the treatment of tardive dyskinesia. Ann Pharmacother. 2002;37:1128-31.

69. Gupta M, Aneja S, Kohli K. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsy Behav. 2004;5:316-21.

70. Fischer TW, Burmeister G, Schmidt HW, Elsner P. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. Br J Dermatol. 2004;150:341-345.

71. Pringsheim T, Magnoux E, Dobson CF, et al. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;42:787-792.

72. Citera G, Arias MA, Maldonado-Cocco JA, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol. 2000;19:9-13.

73. Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study. Maturitas. 2004;47:11-20.

74. Williams G, Waterhouse J, Mugarza J, et al. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest. 2002;32:831-837.

75. Paul MA, Gray G, MacLellan M, Pigeau RA. Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Aviat Space Environ Med. 2004;75:512-519.

76. Rogers NL, Kennaway DJ, Dawson D. Neurobehavioural performance effects of daytime melatonin and temazepam administration. J Sleep Res. 2003;12:207-212.

77. Beaumont M, Batejat D, Pierard C, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. J Appl Physiol. 2003 Sept 5. [Epub ahead of print]

78. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing. 2003;32: 164-170.

79. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, et al. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003;28:191-196.

80. Smits MG, Van Stel HF, Van Der Heijden K, et al. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003;42:1286-1293.

81. Campos FL, Da Silva-Junior FP, De Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2004 Aug 11. [Epub ahead of print]

82. Kemp S, Biswas R, Neumann V, et al. The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. Brain Inj. 2004;18:911-919.

83. Asayama K, Yamadera H, Ito T, et al. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch. 2003;70:334-341.

84. Leppamaki S, Partonen T, Vakkuri O, et al. Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Eur Neuropsychopharmacol. 2003;13:137-145.

85. Rajaratnam SM, Dijk DJ, Middleton B, et al. Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones. J Clin Endocrinol Metab. 2003;88:430-39.

86. Wyatt JK, Dijk DJ, Ritz-De Cecco A, et al. Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep. 2006;29:609-618.

87. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2006;20:1151-1158.

88. Cagnacci A, Cannoletta M, Renzi A, et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens. 2005;18:1614-1618.

89. Song GH, Leng PH, Gwee KA, et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised double blind placebo controlled study. Gut. 2005 May 24. [Epub ahead of print]

90. Lu WZ, Gwee KA, Moochhalla S, et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005;22:927-934.

91. Zhdanova IV, Piotrovskaya VR. Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans. Pharmacol Biochem Behav. 2001;67:131-135.

92. Smith MR, Lee C, Crowley SJ, et al. Morning melatonin has limited benefit as a soporific for daytime sleep after night work. Chronobiol Int. 2005;22:873-888.

93. Weiss M, Wasdell M, Bomben M, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry. 2006 Mar 10 [Epub ahead of print].

94. Dowling GA, Mastick J, Colling E, et al. Melatonin for sleep disturbances in Parkinson's disease. Sleep Med. 2005 Aug 3 [Epub ahead of print].

95. Samarkandi A, Naguib M, Riad W et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol. 2005;22:189-96.

96. Kripke DF M D, Kline LE D O, Shadan FF M D Ph D, et al. Melatonin effects on luteinizing hormone in postmenopausal women: A pilot clinical trial NCT00288262. BMC Womens Health. 2006 May 16 [Epub ahead of print].

97. Sutherland ER, Ellison MC, Kraft M, et al. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol. 2003;112:513-517.

98. Campos FL, Da Silva-Junior FP, De Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2004 Aug 11. [Epub ahead of print]

99. Sury MR, Fairweather K. The effect of melatonin on sedation of children undergoing magnetic resonance imaging. Br J Anaesth. 2006 Jun 17 [Epub ahead of print].

100. Capuzzo M, Zanardi B, Schiffino E, et al. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg. 2006;103:121-123.

101. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006;119:898-902.

102. Turkistani A, Abdullah KM, Al-Shaer AA, et al. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol. 2006 Nov 10. [Epub ahead of print]

103. Wahab MH, Akoul ES, Abdel-Aziz AA. Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in Ehrlich ascites carcinoma-bearing mice. Tumor. 2000;86:157-162.

104. Oz E, Ilhan MN. Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem. 2006;286:11-15.

105. Oz E, Erbas D, Surucu HS, et al. Prevention of doxorubicin-induced cardiotoxicity by melatonin. Mol Cell Biochem. 2005;282:31-37.

106. Kim C, Kim N, Joo H, et al. Modulation by melatonin of the cardiotoxic and antitumor activities of adriamycin. J Cardiovasc Pharmacol. 2005;46:200-210.

107. Balli E, Mete UO, Tuli A, et al. Effect of melatonin on the cardiotoxicity of doxorubicin. Histol Histopathol. 2004;19:1101-1108.

108. Kocak G, Erbil KM, Ozdemir I, et al. The protective effect of melatonin on adriamycin-induced acute cardiac injury. Can J Cardiol. 2003;19:535-541.

109. Reiter RJ, Tan DX, Sainz RM, et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol. 2002;54:1299-1321.

110. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer. 1999;35:1688-1692.

111. Saha L, Malhotra S, Rana S, et al. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol. 2007;41:29-32.

112. Van der Heijden KB, Smits MG, Van Someren EJ, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry. 2007;46:233-241.

113. Klupinska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol. 2007;41:270-274.

114. Wirtz PH, Spillmann M, Bartschi C, et al. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. 2008;44:127-133.

115. Riemersma-van der Lek RF, Swaab DF, Twisk J, et al. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008;299:2642-2655.

116. Otmani S, Demazieres A, Staner C, et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol. 2008 Sep 2.

117. Sadeghniiat-Haghighi K, Aminian O, Pouryaghoub G, et al. Efficacy and hypnotic effects of melatonin in shift-work nurses: double-blind, placebo-controlled crossover trial. J Circadian Rhythms. 2008;6:10.



NOTICE: Due to FDA TGA MOH (plus other institutions with a vestige interest) regulations and various state laws, no medical claims can be made for alternative therapys and technology. All of the information expressed herein must be considered theoretical and unproven and for experimental research only

FAIR USE NOTICE: This may contain copyrighted (C ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a 'fair use' of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit