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Old 06-09-2009, 04:21 PM
Dross Dross is offline
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Default Common chemotherapy drug triggers fatal allergic reactions

A chemotherapy drug that is supposed to help save cancer patients' lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA's Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent - a derivative of castor oil -- that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern's Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

"The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them," Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

"The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment," said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication," Bennett said. "Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor."

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

"The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent," said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Source: Northwestern University Feinberg School of Medicine

Last edited by gdpawel : 08-16-2011 at 05:30 PM. Reason: typo errors
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Old 06-10-2009, 12:27 AM
gdpawel gdpawel is offline
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Default Who Needs Taxol?

In the last decade, the incidence of central nervous system (CNS) metastasis has increased. The very first reference I found of this was a NCI observational study in 1995 that reported experience in their clinic where recurrent systemic disease occurred in all patients for which they received dose-intense Paclitaxel (Taxol) therapy. Brain metastasis was the only site of disease recurrence. The cerebellum was involved in two out of three patients, presenting with headache, dizziness, unsteady gait, nausea and vomiting (all the things that happened to my wife in 1998, after her adjunct Taxol treatment in 1997).

This is what led me to research this further and found out about the rarity of ovarian cancer cells metastasizing to the brain. Ovarian cancer uncommonly involves the nervous system. Brain metastasis was a "rare" complication of ovarian cancer with only 67 well-documented cases in medical literature, until 1994. A multi-institutional study of 4027 ovarian cancer patients over 30 years identified only 32 cases while an autopsy study of ovarian cancer reported an incidence of 0.9%. Even more "rare" is the occurrance of Carcinomatous Meningitis. Until 1994, there have been only 14 cases reported. This presentation is similar to metastases from other solid tumors (breast, lung). (1)

In 2002, I came across a study by Christos Kosmas, M.D., consultant medical oncologist, Department of Medicine and Medical Oncology Unit at Helena-Venizelou Hospital, Athens, Greece entitled, "Carcinomatous Meningitis: Taxane-Induced," which found what is called "dissemination after taxane-based (Taxol) chemotherapy." The study conclusions stated that Carcinomatous Meningitis (a CNS metastasis) after a major response to front-line taxane-based regimens represents a grave disease manifestation and its incidence appears increased when compared retrospectively to non-taxane-treated patients. (2)

A commentary by Dr. Lawrence N. Shulman, Vice Chair for Clinical Services and Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, in the September, 2002 issue of The American Journal of Oncology Review, describes the complete lack of progress in the chemotherapeutic treatment of metastatic breast cancer since 1970. Dr. Shulman noted that a retrospective comparision of a well-characterized "standard-dose" database with a less well-characterized "high-dose" database suggested that there was increased early mortality for "high-dose" therapy. (3)

An editorial by Drs. V. Valero and G.N. Hortobagyi in the March 15, 2003 issue of the Journal of Clinical Oncology, reviewed all of the large, prospective, randomized trials published comparing taxane-based chemotherapy regimens. They conclude that none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at two years or less, or precisely the same results which were being obtained over thirty years ago. (4)

In 2004, as reported at the 27th Annual San Antonio Breast Cancer Symposium, using a technique that quantifies circulating tumor cells, German investigators from Friedrich-Schiller University in Jena, have shown that neoadjuvant chemotherapy with paclitaxel (taxol) causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor. The finding could help explain the fact that complete pathologic responses do not correlate well with improvements in survival.

In the study, according to Katharina Pachmann, M.D., professor of experimental oncology and hematology, breast cancer patients undergoing neoadjuvant chemotherapy gave blood samples in which epithelial antigen-positive cells were isolated. Such cells are detected in most breast cancer patients but are rarely found in normal subjects. The investigators measured the levels of cirulating tumor cells before and during primary chemotherapy with several different cytotoxic agents.

Paclitaxel (taxol) produces the greatest degree of tumor shrinkage but also the greatest release of circulating tumor cells. In three different paclitaxel-containing regimens, circulating cell numbers massively increased, whereas tumor size decreased. These cells remained in the circulation for at least five months after surgery.

The tumor shrinks, but more cells are found in the circulation. This corresponds with a high pathologic complete response during paclitaxel treatment, but in the end, this is not reflected in improved survival. These cells are alive in the circulation. What this study has shown, so far, that in three different paclitaxel (taxol) containing regimens, as the tumor collapses (a clinical response, not cure), it produces the greatest release of circulating tumor cells. The study has not looked at any other combination regimens. (5)

The results of these kinds of study are coming out slowly and quietly (now that Taxol is off-patent) and indicate that taxol containing regimens didn't prolong survival over other more conventional and less expensive cytotoxic drugs. Even before the advent of the CellSearch technique, it had been observed in various "cell death" assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from taxane therapy, even in cases where the majority of the cells are being killed by taxanes. It may indeed give clincial response (tumor shrinkage), sometimes impressive, however, these are mostly short-lived and relapses after a response to taxanes (Taxol) are often dramatic. (6)

With these cells being alive in the circulation, it may mean that a patient with invasive breast cancer without lymph node involvement (where systemic treatment "may" benefit), or a patient with invasive breast cancer that involves lymph nodes (where systemic treatment is "usually" recommended), would need additional (anti-estrogen) treatment, such as Tamoxifen (it may be given alone or in addition to chemotherapy, if given).

It has been shown that Tamoxifen treatment will reduce circulating tumor cells in some patients, but not all. So they develop a drug called Herceptin. Why? It has been shown that Herceptin treatment will reduce circulating tumor cells in patients with HER2-negative tumors, but less pronounced in HER2-positive tumors.

Does Herceptin really work on these circulating tumor cells? A study from the Dana Farber Cancer Institute identified central nervous system metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. (7)

In 2006, another report that CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen. Central Nervous System Relapse in Patients With Breast Cancer Is Associated With Advanced Stages, With CK-19 mRNA-positive Circulating Occult Tumor Cells and With Her2/neu-positive tumors.
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Old 06-10-2009, 12:28 AM
gdpawel gdpawel is offline
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During the past years it has been frequently observed that patients with breast cancer treated with a taxane-containing chemotherapy regimen, either in the adjuvant setting or in the metastatic setting, presenting central nervous system (CNS) involvement as the only evidence of disease progression. More studies were therefore interested to evaluate the incidence of CNS metastases in patients with early and advanced breast cancer treated with a taxane-containing chemotherapy regimen and to identify predictive factors for CNS relapse.

Recent studies reported that breast cancer patients who received a taxane-containing chemotherapy regimen had a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen. There are also data indicating an increased risk for brain metastases in breast cancer patients receiving trastuzumab (Herceptin).

In the present study it was also possible to confirm the initial clinical observation that breast cancer patients who receive a taxane-containing chemotherapy regimen have a significantly higher incidence of CNS metastases compared with that of patients treated with a nontaxane-containing regimen.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS.

Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

Furthermore, the detection of cytokeratin 19 (CK-19) and of mRNA-positive circulating tumor cells (CTCs) in the peripheral blood and the bone marrow of patients with breast cancer is correlated with increased incidence of relapse.

The aforementioned data suggest that taxanes may not penetrate well into the CNS, and therefore the CNS may represent tumor 'sanctuary' sites for taxane-containing chemotherapy regimens. A difference in the incidence of CNS relapses between patients with breast cancer and other solid tumors treated with taxanes was observed. (8)

The percentage of patients that must respond to a drug before it is approved by the FDA varies from as high as 80% to as low as 20%. Thereafter, it is used routinely for all patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean it will help all patients with the same diagnosis. The response rate for Taxol for FDA approval was 30%.

Taxol (Paclitaxel) is known as a taxane type of chemotherapy drug. Taxol is given into a vein, but in order for the body to absorb the drug, it must first be dissolved in a solution. The compound wouldn't dissolve very much in any solution. It was discovered that something Taxol would dissove in the might work in a reasonably safe intravenous solution in humans. It was an elixir made of castor oil and marketed as Cremophor EL. It was the only answer. However, this castor-oil carrier is suspected as the culprit behind the misery which includes nausea, vomiting, joint pain, appetite loss, brittle hair and tingling sensations in hands and feet (neuropathy). (9)

The American Cancer Society has mentioned that the solution can cause dangerous allergic reactions in many people, so patients "must" first take other drugs like steroids and antihistamines in "hopes" to prevent a bad reaction. The solution can also leach chemicals from regular plastic tubes used to deliver medication, so Taxol must be given through special tubing.

A new drug for breast cancer (Abraxane) is a new form of Taxol (Paclitaxel). Abraxane does not need to be dissolved in the castor oil solution and does not require special equipment to be given to patients. However, more of the women on Abraxane had numbness and tingling in their hands and feet. And more suffered nausea and vomiting, diarrhea, muscle and joint pain and anemia.

Taxol (Paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients. Side effects of Taxol (Paclitaxel) include severe allergic reactions, cardiovascular problems (such as changes in blood pressure), infections developing from white blood cell deficiencies, complete hair loss (apolecia), joint and muscle pain, irritation at the Taxol and other chemotherapy drugs injection site, low red blood cell count, mouth or lip sore, numbness or burning in the hands and feet, and stomach upset/diarrhea. (10)

There is a molecular basis for the peripheral pain caused by Taxol. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling, researchers at Yale School of Medicine reported in a study published in the Proceedings of the National Academy of Sciences. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms. These serious side effects limit the drug's effectiveness. Peripheral pain becomes worse with continued use and increased dosages lead to persistent and irreversible pain.

The binding protein is called neuronal calcium sensor (NCS-1). When paclitaxel (taxol) binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme (calpain) that degrades proteins, especially NCS-1. Calcium signals are needed for nerves to be stimulated and to respond and the loss of NCS-1 makes it more difficult to generate any calcium signals. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses. (11)

Taxol actually causes cancer cell microtentacles to grow longer and allows tumor cells to reattach faster, which may have important treatment implications for breast cancer patients. Researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center have discovered that microtentacles, or extensions of the plasma membrane of breast cancer cells, appear to play a key role in how cancers spread to distant locations in the body.

Microtentacles are microtubule-based protrusions that occur in detached cells. These protrusions are unusual in that they are not actin-based. The function of microtentacles may be to aid in metastasis. Breast cancer cells that have microtentacles travel more slowly in blood vessels than breast cancer cells that do not have microtentacles. The microtentacles may allow these cells to latch on to blood vessel walls and invade other tissues.

Chemotherapy designed to kill dividing cancer cells seems to make the tentacles grow further and faster. If you take a cell that doesn't have very many tentacles and actually treat it with the tubulin stabilizer, Paclitaxel (Taxol), that causes this cell to generate more tentacles. So, at the same time you're actually reducing the ability of the tumor cell to divide, you can be increasing its ability to reattach in a distant site. This research will also play a role in other major cancers: lung, colon, ovarian, and prostate.

They feel that more research is needed into how chemotherapies that slow down cell division affect metastasis. The timing of giving these drugs can be particularly important. If you treat people with taxol before surgery to shrink the primary tumor, levels of circulating tumor cells go up 1,000 to 10,000 fold, potentially increasing metastasis. (12)

Sources:

(1) National Cancer Institute
(2) American Journal Clinical Oncology 2002;63:6-15
(3) Am J Oncology Rev 1(3):169-170, '02
(4) J Clin Oncol 21(6): 959-962, '03
(5) Oncol News Int'l, Vol 14, #5, May '05
(6) Cell Function Analysis
(7) Cancer 2003 Jun 15;97(12):2972-7
(8) Breast Cancer Res. 2006;8(4)2006 BioMed Central, Ltd.
(9) Office of Research, Florida State University
(10) Bionumerik
(11) PNAS 104: 11103-11108 June 20, 2007
(12) Oncogene (2010) 29, 3217–3227; doi:10.1038/onc.2010.68

The Human ATP-Binding Cassette (ABC) Transporter Superfamily [url]http://www.ncbi.nlm.nih.gov/books/NBK31/
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Old 07-24-2009, 10:22 PM
gdpawel gdpawel is offline
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Default Unpublished Clinical Trials

One of the researchers listed in the foot notes of my paper had told me that the study he finally published in the journal Oncology, was rejected by all other American & Europen cancer journals (Journal of Clinical Oncology, Cancer, Annals of Oncology, European Journal of Cancer, International Journal of Cancer) where it had been submitted. The journals were reluctant to publish such a scientific report, simply because taxanes (both taxol and taxotere) were at the time very intensively advertized in these journals.

Less than 20 percent of registered clinical trials of cancer drugs are eventually published in medical journals, according to a review published online by the The Oncologist medical journal.

A search of the National Institutes of Health's ClinicalTrials.gov web site identified 2,028 registered research studies of cancer treatments. Major medical journals require all studies considered for publication be registered at ClinicalTrials.gov or another publicly accessible database.

And a subsequent search of the National Library of Medicine's PubMed database showed that just 17.6 percent of the trials were eventually published in peer-reviewed medical journals.

The publication rate was particularly low for industry-sponsored studies, such as those funded by drugmakers (just 5.9% compared to 59% for studies sponsored by collaborative research networks. Of published studies, nearly two-thirds had positive results in that the treatment worked as hoped. The remaining one-third had negative results like the outcome was disappointing or did not merit further consideration of the tested treatment, they report.

The finding raises concern about publication bias in cancer treatment trials, according to the researchers, Scott Ramsey and John Scoggins of University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

The researchers suspect the rate of negative results is much higher in the studies that have gone unpublished. "It is likely that many unpublished studies contain important information that could influence future research and present practice policy," they wrote.

Of course, we know why a registered trial may not be published, some fail and a researcher may decide the result doesn't enhance knowledge or one's reputation. And some sponsors don't want negative results out there. Same goes for some journal editors.

But "unpublished trials may have special importance in oncology, due to the toxicity and/or expense of many therapies," they wrote. In other words, the knowledge base is incomplete. And who does that help?
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Old 01-30-2010, 08:52 AM
gdpawel gdpawel is offline
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Default Hypersensitivity Reaction (HSR) to Docetaxel After a Previous HSR to Paclitaxel

Jason P. Denman, Peter J. Gilbar, Ehtesham A. Abdi

Toowoomba Health Services, Toowoomba, Australia

To the Editor:

Hypersensitivity reactions (HSRs) to paclitaxel are well described in the oncology literature.1-4 The etiology of these reactions has been the source of much speculation, with Cremophor EL, the diluent for the insoluble paclitaxel, commonly blamed.1,5 Premedication with corticosteroids and H1 and H2 receptor antagonists successfully reduces the incidence and severity of the HSR.5 Re-treatment strategies have been developed to allow continuation of the paclitaxel infusion after a HSR, and patients who experience a severe reaction or a second HSR after reinitiation of therapy have received further cycles after undergoing a formal desensitization protocol.2,5 Successful substitution of paclitaxel with docetaxel, another taxane with similar efficacy, has also been described.6-8 However, docetaxel has also been implicated in causing acute HSR,3,4,9 and corticosteroid premedication is recommended. Cremophor EL is not the vehicle for docetaxel (dissolved in Tween 80), which suggests that the taxane moiety is a likely etiologic factor in the incidence of HSR seen with these medications.

In support of this hypothesis, we report a case of a patient who experienced HSR to both agents. A 56-year-old woman underwent surgical debulking at a nearby institution for a uterine mass. This was diagnosed as a poorly differentiated serous papillary adenocarcinoma of the endometrium with bilateral ovarian and peritoneal metastases, and she was prescribed combination chemotherapy with paclitaxel and carboplatin. Before commencement of the paclitaxel infusion, she received standard premedication with dexamethasone, promethazine, and ranitidine. After infusion of 19 mL of paclitaxel (300 mg diluted in 500 mL of dextrose 5% to be administered over 3 hours), the patient experienced sudden onset of dyspnea, wheeze, back pain, and facial flushing. This was followed by a loss of consciousness for approximately 60 seconds, during which time she desaturated as low as 81% (by pulse oximetry) on room air. The paclitaxel infusion was ceased and the patient responded to treatment for an acute HSR. After a period of observation, carboplatin was administered without incident.

After this episode, a decision was made to substitute docetaxel for paclitaxel, and the patient was transferred to our unit for continuation of chemotherapy 3 weeks later. The patient was given the recommended oral corticosteroid premedication, and 30 minutes before commencing the docetaxel, she received additional injections of dexamethasone and promethazine. Five minutes after initiation of the docetaxel infusion (132 mg diluted in 250 mL of sodium chloride 0.9% to be administered over 1 hour), the patient complained of dyspnea and hot flushes, became mildly cyanotic, and desaturated to 90% on room air. The infusion was immediately ceased and the patient was managed appropriately. Again, after a period of observation, carboplatin was administered without incident. She has since completed a third cycle of carboplatin monotherapy without sequelae.

To our knowledge, this case documents the first case of hypersensitivity to docetaxel after a previous HSR to paclitaxel and illustrates the continuing need for caution when administering the taxanes. It also supports the hypothesis that while the Cremophor EL diluent may indeed be responsible for many of the HSRs to paclitaxel, it is probable that there is a distinct subgroup of patients who are hypersensitive to the taxane component of these agents. To confirm this, we are endeavoring to determine whether antitaxane antibodies can be detected and if a suitable assay is available.

Journal of Clinical Oncology, Vol 20, Issue 11 (June), 2002: 2760-2761

REFERENCES

1. Weiss RB, Donehower RC, Wiernik PH, et al: Hypersensitivity reactions from Taxol. J Clin Oncol 8: 1263-1268, 1990

2. Markman M, Kennedy A, Webster K, et al: Paclitaxel-associated hypersensitivity reactions: Experience of the gynecologic oncology program of the Cleveland Clinic Cancer Center. J Clin Oncol 18: 102-105, 2000

3. Gelman K: The taxoids: Paclitaxel and docetaxel. Lancet 344: 1267-1272, 1994

4. Verweij J, Clavel M, Chevalier B. Paclitaxel (Taxol) and docetaxel (Taxotere): Not simply two of a kind. Ann Oncol 5:495-505, 1994

5. Zanotti KM, Markman M: Prevention and management of antineoplastic-induced hypersensitivity reactions. Drug Saf 24: 767-779, 2001

6. Lokich J, Anderson N: Paclitaxel hypersensitivity reactions: A role for docetaxel substitution. Ann Oncol 9: 573-574, 1998

7. Moon C, Verschraegen CF, Bevers M, et al: Use of docetaxel (Taxotere) in patients with paclitaxel (Taxol) hypersensitivity. Anticancer Drugs 11: 565-568, 2000

8. Bernstein B: Docetaxel as an alternative to paclitaxel after acute hypersensitivity reactions. Ann Pharmacotherapy 34: 1332-1335, 2000

9. Cortes JE, Padzur R: Docetaxel. J Clin Oncol 13: 2643-2655, 1995

[url]http://jco.ascopubs.org/content/20/11/2760.full

Of course, this comes from unrestricted grants from Abraxis BioScience, LLC for Abraxane (note that cancer likes Coke rather than Pepsi). Of course, the "assay" they should do is test to see if paclitaxel (Taxol) or docetaxel (Taxotere) is even likely to work, before using them.
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Old 03-20-2010, 07:56 PM
gdpawel gdpawel is offline
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Default Cell Marker Identifies Patients Who Are More Likely to Respond to Taxol?

Taxol inhibits the replication (mitosis) of cells. Rapid mitosis is the basis for tumors. Since the discovery of it in 1960, researchers have produced a multitude of drugs that work on the same principle. The drugs kill cancer cells by interrupting their abilities to divide. They typically do this by wrecking the proteins needed to make ultra-fine filaments called microtubules. To be able to divide, a cell needs to make millions of these tiny structures to use as scaffolding for building the foundation of a new cell. Once the new cell gets fleshed out, the microtubiles automatically disassemble into fragments of tubulin, the structures' original protein building blocks.

However, Taxol doesn't work that way. Instead of preventing microtubules from forming, Taxol serves as a powerful stimulant for their growth. In the presence of Taxol, cells go into overdrive churning things out, eventually clogging up a cell's innards. The process is irreversible, Taxol locks the thickets of microtubles into place and blocks their abilities to disassemble. Choking on their own growths and with no way to divide, the cancer cells soon collapse and die.

The drug targets microtubules (a structure used in the division of cells) and stabilizes them to the extent that mitosis is disrupted. Microtubules transport proteins around the cell and are essential for mitosis. When you inhibit the nature of microtubules, this blocks mitosis and the cell essentially commits suicide. This keeps the cancer from growing.

Taxol works by binding to microtubules to form an inappropriately stable structure which ultimately leads to cell death. In the absence of a protein called tau, Taxol stabilizes microtubules more easily. Patients whose cancer cells have lost their ability to express the tau messenger RNA (mRNA) are twice as likely to have a good response to Taxol treatment, although only a subset of patients ultimately benefit from this treatment. Tumor tissue could be screened to predict if it will respond to Taxol. If not, perhaps other chemotherapy regimens would work better. Examining tau protein expression is done by the routine pathological assay, immunohistochemistry.

Assessment of tau expression at the time of diagnosis could identify about 25% of all patients that show very high sensitivity to Taxol-containing chemotherapy and respond with complete disappearance of cancer after treatment. The rest of patients may not benefit much at all from the drug because none of the patients who have high levels of tau mRNA expression in their cancer experience complete response to therapy.

Neurologic complications may result from chemotherapy agents that promote polymerization and inhibit depolymerization of microtubules. Approximately 60% of patients receiving Taxol at a dose of 250 mg/m2 develop paresthesias of the hands and feet. The toxicity is dose-limiting. A distal sensory and sensorimotor neuropathy as well as a neuropathic proximal motor weakness may also complicate treatment.

Source: M.D. Anderson Cancer Center, University Of Texas
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Old 04-02-2010, 10:46 PM
gdpawel gdpawel is offline
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Default Side Effects of Taxol Use

Taxol (Paclitaxel) is an extremely potent chemotherapy drug, often producing a number of side effects in patients. Side effects of Taxol (Paclitaxel) include severe allergic reactions, cardiovascular problems (such as changes in blood pressure), infections developing from white blood cell deficiencies, complete hair loss (apolecia), joint and muscle pain, irritation at the Taxol and other chemotherapy drugs injection site, low red blood cell count, mouth or lip sore, numbness or burning in the hands and feet, and stomach upset/diarrhea.

Some other common Taxol side effects can trigger hypertension or problems with the heart, such as arrhythmias, congestive heart failure, or bradycardia. Many patients on chemotherapy become anemic, and that can trigger further cardiac complications.

Chemotherapy in general can have a deadly side effect: heart trouble. However, the "antimicrotubules" class of chemotherapy drugs, of which Taxol is a member, is supposed to be relatively rare (they really don't know). The Platins (Carboplatin and Cisplatin) may be much different. Heart problems are more common than people think, affecting up to 25% of cancer patients. According to MD Anderson cardiologists, many doctors do not adequately monitor their patients or manage their care to minimize the health risk. Chemotherapy can help achieve a clinical response (remission), but treatments can also hurt heart muscle by reducing the hearts ability to pump.

Problems can range from insignificant to so severe that a patient can die from the heart damage rather than the cancer itself. In many cases, cancer treatment heart damage isn't detected until it is advanced because traditional heart imaging tools often miss heart muscle damage.

There are problems that traditional heart imaging tests, like nuclear scans (Pet Scan or PET/CT Scan) or ultrasound, often miss until the damage is serious. Wake Forest University Medical Center is testing Magnetic Resonance Imaging as a better way to detect heart trouble in cancer patients. The Center says it is a very promising technology because to date there has not been a method to precisely monitor the heart function or blood flowing through blood vessel.

In patients who are showing heart trouble, the hope is that doctors can tweak therapy and avoid serious damage to the heart. It is hoped to get a two-fold win, detection of cancer and treatment and a nice working heart and cardiovascular system. A high-tech heart check may one day help to wipe out a potentially deadly side effect of cancer treatments. The MRI heart check is still under study, early results show the technology is more effective at detecting early heart muscle damage than the traditional methods.

Ironically, this is what it says on the Warning Label for Taxol (30, 100, 300)

Taxol (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Severe hypersensitivity reactions characterised by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in patients receiving Taxol. Patients receiving Taxol should be pre-treated with corticosteroids, promethazine, and H2 antagonists to prevent these reactions. (See "DOSAGE AND ADMINISTRATION" section). Patients who experience severe hypersensitivity reactions to Taxol should not be rechallenged with the drug.

Taxol therapy should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Taxol.

The polyoxyethylated castor oil in Taxol can result in phthalate leaching from polyvinyl chloride (PVC) containers, at levels which increase with time and concentration. Consequently, the preparation, storage and administration of diluted TAXOL should be carried out by using non-plasticized PVC-containing equipment.
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Old 11-10-2010, 09:37 PM
gdpawel gdpawel is offline
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Default Assay Results Do Not Support Treatment with Taxol + Platinum as First Line Therapy

History of Randomized Clinical Trials in Ovarian Cancer: Pre-Taxol Era

For many years (from the early 60s to late 70s), the "standard" ovarian cancer chemotherapy was single agent melphalan (or chemotherapy with a related "alkylating agent," such as cyclophosphamide). These "alkylators" were inexpensive and usually well tolerated oral drugs. In the late 70s, the NCI reported the results of a randomized clinical trial in the New England Journal of Medicine in which a complex and toxic combination ("HEXA-CAF") ostensibly produced superior results, compared to single agent melphalan. But this study was not confirmed. By the early 80s, some data appeared initially to support the concept that cisplatin-based combinations might produce superior outcomes. The new standard became cisplatin + cyclophosphamide (CTX). Later on, carboplatin was introduced, and the combination of carboplatin + CTX was found to produce results equivalent to cisplatin + CTX, but the former combination was better tolerated. This became the new standard. However, a landmark meta-analysis published in the early 90s, analyzing studies including 8,000 patients and 6,000 deaths to determine what had been learned about optimum first line chemotherapy concluded that "no conclusions could be made." The study authors concluded that previous studies (often involving hundreds of patients) had been much too small to provide statistical power, and the authors announced that their cooperative group was initiating a prospective trial to compare single agent carboplatin versus the combination of cisplatin + doxorubicin + CTX which was to accrue 2,500 patients.

It is very important to note that it is widely accepted that platinum-based combination chemotherapy has been proven to be superior to single agent alkylating agent therapy (used in ovarian cancer since the 1960s). However, this is not true, as clearly shown in the landmark meta-analysis. A re-analysis of the original meta-analysis still did not show any advantage, 10 years out, for platinum-based therapy over single agent alkylator therapy. In other words it has NOT been shown that platinum-based combination therapy is superior to single agent alkylator therapy. Yet many would maintain that not to treat an ovarian cancer patient with platinum is tantamount to malpractice. This position cannot be supported (and is, in fact, refuted) by prospective, randomized clinical trials.

Taxol Bursts Upon the Ovarian Cancer Scene

Midway into the above 2,500 patient study, the glamour drug of the 1990s, paclitaxel (Taxol), came along. A prospective, randomized trial showed the superiority of cisplatin/Taxol over carboplatin/cyclophosphamide, and the former combination quickly became the new standard, which ostensibly made the ongoing, long-term, expensive study of cisplatin + doxorubicin + CTX instantly irrelevant and obsolete. The new cisplatin/Taxol combination is, parenthetically, vastly more expensive and toxic than was the oral melphalan "standard" of the 1970s (>$25,000 per patient, as opposed to <$1,000 per patient). And does Taxol add anything to cisplatin (or carboplatin) alone? Of the drugs introduced in the 1990s, probably no drug was more highly touted than Taxol, and in no disease was it more highly touted than in ovarian cancer. Indeed, it would be accurate to state that most clinical oncologists probably feel that it would be tantamount to malpractice not to use either Taxol/cisplatin or Taxol/carboplatin as first line therapy in ovarian cancer. This point of view is, in fact, given the imprimatur of the NCI's authoritative PDQ description of state of the art therapy.

Flies in the Taxol Ointment

A recent, large, multi-institutional trial (Gynecologic Oncology Group # 132) randomized ovarian cancer patients to (1) Taxol/cisplatin, (2) Taxol alone, and (3) cisplatin alone. Patients could be crossed over to the other drugs in the event of disease progression. The result? Taxol alone was inferior to the other two regimens, while cisplatin alone was, if anything, superior to the Taxol/cisplatin combination in complete remission rate and duration of response and most certainly was no worse than the combination. So what is the level of evidence supporting the use of Taxol/cisplatin over cisplatin alone? And given that carboplatin has been shown (in combination trials) to be therapeutically equivalent to cisplatin, but less toxic, is it not reasonable to consider using single agent carboplatin alone, as first line chemotherapy?

In a very recent editorial (JNCI 92:674-5,2000), Dr. William McGuire succinctly summarized the status of clinical trials in ovarian cancer and presented his own view of the future, stating "thus, even though more than 5400 patients with advanced ovarian cancer have been accrued to randomized trials in the last decade to "fine tune" the regimen with the best therapeutic index, what is best is still unclear." McGuire further maintained that randomized clinical trials must now be international in scope, as single institutions do not have the capability to carry out studies of sufficient statistical power, nor even do individual cooperative groups, nor do intergroup studies combining several cooperative groups; rather only a truly global effort is up to the task of methodically testing all of the myriad potential combinations to define the next 2 month improvement in median survival, based on the paradigm of one size fits all chemotherapy.

By coincidence, in a perfect example of just such a global effort, the results of a very important large international study were presented at the American Society of Clinical Oncology annual meeting in New Orleans, May 20, 2000. The Third International Collaborative Ovarian Neoplasm Study (ICON3) included 2074 patients from 132 hospitals in 8 countries. At the time of this second planned analysis, median follow up was 29 months, 925 patients remained alive without progressive disease and 1293 had either died or developed progressive disease. Two year survival was 64% in the group treated with carboplatin/Taxol (now considered "mandatory" standard therapy in the USA) and an identical 64% in patients treated either with single agent carboplatin or with the very old regimen cyclophosphamide + doxorubicin + cisplatin. Subgroup analysis revealed no group for which treatment assignment caused significant differences in either progression-free survival or overall survival. The study chairman reported that "even if there is (ultimately) a difference in survival, it will probably be only about 2%." Though there had been an initial suggestion (reported in the printed abstract) that patients with bulky disease benefited more from Taxol, this difference was not sustained in the longer-term data which was reported at the meeting.

Conclusions

I doubt that objective reviewers outside of the academic clinical oncology establishment would conclude that the paradigm of performing huge randomized studies to identify the best treatment to give to the average patient has done anything other than waste money and waste patient clinical trials resources (i.e. patient lives), although it has generously supported the careers of its proponents, who are the thought leaders in clinical oncology today. At the end of the day, the only clear conclusion possible after more than 20 years of these cooperative group trials of empiric chemotherapy in ovarian cancer is that there is no clear and meaningful advantage associated with any form of therapy ever examined in these trials. This emperor truly has no clothes. Why is it justifiable to defend (and even insist on) treating all patients with Taxol combinations (which, for the average patient, probably cost $15,000 more than non-Taxol combinations, such as single agent carboplatin or cisplatin-doxorubicin-cyclophosphamide)?

What makes more sense?

1. Treat all patients with carboplatin/Taxol?

2. Choose between reasonable treatment regimens (e.g. single agent carboplatin, carboplatin/Taxol, cisplatin/doxorubicin/cyclophosphamide, gemcitabine/cisplatin, cisplatin/topotecan, cisplatin/vinorelbine, cisplatin/Doxil, cisplatin/etoposide, vinorelbine/Taxol, vinorelbine/docetaxel, gemcitabine/vinorelbine, vinorelbine/thiotepa, cyclophosphamide/doxorubicin, etc.) with the assistance of information from a well-validated Human Tumor Assay performed by an experienced laboratory?

Larry M. Weisenthal, M.D., Ph.D. Weisenthal Cancer Group
April 14, 2003
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Gregory D. Pawelski
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Old 02-11-2011, 11:53 AM
gdpawel gdpawel is offline
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Default Desensitization for chemotherapy hypersensitivity

Allergic reactions are supposed to happen in approximately 25 to 30 percent of patients receiving more than six cycles of a platinum-based chemotherapeutic agent. Here is one study where they attempted to do chemotherapy desentization.

Rapid inpatient/outpatient desensitization for chemotherapy hypersensitivity: Standard protocol effective in 57 patients for 255 courses

Chyh-Woei Leea, Ursula A. Matulonisb and Mariana C. Castellsa,

a Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA

b Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA

Abstract

Objectives.

Hypersensitivity reactions (HR) to chemotherapy often prompt permanent discontinuation and deprive the patient of the most active regimen. We investigated the safety and effectiveness of a rapid desensitization protocol used in inpatient and outpatient settings for patients with HR to various chemotherapy and related agents.

Methods.

A 3-solution, 12-step protocol delivered doubling drug doses by step, infusing the target dose over 5.8 h for inpatient and 3.8 h for outpatient administration.

Results.

57 consecutive patients who had moderate to severe HR to chemotherapy were evaluated for desensitization. All 57 patients successfully completed 255 courses of desensitization (127 to carboplatin, 114 to paclitaxel, and 14 to four other agents) where 16 patients received 51 courses in the outpatient setting (34 to carboplatin and 17 to paclitaxel). 225 courses (88.2%) were completed without any HR. 18 patients had breakthrough symptoms (BS) over 30 courses (11.8%) that were less severe than their initial HR. After management of breakthrough symptoms, these patients finished all 30 courses and tolerated subsequent desensitizations on a modified protocol. 21 of 26 patients (81%) with HR to carboplatin had positive skin tests to carboplatin. Cancer response to chemotherapy administered by desensitization was within the expected range after 1-3 years of follow-up.

Conclusion.

The rapid desensitization protocol was safe and effective in both the inpatient and outpatient settings and allowed appropriate patients with moderate to severe HR to continue chemotherapy. This study warrants the incorporation of the protocol into standard clinical practice.

[url]http://www.ncbi.nlm.nih.gov/pubmed/16054201

P-glycoprotein (PGP) multidrug resistant membrane pump

A genetic predisposition which causes multiple proteins to dot the surface of tumor cells. These proteins are known as P-glycoprotein, or PGP. PGP is a transmembrane efflux pump- it pumps harmful things from the inside of the cell to the outside of the cell. In many cases, PGP is at least partially responsible for a patient's decreased sensitivity to taxane-based chemotherapy (taxol, taxotere, paclitaxel). As soon as the drugs enter the cancer cells, the PGP pumps start pumping the drugs out.

The presence of P-glycoprotein (PGP), signaled that the patients would not respond well to chemotherapy. PGP is primarily responsible for inducing multi-drug resistance, in which the tumors become resistant to many chemotherapy drugs after treatment with just one drug. PGP effectively pumps the drug out of tumor cells before it has time to kill the cells. PGP is just one protein implicated in multi-drug resistance. Harpole found that the 88 patients with PGP survived 20.9 months on average, while the 24 patients without PGP had an average survival of more than 5 years after diagnosis.

The reasons for the association between treatment of breast cancer with a taxane-containing chemotherapy regimen and an increased incidence of CNS involvement could be that taxanes are very lipophilic, their concentration in the CNS is very low after their intravenous administration. Taxanes are unable to penetrate the intact blood-brain barrier, the concentration of radiolabeled paclitaxel in the cerebrospinal fluid is found to be significantly lower than in other organs, and thus undetectable in the brain, in the spinal cord or in any other site of the CNS. Also, paclitaxel is exported from the p-glycoprotein and other ATP-binding cassette transporters placed at the luminal membrane of brain capillaries, as an explanation for the low concentrations of taxanes in the CNS.

Tamoxifen at concentrations of 2.5 micromolar or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance). In most patients, this level can be achieved starting the day before, the day of, and the day after chemotherapy. It is usuall well tolerated, though some patients have GI side effects, and some have headaches which often respond well to Imitrex or similar anti-migraine medications.

Selective Estrogen Receptor Modulators (SERMs) are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

In pharmacology the term agonist-antagonist is used to refer to a drug which exhibits some properties of an agonist (a substance that fully activates the neuronal receptor that it attaches to) and some properties of an antagonist (a substance that attaches to a receptor but does not activate it or if it displaces an agonist at that receptor it seemingly deactivates it thereby reversing the effect of the agonist).

A cell-based functional profiling assay conducted on human tumor samples utilizes native microspheroids (fresh, live cells, not cell lines) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment. This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

Source: Cell Function Analysis
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Last edited by gdpawel : 01-18-2013 at 11:43 AM. Reason: corrected url address
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Old 05-25-2011, 02:58 PM
gdpawel gdpawel is offline
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Default Taxane-induced Peripheral Neuropathy

Researchers have identified a genetic biomarker that can predict a patient's likelihood of experiencing taxane-induced peripheral neuropathy, which is characterized by a pain and numbness in fingers and toes and can keep patients from receiving the intended amount of their therapy, complicating treatment.

The marker in the RWDD3 gene. The findings came from a large genome-wide association study of 2,204 early-stage breast cancer patients enrolled in a clinical trial that used weekly paclitaxel for 12 weeks in all arms. This marked the first time a genetic biomarker has been reported for taxane-induced neuropathy.

Dr. Bryan P. Schneider of the Simon Cancer Center at Indiana University, Indianapolis, and his colleagues, looked for variations in DNA called single nucleotide polymorphisms (SNPs) in each patient. During the study and follow-up period, 613 of the patients reported experiencing grade 2-4 neuropathy.

By looking at more than 1.2 million SNPs in each patient, Dr. Schneider and his colleagues were able to identify genetic subgroups most likely to develop neuropathy.

Those who carried two normal nucleotides in a specific regulatory gene had a 27% chance of experiencing neuropathy. But those who carried one normal nucleotide and one SNP had a 40% chance and those who carried two SNPs had a 60% chance.

The researchers also found that older patients and blacks were much more likely to have peripheral neuropathy. The likelihood of neuropathy increased 12.9% with every decade of age. Blacks saw a two-fold increase in the likelihood of developing neuropathy.

The study was funded by the Eastern Cooperative Oncology Group under the National Cancer Institute.

A Yale School of Medicine study found a molecular basis for the peripheral pain caused by taxanes. It appears to be caused when the drug binds to a protein and initiates improper calcium signaling. This response leads to side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms (PNAS 104: 11103-11108 June 20, 2007). These serious side effects limit the drug's effectiveness. Peripheral pain becomes worse with continued use and increased dosages lead to persistent and irreversible pain.

The binding protein is called neuronal calcium sensor (NCS-1). When paclitaxel (taxol) binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme (calpain) that degrades proteins, especially NCS-1. Calcium signals are needed for nerves to be stimulated and to respond and the loss of NCS-1 makes it more difficult to generate any calcium signals. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses.

Here is some information about natural strategies to reduce Neuropathy:

1) The behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin (Nature Medicine November 2003 Volume 9 Number 11 pp 1383 – 1389).

2) Alpha-lipoic acid (a dietary supplement) is considered safe (Regul Toxicol Pharmacol. 2006 Oct;46(1):29-41. Epub 2006 Aug 14). Also protective for the liver-lipoic acid could offer protection against chloroquine-induced hepatotoxicity. Lipoic acid has a better protective effect when compared with silymarin, a reference drug (Journal of Applied Toxicology Volume 24, Issue 1, Pages 21 - 26).

3) Vitamin B12 (from an article by syndicated columnist Dr. Paul Donohue, To Your Health, in the Palm Beach Post). The recommended daily allowance for vitamin B12 is 2.4 micrograms. Huge doses of vitamin B12 can penetrate the intestinal wall. But, B12 deficiency is an uncommon cause of burning feet.

3) Urea containing preparation appears to be an excellent choice for the prevention and treatment of capecitabine induced hand foot syndrome. This minimizes drug delays, schedule interruptions and maintains the dose density. Owing to reduced morbidity, the drug tolerance and acceptance is considerably improved (ASCO 2004 Abstract No: 8105).

4) Oral Glutamine is effective for preventing Oxaliplatin-induced Neuropathy in Colorectal cancer patients (The Oncologist, Vol. 12, No. 3, 312-319, March 2007; doi:10.1634/theoncologist.12-3-312).

5) A study published in a recent issue of the Journal of Alternative and Complementary Medicine has found that acupuncture can reduce pain and peripheral neuropathy in HIV-infected individuals, especially when treatment is directed at a patient's specific symptoms (Journal of Alternative and Complementary Medicine 2004;10(3):449-455).

6) While nerve conduction velocity did not improve, vibration perception increased. Clinical symptoms also improved in groups treated with acetyl-L-carnitine compared to placebo. Participants who received 1,000 milligrams acetyl-L-carnitine thrice daily demonstrated significant improvement in pain at the study’s midpoint and conclusion.

7) Neuroprotective Conclusion: Supplementation of patients receiving cisplatin chemotherapy with vitamin E decreases the incidence and severity of peripheral neurotoxicity (Journal of Clinical Oncology, Vol 21, Issue 5 (March), 2003: 927-931).
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Last edited by gdpawel : 09-16-2015 at 11:43 PM. Reason: Additional information
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