these studies, but if either pharm companies (unlikely) or the government (likely) funded them, it disproves your concept that there will be no research on this because it can't be patented in any case.
If you were willing to look up the original articles, I will give you one hundred dollars if at least half of them, if not all, are not funded by government grants. Seriously. I could be wrong, it could be some private pediatric neuro disease foundation funding it, but I'll bet it's the NIH/NINCDS etc.
This is from the quickest, most cursory medline search. All U.S. facilities, reputable institutions.
These results are not about cancer, but apparently DCA (dichloroacetate, the drug which is the subject of the recent threads) has been researched at length as a possible treatment for mitochondrial diseases.
Not only that, but it's been found to have nerve toxicity as some of the citations discuss, something that was not mentioned in the New Scientist article. So at least I learned something from this exercise, anyway. Did you?
The point is, someone HAS funded research into this unpatentable drug that no pharma company can make any dough off of, and not only that, the research was into its possible application into mitochondrial diseases that are not very common, that even if the drug WAS patentable, the profit potential would be very low!
So do you feel that this information in any way challenges your concept that if pharmaceutical companies can't profit from it, no research will be done in the U.S. into it? Or do you insist on clinging to your idea that pharm companies and their evil cohorts in the Bush Administration will suppress and prevent any research into cheap cures for cancer, preferring that their friends and acquaintances die horribly from all cancers that could be easily and cheaply prevented, just so their company can continue to make money off the cancer industry?
Sheesh!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16725381&query_hl=1&itool=pubmed_DocSum 1: Mitochondrion. 2006 Jun;6(3):126-35. Epub 2006 May 3.Click here to read Links
Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency.
* Berendzen K,
* Theriaque DW,
* Shuster J,
* Stacpoole PW.
Division of Endocrinology and Metabolism, Department of Medicine, University of Florida College of Medicine, P.O. Box 10226, Gainesville, FL 32610, USA.
[email protected] We reviewed the use of oral dichloroacetate (DCA) in the treatment of children with congenital lactic acidosis caused by mutations in the pyruvate dehydrogenase complex (PDC). The case histories of 46 subjects were analyzed with regard to diagnosis, clinical presentation and response to DCA. DCA decreased blood and cerebrospinal fluid lactate concentrations, and was generally well tolerated. DCA may be particularly effective in children with PDC deficiency by stimulating residual enzyme activity and, consequently, cellular energy metabolism. A controlled trial is needed to determine the definitive role of DCA in the management of this devastating disease.
PMID: 16725381
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16651305 1: Pediatrics. 2006 May;117(5):1519-31.Click here to read Links
Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.
* Stacpoole PW,
* Kerr DS,
* Barnes C,
* Bunch ST,
* Carney PR,
* Fennell EM,
* Felitsyn NM,
* Gilmore RL,
* Greer M,
* Henderson GN,
* Hutson AD,
* Neiberger RE,
* O'Brien RG,
* Perkins LA,
* Quisling RG,
* Shroads AL,
* Shuster JJ,
* Silverstein JH,
* Theriaque DW,
* Valenstein E.
Division of Endocrinology and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida, USA.
[email protected] OBJECTIVE: Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS: Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME: There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor delta-aminolevulinate. CONCLUSIONS: In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.
PMID: 16651305
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16476929 1: Neurology. 2006 Feb 14;66(3):324-30.Click here to read Links
Comment in:
Neurology. 2006 Feb 14;66(3):302-3.
Neurology. 2006 Jul 11;67(1):184; author reply 184.
Neurology. 2006 Oct 10;67(7):1313; author reply 1313.
Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial.
* Kaufmann P,
* Engelstad K,
* Wei Y,
* Jhung S,
* Sano MC,
* Shungu DC,
* Millar WS,
* Hong X,
* Gooch CL,
* Mao X,
* Pascual JM,
* Hirano M,
* Stacpoole PW,
* DiMauro S,
* De Vivo DC.
Department of Neurology, Columbia University, New York 10032, USA.
[email protected] OBJECTIVE: To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). BACKGROUND: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. METHODS: The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. RESULTS: During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. CONCLUSION: DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
PMID: 16476929
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16476925&query_hl=7&itool=pubmed_docsum 1: Neurology. 2006 Feb 14;66(3):302-3.Click here to read Links
Comment on:
Neurology. 2006 Feb 14;66(3):324-30.
Trial of dichloroacetate in MELAS: toxicity overshadows the assessment of potential benefit.
* Schaefer AM.
PMID: 16476925
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17241159&query_hl=1&itool=pubmed_docsum 1: J Neurochem. 2007 Jan;100(2):429-36. Links
Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect.
* Felitsyn N,
* Stacpoole PW,
* Notterpek L.
Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610-024, USA.
Dichloroacetate (DCA) is an investigational drug for genetic mitochondrial diseases whose use has been mitigated by reversible peripheral neuropathy. We investigated the mechanism of DCA neurotoxicity using cultured rat Schwann cells (SCs) and dorsal root ganglia (DRG) neurons. Myelinating SC-DRG neuron co-cultures, isolated SCs and DRG neurons were exposed to 1-20 mm DCA for up to 12 days. In myelinating co-cultures, DCA caused a dose- and exposure-dependent decrease of myelination, as determined by immunolabeling and immunoblotting for myelin basic protein (MBP), protein zero (P0), myelin-associated glycoprotein (MAG) and peripheral myelin protein 22 (PMP22). Partial recovery of myelination occurred following a 10-day washout of DCA. DCA did not affect the steady-state levels of intermediate filament proteins, but promoted the formation of anti-neurofilament antibody reactive whirls. In isolated SC cultures, DCA decreased the expression of P0 and PMP22, while it increased the levels of p75(NTR) (neurotrophin receptor), as compared with non-DCA-treated samples. DCA had modest adverse effects on neuronal and glial cell vitality, as determined by the release of lactate dehydrogenase. These results demonstrate that DCA induces a reversible inhibition of myelin-related proteins that may account, at least in part, for its clinical peripheral neuropathic effects.
PMID: 17241159
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16508366&query_hl=1&itool=pubmed_DocSum 1: Ann Plast Surg. 2006 Mar;56(3):320-6.Click here to read Links
Dichloroacetate reduces tissue necrosis in a rat transverse rectus abdominis musculocutaneous flap model.
* Tyner TR,
* Tong W,
* Donovan K,
* McDonald T,
* Sian K,
* Yamaguchi KT.
Department of Surgery, University Medical Center, Veterans Administration Medical Center, University of California San Francisco-Fresno Medical Education Program, CA 93702, USA.
OBJECTIVE: Ischemia-related complications may occur during postmastectomy transverse rectus abdominis musculocutaneous (TRAM) flap reconstruction. The aim of our study was to investigate whether necrosis of susceptible flap regions could be reduced by dichloroacetate (DCA)-induced stimulation of oxidative metabolism in hypoxic tissue. METHODS: The study was a randomized control trial using male Sprague-Dawley rats. A pedicled TRAM flap based upon the right inferior epigastric artery was elevated and reapproximated. Animals were randomly assigned to 1 of 5 treatment groups (n = 6). Group I received no DCA; groups II through V were administered 75 mg/kg DCA orally 24 hours preoperative; in addition, groups II through IV received 75 mg/kg/d DCA orally postoperative for 4 days; group III also received 75 mg/kg DCA (IP) intraoperatively; groups IV and V were given 15 mg/kg/d DCA orally for 6 days before the 24-hour preoperative treatment. Four days postsurgery, skin paddles were photographed and assessed for viability. Underlying TRAM muscle was biopsied for histologic analysis. Blood lactate levels were measured at pre- and postoperative time points. The mean percentages of viable skin paddle were as follows: 32.0%+/- 4.0% (group I), 68.1% +/- 6.2% (group II), 84.3% +/- 5.9% (group III), 92.8% +/- 2.0% (group IV), 82.6% +/- 5.8% (group V). RESULTS: Statistically significant differences were found in all experimental (DCA) groups relative to the controls (P < 0.01). Group IV (6-day DCA preconditioning, plus 24-hour preoperative and 4-day postoperative treatment) displayed the greatest improvement in flap viability, significantly better than other DCA groups (P < 0.01). Group IV also had significantly lower serum lactate levels than controls (P < 0.05). Histologic examination of muscle biopsies revealed reductions in inflammation and necrosis correlating with DCA treatment and skin paddle survival. CONCLUSIONS: This study indicates that DCA may provide a useful pharmacologic tool for reducing ischemia-related necrosis in TRAM flaps.
PMID: 16508366