July 2013 Blog with Durk and Sandy

KEEP A SUPPLY ON HAND FOR …

When You Need It But Can’t Get It

When we appeared at the recent Life Enhancement Symposium in Las Vegas, one of the things we discussed was how to plan ahead for upcoming shortages due to rationing under government health care programs. In this short supplement to our regular monthly newsletter, we report what might be lifesaving information on a readily available, safe, and inexpensive over the counter cough medicine that has been shown to be effective in rats and mice for the treatment of sepsis (systemic infections with a high mortality rate). With some anti­biotics already becoming difficult for doctors and hospitals to get for patients, this is potentially important information, assuming that it works similarly in humans. We wanted to let you know.

Dextromethorphan, an Effective Treatment of Endotoxic Shock in Mice, Rats

Endotoxic shock (or sepsis) is a severe systemic infection with a high mortality rate. Often occurring in hospitals where large areas of the body can be exposed to bacterial invasion (as in surgical procedures and large area burns) or as a result of catheters or other devices that enter the body through the skin, allowing bacteria to enter.

It has been reported¹ that the readily available and non-prescription cough medicine dextromethorphan provided significant, very impressive protection against endotoxin shock in mice. Endotoxin shock was induced in the animals by administering a single intraperitoneal dose of LPS/GalN (lipopolysaccharide and galactosamine). Control mice received injections of saline. Pretreatment with dextromethorphan (30 minutes prior to LPS) at 25 and 12.5 mg/kg, subcutaneously, significantly increased the survival rate up to 90%, while even at the lower dose, survivorship was increased to 67%.

The researchers found that TNF-alpha (tumor necrosis factor-alpha), a powerful proinflammatory cytokine associated with sepsis, was significantly decreased by dextromethorphan in both liver and serum. Interestingly, TNF-alpha is increased in people with rheumatoid arthritis, suggesting that dextromethorphan might be a useful treatment for that disease as well. And unlike the TNF-alpha monoclonal antibodies currently in use in the treatment of rheumatoid arthritis, dextromethorphan would not have the severe off-target effects (particularly the risk of infection and leukemia) associated with those treatments.

The authors¹ note in their abstract that “DM [dextro­methorphan] may be a novel compound for the therapeutic intervention for sepsis.” Our comment: Don’t wait for FDA approval. Dextromethorphan is already an FDA approved over-the-counter (no prescription required) inexpensive cough medicine.

Another paper² reported that pretreatment with dextromethorphan (1, 5, and 10 mg/kg i.v.) attenuated the deleterious effects (e.g., hypotension and tachycardia) in rats treated with LPS (lipopolysaccharide, a component of bacterial cell walls). The researchers suggested that, “DM can possibly be used as a prophylactic agent for sepsis in the future.”

The recommended human dose for cough control is 60 mg dextromethorphan every 12 hours, which is likely to be effective for sepsis, too, based on the mouse and rat experiments (scaling the mouse dose to human dose on the basis of food consumption—similar to scaling via body surface area—the approximate human dose would be 37.5 mg to 75 mg).

Then, in 2011, another paper on the antimicrobial and antisepsis effects of dextromethorphan was published.³ In this study of gram-positive Group A streptococcus (GAS) infections, dextromethorphan was found in mice to increase survival, enhance bacterial clearance, and reduce systemic inflammatory response and organ injury. The animals were inoculated in the air pouch with a lethal dose of GAS NZ131 microbes with or without dextromethorphan (DM) treatment (12.5 mg/kg) 30 minutes before and 1, 12, and 24 hours after bacterial inoculation.

After 14 days, the survival rate of GAS-infected mice without DM treatment was only 10%, while the DM treated GAS infected mice showed approximately 72% survival.³Liver damage (as shown by fatty degeneration of liver cells, in which the cytoplasm was filled with foamy vacuoles of fat) was inhibited by DM, which was also reflected by lower serum levels of AST (a liver enzyme increased under conditions of liver injury) in the GAS infected, DM-treated mice as compared to the GAS infected (but no DM) mice. The researchers explain: “Although infecting bacteria can be taken care of by antibiotics, the bacterial components released from dead bacteria, such as peptidoglycans, lipoproteins, lipoteichoic acids, and LPS, may be responsible for systemic inflammation and cause organ failure and sepsis.”³ By contrast, DM reduces the inflammatory response. With respect to dosage, the authors say, “[c]ombined with antimicrobial agents, the dosage of DM may be reduced comparably to the recommended doses as a cough suppressant, but this issue needs to be tested.”

The bacteria used in this experiment are one of the infamous “flesh eating bacteria” that rapidly devour human flesh and often require limb amputation.

Interestingly, one of the papers³ reports that DM has been shown in previous studies to decrease ROS at least in part through the inhibition of NADPH oxidase, a major source of oxidative stress.

This is a medicine that could be stockpiled for use when you or a loved one are threatened by sepsis and either the infection is antibiotic resistant (a rapidly growing problem due to out-of-control drug approval costs) or supplies of antibiotics are limited due to health care system rationing or other problems. Dextromethorphan is stable and can be stored for at least a few years.

Just as we were wrapping up this article, we found an earlier paper4 that adds to the remarkable anti-inflammatory effects of dextromethorphan. In this earlier study, scientists found that the death of dopaminergic neurons in neuron-glia cell culture by inflammation induced by activated microglia (as occurs in Parkinson’s disease) could be decreased by dextromethorphan at the unbelievably low levels of micromolar and even femtomolar concentrations. This is far lower than the dose used in the control of cough. The authors of this paper suggest that their findings offer a “novel therapeutic concept of using ‘ultra-low’ drug concentrations for the intervention of inflammation-related neurodegenerative diseases.”⁴ (Note: ultra-low dose treatment cannot be assumed to work for any antiinflammatory substance; dextromethorphan in this study has been tested for and found effective at that low dose in cell culture.)

References

1. Li et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol. 69:233-40 (2005).
2. Wang et al, “Dextromethorphan prevents circulatory failure in rats with endotoxemia. J Biomed Sci. 11:739-47 (2004).
3. Li et al. Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents Group A streptococcal sepsis. Antimicrob Agents Chemother. 55(3):967-73 (2011).
4. Li et al. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. FASEB J. 19:489-96 (2005).