Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

Source:

UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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Diagnosis of food poisoning

Food poisoning is usually a mild illness that may resolve on its own after a bout of stomach upset. However, in some cases it might be more serious needing therapy.

Symptoms of food poisoning like abdominal cramps, nausea and vomiting, diarrhea and weakness and association with a recent intake of contaminated food or water is often diagnostic of the condition.

However, sometimes blood tests, tests for the infected stools or even a sigmoidoscopy and other imaging tests may be prescribed to find out the causative organism. (1)

There are several steps for the diagnosis of food poisoning. (1-5)

History of intake of contaminated food

In most cases, the patient volunteers such information.

History of recent return from travel to a developing or underdeveloped country and drinking contaminated water or eating contaminated food should also be mentioned.

Physical examination

A complete physical examination may be needed especially to rule out signs of dehydration.

Dehydration is usually caused due to excessive fluid loss due to diarrhea or vomiting.

Dehydration is characterized by dry skin that remains tented after a pinch, sunken eyes, dry mouth, no sweating in the groins or armpits, no urination for long durations etc.

Weakness or paralysis may also be diagnosed on physical examination and may be indicative of Botulism which needs immediate therapy.

Blood pressure, pulse and temperature are also measured. Severe dehydration is manifested with weak pulse and low blood pressure.

If there is accompanying fever, temperature assessment may be helpful.

Routine blood tests

Routine blood tests may be ordered in some patients with severe food poisoning.

Sometimes these are ordered to check for levels of blood electrolytes and to check for adequate kidney functions.

In case of suspected hepatitis A liver function tests may also be ordered.

Stool examination

Stool samples are examined in case of Salmonella, Shigella and Campylobacter. These infections commonly lead to bloody diarrhea.

If there is a suspected parasitic infestation the stool samples are examined and the parasite is identified under the microscope.

Sometimes stool culture may be prescribed. The sample is allowed to stand in the laboratory in ideal environmental conditions and growth of the microorganism is checked.

Rectal examination

Rectal examination may be needed especially in case of bloody stools.

The doctor inserts a lubricated and gloved finger gently into the rectum for this tests and assess if there are breaks in the rectal wall.

Imaging studies

If the symptoms are suspected to be caused by any other illness, imaging studies are recommended.

These include CT scan of the abdomen.

Sometimes a sigmoidoscopy may be recommended. This involves insertion of a thin long tube within the rectum up to the colon. The tube has a camera on the tip. This helps diagnose any pathology within the intestinal walls.

Toxoplasmosis test

In pregnant women with symptoms there may be a risk of Toxoplasma infection. For this a toxoplasmosis test is advised.

Sources:

  1. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002618/
  2. http://www.medicinenet.com/food_poisoning/page4.htm#diagnosed
  3. www.emedicinehealth.com/food_poisoning/page5_em.htm#Exams and Tests
  4. www.webmd.com/…/food-poisoning-exams-and-tests
  5. http://www.nhs.uk/Conditions/Food-poisoning/Pages/Diagnosis.aspx

Further Reading

  • All Food Poisoning Content
  • What is Food poisoning?
  • Food poisoning Causes
  • Food poisoning Symptoms
  • Food poisoning Treatment

Last Updated: Jun 4, 2019

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.

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Can Antibiotics Increase the Risk of Arthritis?

Rheumatoid arthritis (RA) is an autoimmune disorder that causes inflammation of the joints. RA is a chronic and progressive condition that causes debilitating effects on the patient. The condition is characterized by pain and stiff joints.

Image Credit: Puwadol Jaturawutthichai / Shutterstock.com

Another typical feature of this disorder is bone and joint destruction and the presence of autoantibodies in the serum and synovial fluid. Synovial fluid is the fluid that lubricates the synovial joints.

What causes rheumatoid arthritis?

The exact mechanism by which patients develop RA is unknown; however, a combination of genetic and environmental factors is likely. Autoimmune antibody production is proposed to be the main mechanism responsible for bone and joint destruction, and the related RA pathology. Infections, hormonal alterations, and stress are some potential triggers of RA.

Recent research suggests an association between antibiotic use, gut microbiota changes, and RA flares.

Antibiotics and the gut microbiota

Antibiotics are widely used for the treatment of bacterial infections associated with the respiratory system, gastrointestinal system, and urinary tract. Although antibiotics act against pathogenic bacteria, they can also modify the normal gut microbiota.

The gut microbiota is a diverse system of microorganisms residing in the gastrointestinal tract of the human body. Gut microbiota plays a vital role in maintaining the body’s digestive health. Gut microbiota is also involved in the immune system and the synthesis of vitamin B and vitamin K.

Various epidemiological studies have demonstrated associations between the occurrence of bacterial infections and RA. Furthermore, microbiome alterations have been indicated as a potential mechanism for the effect of infection in RA pathogenesis. Antibiotics substantially disturb the gut microbiome, with studies demonstrating significant microbial shifts in the gastrointestinal tract following their use.

The alterations in the gut microbiome may last up to a year after treatment periods of only one week. As per a recent study by Nagra et al., the risk of RA flare was significantly increased in the 1–12 months after commencing treatment on sulphonamide and trimethoprim antibiotics.

Antibiotic usage and the risk of rheumatoid arthritis

Emerging research suggests that infections are potential risk factors for RA pathogenesis and flares. Respiratory infections have been particularly linked with the development of RA. Antibodies to citrullinated peptide antigens (ACPA) are one of the autoantibodies associated with RA.

ACPAs have been found to be produced in response to certain bacterial components, which suggests the potential role of infections in RA pathogenesis. As per a population-based study published in 2019, respiratory tract pathogens such as Chlamydia pneumoniae are associated with elevated circulating autoimmune antibodies.

The study analysis found that the strongest association of infections and RA was identified only in subjects treated with an antibiotic and not in untreated subjects. These findings suggest that antibiotic use may be the probable reason for the increased occurrence of RA.

As per the authors of the study, “Individuals exposed to one or more antibiotic prescriptions were 60% more likely to develop RA than their unexposed counterparts”.

Concluding remarks

Although several studies have described the potential role of antibiotic use on the microbiome, which is potentially disrupted in RA, further research is required to explore the exact mechanism responsible for the same.

Sources

  1. Sultan, A. A., Mallen, C., Muller, S., Hider, S., Scott, I., Helliwell, T., & Hall, L. J. (2019). Antibiotic use and the risk of rheumatoid arthritis: a population-based case-control study. BMC medicine, 17(1), 154. doi:10.1186/s12916-019-1394-6
  2. Nagra, N. S., Robinson, D. E., Douglas, I., Delmestri, A., Dakin, S. G., Snelling, S., … Prieto-Alhambra, D. (2019). Antibiotic treatment and flares of rheumatoid arthritis: a self-controlled case series study analysis using CPRD GOLD. Scientific reports, 9(1), 8941. doi:10.1038/s41598-019-45435-1
  3. Yoshii, K., Hosomi, K., Sawane, K., & Kunisawa, J. (2019). Metabolism of Dietary and Microbial Vitamin B Family in the Regulation of Host Immunity. Frontiers in nutrition, 6, 48. doi:10.3389/fnut.2019.00048

Further Reading

  • All Arthritis Content
  • What is Arthritis?
  • Types of Arthritis
  • Arthritis Treatment
  • Arthritis History
More…

 

Last Updated: Nov 18, 2019

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