La risorsa globale per le prove scientifiche sulla sperimentazione animale

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Dog

Dogs have a long history in research. From the 1600s, as our understanding of physiology began to accelerate, to modern day, as we progress in the age of genetics, dogs have played a vital role in shaping our understanding and developing new treatments for a wide range of diseases.


Fundamental biology
Vaccines
Heart
Treatments
Toxicology
References

Fundamental biology

In 1889 Joseph von Mering and Oskar Minkowski showed that removing the pancreas from a dog produced diabetes.ANCHOR This was the first demonstration of an anti-diabetic factor, later discovered to be insulin, produced by the pancreas which enabled the body to regulate sugars in the blood. In 1909 Forschbach showed that crude insulin extracts could reduce blood sugar levels by 90% in these dogs. Unfortunately, impurities in the extract meant this preparation of insulin had toxic effects. When James Collip and Frederick Banting developed a new technique for purifying insulin from cow pancreas, it was tested successfully in dogs and then in patients in 1922 with dramatic results, leading to Banting being awarded a Nobel Prize the next year.

Ivan Pavlov’s experiments on the digestive systems of dogs provided the first detailed observations of how the digestive system worked.ANCHOR ANCHOR This was made possible through his surgical techniques that allowed him to observe the digestive processes while the animals were able to behave normally. This provided new insights that could not have been achieved previously when the dogs were killed during the study. Among his findings, Pavlov described the physiology of the salivary glands, the stomach and the intestines in detail. He showed that the digestive tract is influenced by the central nervous system in a complex manner, and that psychological process can influence the nature of the fluids secreted into the digestive tract. For this work, Pavlov was awarded a Nobel Prize in 1904.

Although dogs were commonly used in experiments through history, their use is now limited to a few disease models, such as muscular dystrophy, and drug safety testing.Against a backdrop of widespread rickets among children in the population, Edward Mellanby discovered that a restricted diet of oats and being kept indoors resulted in rickets in dogs.ANCHOR ANCHOR ANCHOR Simply adding cod liver oil to their diet led to quick recovery. This is because rickets is caused by a deficiency in vitamin D, which had not been discovered at the time. We now know that the body creates vitamin D naturally when exposed to sunlight but can also be found in cod liver oil.

Vaccines

In 1880, Louis Pasteur developed an anti-rabies vaccine for dogs, by using dogs in his research.ANCHOR ANCHORPasteur used injections of infected nervous tissue into the dogs’ brains to reproducibly induce rabies in the dogs. By drying nerve tissue of infected rabbits, Pasteur produced a weakened sample of the virus. When this was given over a 2 week period with  stronger doses each time, he was able to immunise the dogs so that they became resistant to the virus.

After his work was published, Pasteur soon found himself being implored by the families of people who had been bitten by rabid dogs. Of the first 350 people he first treated only one went on to develop rabies, compared to the 40-80% that would have developed the fatal condition without his intervention. His vaccine continued to be used until after the Second World War when it was replaced with one produced in cell culture.

Heart

Dogs were the first animals to receive an intravenous injection. Sir Christopher Wren, although better known as an architect, developed a system involving a quill and a pig bladder to inject alcohol into a dog’s veins. Over the years this developed into blood transfusions and dogs were test subjects for many of the advances made in the procedure. For more details, visit the blood transfusion page.

Ventricular fibrillation is a common cause of cardiac arrest where the muscles of the heart are uncoordinated and fail to pump blood. This was first described in dogs in the 1840s when scientists discovered it could be induced by ligating the coronary artery or applying an electric current. In 1899, Jean Louis Prevost and Frederic Batelli in Geneva demonstrated that electrical currents could also be used to restore normal rhythm to a dog’s heart, thereby inventing the first electrical defibrillator.ANCHOR

The application of this was aided by the development of the electrocardiogram (ECG) by Willem Einthoven. He won the Nobel Prize in 1924 for this and his characterisation of the changes to the heartbeat with different diseases and stimuli in humans and dogs. In 1947 the surgeon Claude Beck carried out the first successful defibrillation on a human using a machine installed in the operating theatre.ANCHOR However the paddles had to be applied directly to the heart; the first successful "closed chest" defibrillation was performed by Paul Maurice Zoll in 1956.ANCHOR Paul Zoll's achievement was based on research using dogs undertaken a couple of years earlier by William Kouwenhoven and William Milnor, and his own early animal and clinical research on the external pacemaker. In 1962, Bernard Lown refined the wave form of the electric shock to reduce damage to the heart, after he carried out a series of studies involving hundreds of dogs.ANCHOR The Lown waveform became the standard for defibrillation, until it was superseded by the biphasic truncated waveform in the 1990s.

In 1950, WG Bigelow studied the effects of hypothermia on the energy use of dogs. He found that they could be cooled to 20C with no ill effects and their oxygen consumption and heart rate reduced by 85%.ANCHOR This was viewed as a means to allow the heart to be isolated while doing surgery, while minimising the damage to the body. At lower temperatures the heart would undergo ventricular fibrillation and stop completely. Bigelow discovered that the dogs’ heart could be restarted with an electrical charge, leading to the design of the pacemaker.

Further understanding and treatments for the heart raised the possibility of replacing defective heart valves with artificial ones in the 1950s. Initial designs based on the natural structure had issues with strength and clotting when implanted into dogs.ANCHOR Refinements on the design over the next decade eventually led to dogs surviving for over a year without anticoagulant treatment.ANCHOR By October 1961, of the 12 patients who had received artificial mitral valves, two had died from unrelated causes, and three from infections.ANCHOR The remaining patients were well and two had returned to work. Its success encouraged development and testing, in calves and dogs, of further designs, that are still in use today.

The possibility of using transplanted valves was also explored in dogs and the best methods of preparation and storage were established. There was not an adequate supply of human valves so by the mid-1960s it was realised that the answer lay in transplanted valves from other species. Xenograft valves, from pigs, sheep, calves and goats were transplanted into dogs in the early 1970s.ANCHOR Further work to tackle durability and rejection was conducted using rabbits, guinea pigs and rats, resulting in biologically inert, functional and durable valves.ANCHOR Such 'bioprosthetic' valves, usually from pigs, have been used successfully in many human patients.

Treatments

Duchenne muscular dystrophy is the most common form muscular dystrophy, affecting 1 in 3500 boys born. The only animal model that reproduces the human pathology and biochemical mechanisms is the Golden Retriever dog. Researchers took stem cells taken from these dogs and corrected the mutated gene before injecting back into the dogs’ muscle tissue. There the stem cells formed muscle fibre and restored some level of function to the muscles.ANCHOR

   
In November 2012, researchers published the first double-blinded, randomized, controlled study into using cell transplants to treat spinal cord injury. The trial was conducted on pet dogs, mostly dachshunds, which had had spinal injuries through accidental injury. The researchers took a sample of olfactory ensheathing cells (OECs) from the noses of each of the dogs. These cells were known to promote nerve growth, as the nose is the only part of the body where nerve cells continue to grow in adulthood. This study garnered much media attention with videos of the dogs’ remarkable improvement.

Prostate cancer only naturally occurs in significant numbers in humans and dogs. While the cancer in dogs shares characteristics with humans, there are differences in the likelihood of the cancer metastasizing and the tissue of the prostate.ANCHOR However, by studying the prostate gland in dogs, Charles Huggins discovered that the growth of tumours was dependant on the natural hormones of the body. Reducing male sex hormones or increasing female hormones could treat prostate cancer. Even patients with only a short time to live showed improvement from this new type of treatment, which  had fewer side effects than other therapies. For his work and the treatments he helped to develop, Charles Huggins was awarded a Nobel Prize in 1966.

George Whipple investigated the effects of diet on anaemia by bleeding dogs and comparing their recoveries when fed different diets.ANCHOR He noted that a quick recovery followed a diet consisting of large amounts of liver. He then suggested, and tested, that a liver-rich diet could be used to treat pernicious anaemia in humans. His success in treating pernicious anaemia was recognised by a Nobel Prize in 1934, although we now know that the anaemia in the dogs was treated by the iron in the liver, while the pernicious anaemia in humans was responding to the extra vitamin B12.

Toxicology testing

For a new drug to reach clinical trials in humans, regulatory bodies usually require toxicity tests in both a rodent and a non-rodent mammal. The rodent will often be a rat and dogs are usually the other mammal. Dogs are used because they are physiologically similar to humans and are readily available. These tests account for about 75% of the dogs currently used in research.ANCHOR Dogs can be used for maximum tolerated dose studies which help to determine dose selection for human trials.

Despite the emotional and ethical issues around the use of dogs in testing, regulations are slow to change because of potential safety implications if a serious adverse effect is missed at this stage.ANCHOR Much research has gone into finding other animals and in vitro alternatives, however these are limited to only certain tests. For example, hERG assays are used to test whether a drug could interfere with the heartbeat and mini-pigs can be used in cases where dogs are not suitable, such as hormone therapies.

During testing, the dogs can be monitored remotely and continuously through implanted transmitters or specially designed jackets. These keep track of blood pressure, heart rate, body temperature and electrocardiogram while the dogs behave normally. The effects of the drug are also examined on dogs under terminal anaesthesia.ANCHOR This gives researchers a clearer picture of the haemodynamics in addition to the telemetry gained.


References

  1. Thorsons Von Mering J & Minkowski O (1889) Diabetes mellitis nach pankreas extirpation. Archiv Exp Path Pharmak 26, 371
  2. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1904/pavlov-bio.html
  3. Gerard P. Smith (2000) Pavlov and integrative physiology Am J Physiol Regul Integr Comp Physiol 279:(3) R743-R755
  4. Mellanby, E. (1976), An experimental investigation on rickets Nutrition Reviews 34:338–340 doi: 10.1111/j.1753-4887.1976.tb05815.x
  5. http://www.nndb.com/people/091/000275263/
  6. http://www.diet.com/g/mellanby-edward
  7. http://pyramid.spd.louisville.edu/~eri/fos/interest1.html
  8. http://pyramid.spd.louisville.edu/~eri/fos/Rabies.html
  9. J.L. Prevost and F. Batelli, (1899) "Sur quelques effects des décharges électriques sur le cœur des Mammifères." C R Seances Acad. Sci 129, pages 1267–1268.
  10. C.F. Beck, W.H. Pritchard and H.S. Feil (1947) "Ventricular fibrillation of long duration abolished by electric shock." JAMA 136, pp. 985–986.
  11. Zoll PM et al (1956) "Termination of ventricular fibrillation in man by externally applied electric countershock." N Engl J Med 254, pages 727–73
  12. B. Lown, R. Amarasingham and J. Neuman (1962) "New method for terminating cardiac arrhythmias: use of synchronized capacitor discharge." JAMA 182, pages 548–555.
  13. Bigelow WG, Callaghan JC, Hopps JA. (1950) Ann Surg. Sep;132(3):531–537
  14. Frater R and Ellis L (1961) In Merendino, ref 1
  15. Starr A (1961) J Thoracic Cardiovasc Surg 42, 673
  16. Starr A and Edwards M (1961) Ann Surg 154, 726
  17. Paton B (1972) in Biological Tissue in Heart Valve Replacement. Ed Ionescu M, Ross D and Wooler G. Butterworths, London
  18. Carpentier A et al. (1969) J Thoracic Cardiovasc Surg 58, 467
  19. Sampaolesi M et al (2006) Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs Nature 444, 574-579 doi:10.1038/nature05282
  20. Valkenburg KC and Williams BO (2011) Mouse Models of Prostate Cancer Prostate Cancer Article ID 895238 doi:10.1155/2011/895238
  21. G. H. Whipple, F. S. Robscheit and C. W. Hooper (1920) Blood regeneration following simple anemia. IV. Influence of meat, liver and various extractives, alone or combined with standard diets. American Journal of Physiology, 53: 236-262
  22. https://www.gov.uk/government/publications/statistics-of-scientific-procedures-on-living-animals-great-britain-2012
  23. Nature 474, 551 (2011) doi:10.1038/474551a
  24. The ethics of research involving animals, Chapter 9 http://www.nuffieldbioethics.org/sites/default/files/files/Animals%20Chapter%209%20Animal%20Use%20in%20Toxicity%20Studies.pdf

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