“N. P. Kravkov’s role in Russian pharmacology is as great as I.P. Pavlov’s in physiology”
Professor A.I. Kuznetsov, a former student of N.P. Kravkov
Nikolai Pavlovich Kravkov
8 March 1865 (Ryazan) – 24 April 1924 (Leningrad)
The father of Russian pharmacology,
Doctor of Medicine (1894),
full member of the Military Medical Academy (1914),
Corresponding Member of RAS (1920),
Lenin Prize laureate (1926, posthumously)
Photo: 1904, from the family’s archive.
Academician Nikolai Petrovich Kravkov is considered the father of Russian pharmacology. He sought to bring together laboratory science and clinical practice, always contemplating how the results of his research could benefit humanity. As a talented teacher, he not only left a legacy of remarkable scientific works but also, no less importantly, created a scientific school.
Nikolai Kravkov was born on May 8, 1865 in the city of Ryazan (Russia) into a small family of a military clerk. It is noteworthy that Pyotr Dmitrievich Pavlov, a clergyman and the father of the renowned physiologist I.P. Pavlov1, baptized him. Nikolai was the sixth of the nine children in the family. Although the Kravkovs were by no means financially well off, all the children received an education. As a child, Nikolai was a very boisterous and fidgety boy, who used to run away from classes, breaking out into “the outer world”. From the age of twelve, he was a passionate lover of hunting. At one point, he even dropped out of gymnasium but, thanks to his elder brother, he was allowed to complete the course1-2. There was an occasion during that time that profoundly influenced Nikolai’s choice of his future career.
One day, he was strolling out in the woods, with his ever-present sporting gun, when he came across pages from the “Reflexes of the brain” book by I.M. Sechenov, who was already a famous physiologist at that time. Having taken keen interest in the book, and biology as a whole, Kravkov was soon determined to leave home and enroll as a student to study under Prof. Sechenov, whatever the cost1. So in 1884, he was accepted into the natural science division of the Faculty of Mathematics and Physics at St. Petersburg University (at which point the well-known physiologist was a member of the university’s teaching staff), where he was lucky to be able to work at Sechenov’s famous physiology laboratory. Shortly after he graduated from university in 1888, with a candidate of science degree in natural science1-3, Kravkov went on to train at the Military Medical Academy, from which he qualified with distinction as a GP in 18921-3. While at the academy, he joined the Laboratory for General and Experimental Pathology under Prof. V.V. Pashutin, Sechenov’s former student.
In recognition of his achievements, Kravkov was offered a placement within the department of general and experimental pathology, and in 1894, aged 29 years, he successfully defended his doctoral thesis and was sent abroad on a study tour1-3. From 1896 to 1897, he visited Germany, Austria, France, Italy and Switzerland, attending lectures by top European academics and carrying out experimental studies at research institutes and universities. After completing his particularly fruitful residency in Strasbourg, at the laboratory of O. Schmiedeberg, an outstanding experimental pharmacologist, Kravkov ultimately decided to devote himself to pharmacology2. On returning to Russia in 1899, Kravkov was voted to fill a professor’s chair in the department of pharmacology at the Military Medical Academy, which he held permanently until his death (for nearly 25 years1-3). During that time, Kravkov founded his widely known school of pharmacologists, which paved the path for pharmacological research in Russia.
His colleagues recognized Kravkov as an outstanding scientist. In 1904, he was elected Honorary Member of the Academy of Physics and Chemistry of Italy (Palermo) and awarded a Class 1 Medal for his scientific works. In 1914, Kravkov was elected full member of the Imperial Military Medical Academy. Over the years of his service, the professor was awarded an Order of St. Anna, 3rd class, and two Orders of St.Vladimir, 4th class and 3rd class. On December 1, 1920, following an endorsement by I.P. Pavlov, Kravkov was elected Corresponding Member of the Russian Academy of Sciences, and in 1923, he became the head of the newly opened pharmacological unit at the Institute of Experimental Medicine — the country's major research center4. However, the unit’s team lost their leader shortly after the opening – Nikolai Kravkov died in the prime of his productive career in 1924, of cerebral thrombosis1-2.
Kravkov was a talented teacher. Once he had to struggle his way to the speaker’s stand through such a huge audience of attendees that he eventually had to be carried there bodily by the students1. His brilliant textbook called “The Fundamentals of Pharmacology” (1904-1905), used by multiple generations of Russian biologists and doctors as a mainstay clinical pharmacology guideline, has had 14 editions1-2. The book was to be published in Germany (it was even translated by the author into German) but the manuscript was lost while being delivered from Russia1.
Kravkov’s scientific legacy is extensive and diverse. In the midst of excruciating hardships in the country’s history (World War I, the Revolution and the Civil War), and often with a shortage of reagents and materials, Kravkov managed to make scientific breakthroughs which were ahead of his time. Krakov primarily accomplished these discoveries through a wide application and improvement of the isolated organ approach. Inlet and outlet tubes were gently attached to the vessels of an isolated organ (the kidney and adrenals, spleen, lungs, pancreas and even human fingers) and special solutions were passed through the organ, keeping it viable and suitable for observing its response to various chemical compounds. This method permitted Kravkov to conduct research into a large number of processes and analyze the mechanisms of action of many pharmacological agents. In this way, he found that vessels were able to independently (of the heartbeat) change the size of their lumens (enlarge or narrow them) and this process varied with different agents being added. Kravkov demonstrated a relationship between a substance’s chemical structure and its physiological effect.
For example, he showed that different saccharides (glucose, mannose, and galactose) affect differently on cardiac function. Kravkov was one of the world’s first researchers to investigate the effects of drugs (adrenaline, caffeine, morphine, etc.) on gas exchange. By examining the functions of isolated endocrine glands, the scientist was able to extract adrenal and pancreatic secretions and study the effects of different agents on their production. The secretion of the pancreas, similar in its properties to insulin, was called by Kravkov ‘pancreotoxin’, and since Banting and Best's research on isolated insulin had not been much heard of by that time, it is righteous to say that Kravkov had discovered this vital hormone independently of the Canadian scientists.
He is also credited with the discovery of intravenous hedonal anesthesia (before that, only inhaled hedonal was used for this purpose), which acquired a wide application both within and outside Russia and became known as “Russian anesthesia”. Kravkov’s experiments to “reanimate” organs and tissues seemed miraculous. Furthermore, the scientist succeeded in restoring sensitivity of embalmed human fingers, and in maintaining, the response of the kidney and the spleen to drug exposure for 10 days after the individual or animal died. Nikolai Kravkov is also one of the pioneers of evolutionary and comparative pharmacology, not only in Russia but also around the globe1-3.
For many years, Kravkov was looking into the sensitivity of living tissue (protoplasm) to various agents2. This research resulted in a paper called “On sensitivity limits of living protoplasm” (1924), which described experiments with the isolated rabbit ear5. The scientist noticed that organ vessels were responsive to extremely diluted drugs, heavy metals and other chemicals. Moreover, the vascular response in the ear varied quantitatively and qualitatively with increasing level of dilution, up to effect inversion (distortion).
For example, adrenaline and other vasoconstrictors exhibited a vasodilator effect with higher dilution levels5 (today we know that this effect is caused by the mutually opposite action of the different types of the adrenaline receptor, with one having a lower sensitivity threshold and therefore becoming activated following a smaller concentration of adrenaline). Kravkov also noticed that highly diluted substances exhibited a stronger effect than when at high concentrations5. These experiments stirred huge interest among doctors, physicists, chemists and biologists. Krakov himself would joke that even one gram of a substance dissolved in Lake Ladoga would still have its effect on the body1. However, experiments with high dilutions posed more questions rather than providing answers. The reason was that the level of dilution (with the starting concentration of 0.01%), at which substances could still be observed to exhibit activity, was 10-32. The concentration of a substance in such dilutions was a molecule per thousands of liters, so the scientist assumed that he was dealing with matter-to-energy conversion experienced by living protoplasm5
Nikolai Kravkov maintained a viewpoint that the action of microdoses2 has a material basis, yet he could not himself explain all his experimental findings. That might be reason why he did not publish these findings while alive nor included them in “The fundamentals of pharmacology”. The scientist drew an analogy with odorous substances that can be sensed by animals at kilometers’ distance away from the source, when none of the then-known devices was able to detect the active molecules of a substance2 (now it is known that insects, for example, can sense an odor, with only one pheromone molecule present, whereas at least 50 molecules is required for a human)6.
Of course, the methods used by Kravkov to investigate the sensitivity of living tissue to various agents cannot be considered accurate these days. Besides, the scientist himself did not regard the isolated organ approach as universal. Prof. A.I. Kuznetsov, one of Kravkov’s former students, subsequently recalled, “when working with isolated organs, Nikolai Pavlovich and his students never made mechanistic mistakes in their interpretations of the results. They never considered these organs to be a proper and accurate reflection of the effects that occur in the whole body.” 1 The sensitivity of vessels in the isolated ear is unstable, i.e. it varies with time and slightest changes in the conditions5, which prevents establishing a precise baseline level or clear causal relationship between the solution introduced and its effect. That was clear to both the author and his contemporaries, who were critical of the above-mentioned study. This is perhaps why the related research paper only contains examples of effects produced by various agents and their micro doses but does not include any data from quantitative reproducibility analysis. Kravkov wrote: “The effects of enormously diluted poisons appear to lose their specific qualities and become identical with one another, notwithstanding their chemical and pharmacological nature5.”
In 1926, N.P. Kravkov became the first winner of the Lenin Prize, the most prestigious award of the Soviet Union, for outstanding accomplishments in science and technology. It was awarded to him posthumously for his scientific works including: “The data and prospects for the reanimation of tissue from the dead”, “On functional changes in human and animal vessels in various pathologic conditions”, “On sensitivity limits of living protoplasm”, and “The fundamentals of pharmacology1-4”.
1. Uzbekova, D.G. (2013). Nikolai Pavlovich Kravkov – the father of the national school of pharmacologists. Lichnost’ v Menyayushchemsya Mire: Zdorovye, Adaptatsiya, Razvitiye [The Personality in the Changing World: Health, Adaptation and Development] [in Russian], (1), 13–34.
2. Shabanov, P.D (2015). The prominent Russian pharmacologist N.P. Kravkov and his contribution to the world’s pharmacology (in commemoration of the 150th anniversary). Obzory po Klinicheskoi Farmakologii i Lekarstvennoi Terapii [Clinical Pharmacology and Drug Therapy Reviews] [in Russian], 13(2), 54–71.
3. Knopov, M.S., Taranukha V.K. (2014). Nikolai Pavlovich Kravkov –lifelong devotion to pharmacology. Eksprerimentalnaya i Klinicheskaya Farmakologia [Clinical and Experimetal Pharmacology] [in Russian], 77(4), 3–5.
4. Uzbekova, D.G. (2015). Academician N. P. Kravkov – a scientist and a teacher (in commemoration of the 150th anniversary). Lichnost’ v Menyayushchemsya Mire: Zdorovye, Adaptatsiya, Razvitiye [The Personality in the Changing World: Health, Adaptation and Development]. No. 1 (8), 107-123.
5. Kravkov, N.P. (1924). On sensitivity limits of living protoplasm. Uspekhi Eksperimentalnoi Biologii [Advances in Experimental Biology]. 3(3−4), 147-172.
6. Menini, A., Picco, C., Firestein, S. (1995). Quantal-like current fluctuations induced by odorants in olfactory receptor cells. Nature, 373(6513), 435–437.