The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puscas (1932-2015).

Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puscas used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the ß-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puscas for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.

[Pharmacologists in the camps in the Third Reich--part second]. / Farmakolodzy w obozach III Rzeszy--czesc druga.

SS Hygiene Institute provided adequate funding for research on the treatment of mycobacterial infections, and two scientists who became famous in the subject were Dr. Waldemar Hoven (KL Buchenwald) and Dr. Kurt Heissmeyer (KL Neuengamme). They conducted researches not only on adult prisoners, but also on the Jewish children. Studies of tuberculosis were also conducted under the auspices of the German Medical Association by Dr. Rudolf Brachtel. In turn, Dr. Klaus Schilling dealt with the treatment and immunoprophylaxis of malaria. He tested such substances, as pyramidon, aspirin, quinine and atebrin on more than 1200 prisoners. These sulfonamide-derived drugs, were also studied by prof. Karl Gebhardt and Dr. Fritz Fischer. They assessed the efficacy of these drugs in the treatment of "dirty" wounds incurred by German soldiers. Dr. Heinrich Schutz, Karl Babor and Waldemar Wolter they were enthusiasts in so-called biochemical therapy, based on the use of substances of natural origin, such as salt. After termination of War, during the Nuremberg Trials, many of them evaded responsibility, they were running medical practices, some were publishing. However, despite those facts, trials of Nazi war criminals were not result less, they opened world's eyes for the necessity of clarifying rudiments of human subject research, they gave foundations to define records like The Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine or Good Clinical Practice.

[The infectious diseases experiments conducted on human guinea pigs by Nazis in concentration camps]. / Gli esperimenti di infezioni su cavie umane compiuti dai nazisti nei campi di concentramento.

The author systematically examined all available publications and web documents, with regard to scientifically documented experiments carried out by Nazi physicians in their concentration camps during World War II. This research focused on human experiments dealing with: malaria, tuberculosis, petechial typhus, viral hepatitis, and those regarding sulphonamides as antimicrobial agents. The concentration camps involved by experimental programmes on human guinea pigs were: Natzweiler Struthof, Dachau, Mauthausen, Buchenwald, Neuengamme, Ravensbrück, Sachsenhausen and Auschwitz. Overall, around 7,200 deported prisoners went to their deaths during or because of these experiments (also considering human trials other than previously quoted ones). At the end of the war several physicians were charged with war crimes in two trials (Nuremberg and Dachau), and those found guilty were sentenced to death, or years of imprisonment. Some of them, including the notorious Josef Mengele, succeeded in escaping capture and being brought to justice. Thanks to these trials, partial light has been shed on these crimes, which not infrequently had children as designated victims, selected with excruciating cruelty in special segregation sections. The SS was the key structure which ensured maximum efficiency for these experimental programmes, from both logistic planning through to an operative control system carried out in concentration camps, and thanks to an autonomous, dedicated medical structure, which included a rigid hierarchy of physicians directly dependent on the head of SS forces (Reichsführer), i.e. Dr. Heinrich Himmler. Moreover, it is worth noting that also physicians who were not part of the SS corps collaborated in the above experiments on human guinea pigs: these included military personnel belonging to the Wehrmacht, academic physicians from German universities, and researchers who worked in some German pharmaceutical industries, such as IG Farben, Bayer and Boehring.

The management of subacute bacterial endocarditis superimposed on rheumatic heart disease in the immediate pre-penicillin era: the case of Pasquale Imperato.

Subacute bacterial endocarditis (SBE) was invariably a fatal disease in the pre-penicillin era. The availability of sulfonamide antibiotics beginning in the mid-1930s raised hopes that they would be effective in SBE. Unfortunately, except in rare instances, they were not. This paper reviews the clinical experience with sulfonamides in the pre-penicillin period in treating patients with SBE. It presents in detail the case of Pasquale Imperato, who died from the disease at the age of 72 years on 30 November 1942. In so doing, it focuses on the medical management measures then available to treat patients with SBE and on the inevitable course of the illness once it began. Also discussed is the relationship of acute rheumatic fever and its sequela, rheumatic heart disease, to predisposing people to SBE and possible genetic factors. The well-known case of Alfred S. Reinhart, a Harvard Medical School student who died from SBE in 1931 and who kept a detailed chronicle of his disease, is also discussed and contrasted with Pasquale Imperato's case.

"A startling new chemotherapeutic agent": pediatric infectious disease and the introduction of sulfonamides at Baltimore's Sydenham Hospital.

Using pediatric patient records from Baltimore's Sydenham Hospital, this article explores the adoption of sulfa drugs in pediatrics. It discusses how clinicians dealt with questions of dosing and side effects and the impact of the sulfonamides on two diagnoses in children: meningococcal meningitis and pneumonia. The care of infants and children with infectious diseases made demands on physicians and nurses that differed from those facing clinicians treating adult patients. The article demonstrates the need to distinguish between pediatric and adult medical history. It suggests that the new therapeutics demanded more intense bedside care and enhanced laboratory facilities, and as a result paved the way for the adoption of penicillin. Finally, it argues that patient records and the published medical literature must be examined together in order to gain a full understanding of how transformations in medical practice and therapeutics occur.

The war against bacteria: how were sulphonamide drugs used by Britain during World War II?

Penicillin is often considered one of the greatest discoveries of 20th century medicine. However, the revolution in therapeutics brought about by sulphonamides also had a profound effect on British medicine, particularly during World War II (WWII). Sulphonamides were used to successfully treat many infections which later yielded to penicillin and so their role deserves wider acknowledgement. The sulphonamides, a pre-war German discovery, were widely used clinically. However, the revolution brought about by the drugs has been either neglected or obscured by penicillin, resulting in less research on their use in Britain during WWII. By examining Medical Research Council records, particularly war memorandums, as well as medical journals, archives and newspaper reports, this paper hopes to highlight the importance of the sulphonamides and demonstrate their critical role in the medical war effort and their importance in both the public and more particularly, the medical, sectors. It will present evidence to show that sulphonamides gained importance due to the increased prevalence of infection which compromised the health of servicemen during WWII. The frequency of these infections led to an increase in demand and production. However, the sulphonamides were soon surpassed by penicillin, which had fewer side-effects and could treat syphilis and sulphonamide-resistant infections. Nevertheless, despite these limitations, the sulphonamides drugs were arguably more important in revolutionising medicine than penicillin, as they achieved the first real success in the war against bacteria.

Karl Gebhardt (1897-1948): a lost man.

Karl Gebhardt (1897-1948) had a distinguished career as professor of sports medicine before the Second World War. He developed sports for the disabled at a specialised orthopaedic clinic at Hohenlychen and was President of the Red Cross in Germany. During the war, Gebhardt also acted as Heinrich Himmler's personal physician and was responsible for medical experimentation on prisoners in the concentration camps at Auschwitz and Ravensbrück. In his capacity as SS consultant surgeon, he treated Reinhard Heydrich (a high ranking Nazi official, also known as 'the Hangman') after an attempt was made on his life. When Heydrich died, Gebhardt was accused of failing to treat him with sulphonamides. To prove his innocence he carried out a series of experiments on Ravensbrück concentration camp prisoners, breaking their legs and infecting them with various organisms in order to prove the worthlessness of the drugs in treating gas gangrene. He also attempted to transplant the limbs from camp victims to German soldiers wounded on the Russian front. He was tried after the war and executed for these crimes in 1948. This paper explores the paradox of a gifted doctor who was also the perpetrator of inhuman crimes.

[History of antibiotics and sulphonamides discoveries]. / Historia odkrycia antybiotyków i sulfonamidów.

In the 19th century, the effect of mould on bacterial colonies was investigated. In 1921, Alexander Fleming examined systemic fluids and observed some substances called lyzosomes which were capable of dissolving bacteria. In 1928, he discovered that a specific mould species inhibited the development of Staphylococcus bacteria. The species was known as Pencillium notatum and the filtrate was called penicillin. In 1940, Howard Florey and Ernst Chain worked out the industrial production of penicillin. All three researchers were awarded the Nobel Prize in 1945, and since then the era of antibiotics has been initiated. In 1935, Gerhard Domagk discovered the first sulphonamide--prontosil rubrum. Four years later he received the Noble Prize.

[Sulfonamide-research on human subjects in Nazi concentration camps: a critical re-evaluation of the epistemological and ethical dimension]. / Die Sulfonamid-Experimente in nationalsozialistischen Konzentrationslagern: Eine kritische Neubewertung der epistemologischen und ethischen Dimension.

Existing scholarship on the experiments performed in concentration camps beginning in 1942 on the value of sulfonamides in treatment of wound infections, in which inmates were used as experimental subjects, maintains that not only were the experiments ethically and legally completely reprehensible and unacceptable, but that they were also bad science in the sense that they were investigating questions that had already been resolved by valid medical research. In contrast to this, the paper argues on the basis of contemporary publications that the value of sulfonamides in the treatment of wound infections, including gas gangrene infections, was not yet established, that is, that the questions pursued by the experiments had not been resolved. It also argues that regarding their "design" and methodical principles, the experiments directly followed the rationality of contemporary clinical trials and animal experiments. However, for the step from animal to the human experiment, the experimental "objects" were only in regard to their body, but not to their individuality and subjectivity regarded as "human". In a concluding section, the paper lines out some implications for an adequate historical reconstruction of medical research on humans, in particular the importance of a combined focus on the scientific rationality as well as explicit or implicit value hierarchies. Further, the article points to the potential impact of such a revised image of the sulfonamide experiments for present day debates on the ethics of medical research.

[Ophthalmia neonatorum of the newborn and its treatments in Canadian medical publications: 1872-1985]. / L'ophtalmie du nouveau-né et ses traitements á la lecture des publications médicales canadiennes: 1872-1985.

In the 19th century the occurrence of ophthalmia neonatorum had reached alarming rates in the maternity wards not only of Europe but also across Canada. The impact of this blinding ocular infection on Canadian medicine from 1872 to 1985 is examined through a review of 80 medical journals, books, and lay press articles of that period. The prophylactic and therapeutic use of 2% silver nitrate introduced by Credé in 1880 to prevent neonatal blindness is reviewed. The signs, symptoms, and corneal complications of this disease as well as the multiple ocular drugs used during this era will be presented. The judicial consequences on midwives and obstetricians will be discussed. The subsequent use of colloidal silver based agents such as collargol, protargol and argyrol followed by the introduction of sulfonamides and finally the routine use of prophylactic topical antibiotics will be reviewed.

[The discovery of hypoglycemic sulfonamides]. / La découverte des sulfamides hypoglycémiants.

In 1933 Auguste Loubatières started to work at the Physiological Laboratory of the Montpellier Medical School, famous for the scientific work of Emmanuel Hédon and then Louis Hédon on experimental diabetes mellitus. Auguste Loubatières was particularly interested in the study of a new preparation of long-lasting insulin (insulin-protamine-zinc: IPZ) in the totally pancreatectomized dog. In 1938, he observed that high doses of IPZ induced a severe and protracted hypoglycemia entailing convulsive attacks and even irreversible coma. The story of hypoglycemic sulfonamides started in France in spring 1942. During the second world war, because of the food shortage in Montpellier, a lot of people ate rotting food or even food contaminated with bacteria, such as shellfish. Many cases of thyphoid fever were diagnosed and treated by Marcel Janbon at the Clinic of the Montpellier Medical School with a new sulfonamide (VK 57 or 2254 RP). Adverse reactions were observed: in some patients, convulsions and even prolonged coma occurred; in some others a major drop in blood glucose was observed. M. Janbon informed the physiologists about these observations questioning them for an interpretation. A. Loubatières was particularly interested and immediately undertook animal trials. On June 13, 1942, he observed that repeated oral administration of 2254 RP in the normal fasting conscious dog induced a progressive, marked and long-lasting decrease in glycemia. He continued his experiments and definitively established the hypoglycemic effect of this sulfonamide. However the mechanism of action remained to be established. The pattern of some graphs reminded him that of some others he could previously observe in the study with IPZ; it occurred to him that 2254 RP could lower the blood glucose concentration by stimulating insulin secretion. He had then to establish the validity of his hypothesis. From 1942 to 1946, A. Loubatières performed a systematic study of the effects of 2254 RP and structural analogs and investigated the mechanism involved in the hypoglycemia. These results are reported in his "Doctorat ès-Sciences" thesis (1946). He observed that 2254 RP was ineffective on glycemia in totally pancreatectomized dogs but was effective in partially pancreatectomized ones. The hypoglycemic effect in normal dog was dependent on the plasma sulfonamide concentration; this effect appeared whatever the route of administration and was unaffected by vagotomy. Furthermore, Loubatières performed cross-circulation experiments. In these experiments, the pancreatico-duodenal vein of a normal dog was anastomosed to the jugular vein of a receiver dog made diabetic by alloxan; in this case, the injection of 2254 RP into the donor induced a decrease in blood glucose levels in the receiver. In early 1946, Auguste Loubatières proposed that the hypoglycemic property of 2254 RP was due to its ability to stimulate insulin secretion through a direct action on pancreatic islets; he wrote in his thesis "A notre avis, le para-amino-benzène-sulfamido-isopropylthiodiazol (2254 RP) est donc un corps essentiellement insulino-sécréteur; son action s'exerce directement sur les îlots de Langerhans". He also proposed to use such hypoglycemic sulfonamides in certain forms of diabetes "que l'on peut qualifier de fonctionnels et qui sont la conséquence d'une paresse des mécanismes insulino-sécréteurs". In 1992, Jean-Claude Henquin demonstrated that the sequence of events triggered by 2254 RP at the level of islet beta-cells was similar to that induced by sulfonylureas of the first or second generation. Thus, the 2254 RP, proposed by Auguste Loubatières in the treatment of certain forms of diabetes, was the first of oral hypoglycemic sulfonamides currently used in the treatment of type 2 diabetes mellitus.

Hechos históricos de las sulfamidas divulgados por la prensa: el caso de The New York Times / Sulfamides historical facts disclosed through the news media: the case of The New York Times

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