The problem of treating diabetes mellitus seemed to have been solved by the discovery of insulin and the production of purified crystalline insulin compounds whose time of effect can be varied by using different additions. Orally applicable substances for reducing the blood-sugar level have been searched for in order to free the diabetic from the necessity of daily injections. There are also other reasons for this research. Pathophysiological investigations in diabetes mellitus have shown that metabolic errors are not always based on a simple insulin deficiency but that in many cases other insulin antagonistic factors playa part. For instance ,the concept of deficiency diabetes growth-onset type, usually found in juveniles and ectomorphs, was contrasted with the concept of hypertensive diabetes (R. SCHMIDT 1924, 1930) or "Gegenregulationsdiabetes" (BERTRAM) or ,,"Oberfunktionsdia betes" (BARTELHEIMER 1940) or "Lipoplethoric diabetes" (LAWRENCE) in which there is a positive correlation to the adipose hyperplastic habitus with hypertensive tendencies (BARTELHEIMER 1940, ApPELS 1951). In this type of diabetes there is no ketosis tendency and a low insulin glucose equivalent, i. e. relative insulin resistance (F ALTA) due to a hormonal imba lance (too much blood-sugar-raising hormone is produced by the anterior pituitary lobe and the supra-renals and possibly also glucagon) or, to increased insulin de gradation in the organism, especially the liver (insulinase system, MIRSKY 1949, 1956).

Blood sugar lowering sulphonamide derivatives

A. Thiodiazole derivatives
I. Experiments
II. Clinical experience with thiodiazole derivatives
B. Sulphonylureas
I. Constitution and activity
a) Sulphonylureas
b) N-sulphonyl-N'acylureas
c) Sulplhoonylurethane
d) 2-sulphonamido-1,3,4-thiodiazoles
e) Sulphonylthioureas
f) Ineffective sulphonylureas and their derivatives
II. Animal experiments with BZ 55 and D 860
a) Pharmacology and toxicity
1. Methods for determining in blood and urine
2. Absorption from the intestine
3. Distribution in the organism, tissue and protein bond
4. Degradation and excretion
5. Plasma level and blood sugar lowering (relationship of dose and effect)
6. Bacteriostatic characteristics
7. Toxicity in animals
?) Acute toxicity
?) Chronic toxicity
8. Incompatibility and the influence of other drugs on the mode of action
b) Mode of action
1. Research in vitro
?) Muscle tissue
?) Adipose tissue
?) Liver tissue
?) Insulinase system
?) Insulin aggregation in vitro
?) Respiratory activity of kidney slices and dopadecarboxylase
2. Effect in the eviscerated, decerebrated and diabetic animal
?) Eviscerated and decerebrated animal
?) Diabetes after total pancreatectomy
?) Alloxan diabetes
?) Pituitary and steroid diabetes
?) Starvation diabetes ("Hungerdiabetes")
?)Spontaneous canine diabetes and hereditary adiposity hyperglycaemia syndrome in the mouse
3. Influencing of ?-cells and the glucagon effect
4. ?-cells and insulin secretion
?) Morphological findings in the ?-cell system
?) Pancreatic insulin content
?) Activity of the plasma insulin and cross-circulation experiments
?) The action on various metabolic parameters influenced by insulin
?) Glucose tolerance
?)The mechanism of ?-cell influencing
5. The role of other endocrine organs
?) Thyroid
?) Supra-renals
?) Pituitary
6. The role played by the liver
?) Depression of the blood sugar in the hepatectomised animal
?) Liver glycogen
?) Fat and protein metabolism in the liver
?) The action on the glucose output by the liver
7. The influence on glucose absorption from the intestine
III. Clinical observations with BZ 55 and D 860
a) Plasma level, degradation and excretion in man
1. BZ 55
2. D 860
b) Results of the sulphonylurea therapy in diabetes mellitus
1. Investigations on the controllability of diabetics using oral therapy
?) Statistical results
?) Test methods for judging controllability
?) Therapeutic successes in special cases of diabetes and the effect in rare disturbances in the carbohydrate metabolism
2. Lasting success, indication and contra-indication, treatment
?) The problem of the so-called seconadry failures in diabetes therapy
?) Indication and contra-indication
?) Combination therapy with insulin
?) Practical treatment
3. Side-effects, hypersensitivity reaction, cases of death
?) Hypoglycaemia
?) Skkin reactions
?) Haematopoetic system
?) Liver damage
?) Kidney changes
?) Nervous system
?) Thyroid gland
?) Gastro-intestinal disturbances, intestinal flora
?) Intolerance to alcohol
c) Clinical experimental research on the mechanism of action of the sulphonylureas
1. Plasma insulin determination
2. Potentiating of the insulin effect and insulin degradation
3. Acute blood sugar decrease and effect on various metabolic parameters influenced by insulin
4. Effect on hepatic metabolism in man
5. Influence on the glucagon effect
6. Influence on adreno-cortical function
7. Islet-cell system in diabetics receiving sulphonylurea therapy
8. Conclusions about the mode of action in man and animal from the experiments
d) Sulphonylureas as therapeutics in non-diabetic diseases
1. Dermatological diseases
2. Diseases ofgthe liver
3. Epilepsy
4. Psychiatric shock therapy
IV.Other clinically tested sulphonylureas
a) 1-cyclohexyl-3-p-tolylsulphonylurea (K 386)
b) N-propyl-3-p-chlorbenzoylsulphonylurea (chlorpropamide P 607)
1. Methods of determination ; distribution and excretion in animals and man
2. Toxicity, acute blood sugar decrease and mechanism of action
3. Permanent therapy and side-effects
c) N-(3-amino-4-methylbenzoylsulphonyl)-N'-cyclohexylurea (Metahexamide)
1. Methods for determination, distribution, excretionin animals and man
2. Toxicity, acute blood sugar decrease and mode of action
3. Long-term therapy and side-effects
Guanidine and guanidine derivatives
A. Guanidine
a) Pharmacological and metabolic properties
b) Acute toxicity
c) Investigations on the mechanism of the blood sugar lowering by guanidine
B. Constitution and the blood sugar lowering effect of various guanidine derivates
C. Experimental research on various guanidine derivatives
I. Pharmacology and toxicology
a) Acute toxicity
1. Synthalin
2. Biguanides
3. Symptomatology of the acute poisoning
b) Chronic toxicity
c) Comparing the effectiveness of guanidine derivatives and the sensitivity in different animal species
d) The guanidine-like properties of the guanidine derivatives
e) Action of glucose in the hypoglycaemic shock
f) Initial hyperglycaemia, epinephrine secretion, the effectiveness of epinephrine and glucagon
g) Liver glycogen
II. Animal experiments on the mechanism of blood sugar lowering through guanidine derivatives
a) Investigations with synthalin
b) Investigations on the biguanides
1. Investigations in vitro
?) Glucose uptake
?) Glucose output from liver tissue, the glycogen content of liver slices and diaphragm
?) Oxygen consumption
?) Glyycgolysis
?) Cellular permeability for glucose and other sugars
?) Investigations on the localisation of the biguanide effect in the intermediary metabolism
?) Potentiation of the insulin effect in vitro
2. Investigations on the non-diabetic animal
?) Glucose uptake
?) Glycolysis
?) Hepatic glucose output
?) Effect on gluconeogenesis
?) Inhibition of insulin degradation
?) Combination with insulin and tolbutamide
?) The effect of methylene blue on the blood sugar decrease
?) Indirect metabolic changes caused by epinephrine release
?) Stimulation of insulin secretion
?) ?-cell changes following guanidine derivatives
?) Effect on the glucose absorption from the intestine
3. Experimental diabetes
?) Diabetes following pancreatectomy
?) Alloxan diabetes
?) Phlorhizin diabetes
III. Investigations on the mechanism of action in man
a) Theory of glycolysis
b) Liver-glucose output and peripheral glucose utilization
c) Other endocrine organs
d) Stimulation of insulin secretion
e) Conclusion
D. Clinical experiments with various guanidine derivatives
I. Synthalin
a) Dosage
b) Effect of synthalin on the diabetic metabolic state
1. Glucosuria and hypoglycaemia
2. Ketoacidosis
c) Indication range
d) Toxic effects of synthalin in man
1. Acute toxic symptoms
?) Symptomatology
?) Measures for preventing symptoms of intolerance
2. Toxic symptoms during long-term synthalin treatment
?) Liver damage
?) Kidney damage
II. Galegine
III. Biguanides
a) The effectiveness of the biguanides on the blood sugar in the healthy human subject
b) Results of the biguanide therapy in diabetes mellitus
1. Investigations on the controllability of diabetes with biguanides alone
2. Effectiveness in different forms of diabetes
?) Stable diabetes in the adult
?) Mild juvenile diabetes
?) Insulin deficiency diabetes of the juvenile and adult
?) Rare, special forms of diabetes
3. Metabolic observations in diabetics treated with biguanides
?) Daily blood sugar profile, glucose tolerance, insulin and glucagon loading
?) Biguangide therapy and ketosis
4. Indication and contra-indication, practical treatment
?) Indication and contra-indication
?) Combined treatment with insulin and sulphonylureas
?)Therapeutical measures in control and dosage
5. Symptoms of intolerance and toxicity of the biguanides in man
?) Symptoms of intolerance and their treatment
?) Hypersensitivity reaction and organ changes
6. Comparison between synthalin and biguanide therapy in diabetes
Further substances proved as oral anti-diabetic drugs
A. Salicylate and salicylate derivatives
I. Experimental investigations
a) Blood sugar decrease in the animal
b) Investigations on the mechanism of the blood sugar decrease
1. Investigations in vitro
2. Experiments in vivo
3. Uncoupling of oxidative phosphorylation
II. Investigations with salicylates and salicylate derivatives in man
a) The effect of salicylates and salicylate derivatives on the metabolism of nondiabetics
b) The effect in diabetes mellitus
1. Clinical experience
2. Side-effects
3. Practical value of the salicylates in the diabetes therapy
B. Other benzoic acid derivatives
I. p-amino benzoic acid (PABA)
II. p-aminosalicylic acid (PAS)
C. 2,4-dinitrophenol (DNP)
D. Mesoxalic acid
I. Experimental investigations
a) Toxicity
b) Mechanism of action
II. Clinical investigations
E. Antihistamines and sympathicolytica
I. Secalealkaloides
II. Sympatheticolytic imidazole derivatives
III. Antihistamines
IV. Mechanism of action
Blood sugar lowering substances without clinical significance
A. Hypoglycin A and B
I. Structure of the hypoglycins
II. Experimental investigations
a) Toxicity and the blood sugar lowering
b) Mechanism of action
1. Investigations in vitro
2. Investigations in vivo
B. Mono-iodo-acetic acid and iodo-acetamide
C. Tris(hydroxy-methyl)-amino-methane (TRIS-buffer)
D. Less important blood sugar decreasing drugs and insufficiently investigated preparations
References.