Biomedical subjects
Publications and source records attributed to B Roth.
The mass spectra of 75 analogs of trimethoprim were used in a study correlating mass spectrometric data with biological activity. Using pattern recognition techniques a correlation was obtained. Experiments to elaborate the basis of the correlation are described.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
A questionnaire survey has been made of the life effects of narcolepsy in 180 patients, 60 each from North American, Asian and European populations, with 180 similarly distributed age and sex matched controls. Life-effects were attributed by the patients to the primary symptoms of excessive daytime drowsiness, sleep attacks, cataplexy, vivid hypnagogic hallucinations and sleep paralysis, and also to other frequent symptoms such as visual problems (blurring, diplopia) and memory impairment. Occupational problems were prevalent (over 75%) and included statistically significant deleterious effects upon performance, promotion, earning capacity, fear of or actual job loss and increased disability insurance. Driving was greatly affected and patients fell asleep at the wheel more frequently (66%), had near or actual accidents from drowsiness or falling asleep at the wheel (67%), and could experience cataplexy (29%) or sleep paralysis (12%) while driving. Work or home accidents attributed to sleepiness or sleep (49%) or related to smoking (49%) were much more common in patients. There were also deleterious effects on education, recreation and personality related to disease. Narcolepsy can produce a variety of life-effects probably more serious and pervasive than, for instance, those of epilepsy, therefore emphasizing the importance of early diagnosis and treatment.
Forty trimethoprim analogues in which the para substituent in the benzene ring was varied were prepared for antibacterial evaluation. All were very potent inhibitors of Escherichia coli dihydrofolate reductase. The similarity of their inhibitory activities strongly suggested that the side chains beyond the first two atoms were not in contact with the enzyme. However, among 38 ether derivatives which varied widely in their bulk and lipophilicity, very few approached trimethoprim in their broad-spectrum in vitro antibacterial activity. The 4'-methyl and 4'-ethyl analogues and the allyloxy and gamma-chloropropoxy ethers had activities fairly close to that of trimethoprim. The two ethers were chosen for further evaluation in vivo. Neither compound quite matched trimethoprim in efficacy in mice, and their half-lives, as well as that of the beta-methoxyethoxy analogue, were found to be shorter in dogs.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Eight patients suffering from idiopathic hypersomnia with sleep drunkenness were given neurological, psychological and polygraphic investigations, and that after 4, 8 and 12 hours of nocturnal sleep. Also examined and tested were 8 controls - after 4, 8 and 0 hours of sleep during the preceding night. The patients and the controls were awakened and tested in the afternoon hours 30-45 minutes after they had fallen asleep. Under those circumstances the state of sleep drunkenness was observed in the patients in 19 instances, but only once in the controls. While experiencing sleep drunkenness the subjects were found to have prominent cerebellar signs, proprioceptive hypo- or even areflexia, signs of vestibular and, rarely, pyramidal tract involvement. Psychological tests scores and scores for the fine and gross motricity tests were substantially worse in sleep drunkenness than in wakefulness. Sleep drunkenness manifested itself in the polygraphic recordings by signs of microsleep. Pathological predisposition to the development of sleep drunkenness in hypersomniacs was found to be the most significant factor responsible for the occurrence of this state. Attention is drawn to the analogy between states of sleep drunkenness and automatic behaviour in narcoleptics and hypersomniacs as a common feature of both states. The authors believe that sleep drunkenness in idiopathic hypersomnia develops as a result of chronic relative sleep deprivation in those patients whose sleep requirements are greater than conditions of normal life can permit.
Immunopathological findings in a case with infantile X-linked agamma globulinemia (Bruton's disease) are reported and compared to similar data from two cousins of the patient. Besides a severe decrease in B-lymphocytes in blood and lymph node, residual B-cells showed an almost total defect in Ig surface receptor expression. In addition, there was an unusual lymphocyte population which apparently exhibited E-rosette formation (i.e. T-cell characteristics) and phagocytosis. The data suggest that in Bruton's disease there may be a disturbance of the T-cell system besides the well known B-cell deficiency.
A new route to 5-(p-hydroxybenzyl)pyrimidines has been developed which utilizes phenolic Mannich bases plus pyrimidines containing at least two activating groups. The products can be alkylated on the phenolic oxygen or on the pyrimidine N-1 atom, depending on conditions. This method has been used to prepare trimethoprim, a broad-spectrum antibacterial agent, starting from 2,4-diaminopyrimidine and 2,6-dimethoxyphenol.
Electrophilic substitution of 2,4-diaminopyridine by 2,6-disubstituted -4-[(N,N-dimethylamino)methyl]phenols and by halogens (bromine and fluorine) produces 3-benzyl and 3-halo derivatives, plus a small amount of disubstitution at the 3,5 positions. Treatment of a 2,4-diamino-3-halopyridine with phenolic Mannich bases gives 5- and N-benzylation. 2,4-Diamino-3-bromo-5-(4-hydroxy-3,5-dimethoxybenzyl)pyridine was methylated on the phenolic group in good yield and dehalogenated to produce 3-deazatrimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyridine]. This compound is about 300-fold less active as an inhibitor of Eschericia coli dihydrofolate reductase than is trimethoprim. 2,6-Diaminopyridine is very readily dibenzylated at the 3,5 positions as well as on an amino group, by a phenolic Mannich base; use of a fourfold excess of the pyridine provided a 3-benzylated 2,6-diaminopyridine in 50% yield; this was inactive as an inhibitor of dihydrofolate reductase at 10(-4) M. 2-Amino- and 4-aminopyridines do not produce C-benzylated products under the conditions reported here.
The preparation of a wide variety of 6-substituted trimethoprim analogues was readily accomplished by the reaction of 2,4-diamino-6-substituted-pyrimidines with 2,6-dimethoxy-4-[(N,N-dimethylamino)methyl]phenol at 120--160 degrees C. The less reactive 2,6-dialkyl-4-[(N,N-dimethylamino)methyl]phenols reacted successfully with 2,4-diamino-6-(alkylthio)pyrimidines to give 5-(substituted benzyl)pyrimidines. The phenolic groups of the products were alkylated in high yield when a nonreactive 6-substituent was present in the pyrimidine ring. 6-(Alkylthio) groups were easily removed with Raney nickel. Trimethoprim was thus obtained in high yield from its 6-(methylthio) counterpart. The 6-substituted trimethoprim analogues all had low activity as inhibitors of Escherichia coli dihydrofolate reductase and as antibacterial agents.
The growth hormone (GH) and prolactin (PRL) responses to metoclopramide (MCP) were compared to those with arginine and insulin-induced hypoglycaemia in eight children. While a significant rise in GH release after stimulation with arginine and insulin occurred in all subjects (P less than 0.05), no significant increase after MCP ingestion was observed. Metoclopramide, a dopamine antagonist, stimulated PRL release in all children, while arginine and insulin-induced hypoglycaemia stimulation tests showed variable PRL responses. A statistically significant increase in cortisol secretion 5 h following MCP was observed (trend test, Cox & Stuart, 1955) (P less than 0.05), but the plasma concentration at this time was still within the normal range. Metoclopramide stimulation is not a suitable test for growth hormone deficiency in children.
Basal prolactin concentrations in forty-eight children with acute or chronic renal disease have been compared with those in thirty-four healthy control subjects. Elevated basal prolactin levels and an abnormal prolactin response to intravenous thyrotropin-releasing hormone were found in children with chronic renal failure on maintenance intermittent haemodialysis. No significant change in plasma prolactin concentrations and osmolality was observed before and after haemodialysis, despite a fall in plasma creatinine concentrations. The elevated prolactin levels fell to normal in three patients after successful renal transplantation. It is suggested that the kidney has an important role to play in prolactin metabolism.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.