Biomedical subjects
Publications and source records attributed to H Jones.
5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.
We have made a series of 4- and 5-aryl- and 4- and 5-heteroarylsalicylic acid derivatives with the objective of reducing gastric irritation and increasing potency. Here we describe a series of 4- and 5-heterocyclic salicylic acids and their antiinflammatory-analgesic potencies measured in comparison to aspirin. An improvement of the therapeutic index over aspirin of 100 was achieved; however, the heterocyclic salicylic acids lacked antipyretic activity. Some physicochemical parameters which may bear on the antiinflammatory activity of these compounds are discussed.
The long-term effect of prednisone in Crohn's disease has been examined in a double-blind controlled trial. Clinical relapse, recurrence, and extension of the disease were examined in 64 patients followed-up for up to three years. Fourteen patients were withdrawn because of severe symptoms (eight on prednisone and six controls); the withdrawal rate in both groups was 30% at three years. Nine other patients had radiological recurrence or extension of disease (five prednisone and four controls). Prednisone did not improve the relapse rate, nor did it affect recurrence or extension of disease.
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Forty-four adult male mongrel dogs were used to compare segmental cortical freeze-dried allogeneic bone grafts with fresh autogenous, freeze-dried autogenous, and fresh allogeneic segmental cortical grafts. Group I consisted of bilateral fresh autografts as external controls; Group II, a fresh autograft on one side for internal control and a freeze-dried autogenous graft on the other side to evaluate the effect of freeze-drying on repair; Group III, a fresh autograft on one side and a fresh allograft on the other side to measure the differences between autogenous and allogeneic grafts; and Group IV, a fresh autograft on one side and a freeze-dried allogeneic graft on the other to see if freeze-drying altered the repair of allogeneic grafts. The grafts were analyzed qualitatively over a six-month period by the use of interval roentgenograms to determine the times of graft-host union and the incidence of fatigue fractures. Six months after operation, the repair processes in the four groups were compared quantitatively with respect to biological repair and physical strength using torsional stress-testing, tetracycline labeling, and microradiography. The results indicate both qualitatively and quantitatively that: (1) fresh bilateral segmental cortical autografts show reproducible characteristics, so that the canine fibula furnishes a satisfactory model (Group I); (2) freeze-drying does not inhibit the repair process per se (Group II); (3) fresh allografts are rejected in varying degrees of intensity (Group III); and (4) freeze-drying does not protect cortical allogeneic grafts from such rejection (Group IV).
A series of peptides and depsipeptides containing 2-methylcarbazic acid (H-Mec-OH), the 2-aza analogue of alanine, was prepared and tested as inhibitors of pancreatic and human granulocyte elastases. A requirement for a minimum chain length as well as specific amino acid sequence was observed which correlates well with both substrate and inhibitor studies by others in this field. The most active inhibitors have the structure Ac-Ala-Ala-Pro-Mec-Lac-R. When Lac-R is an ester, only the pancreatic enzyme is inhibited. When Lac-R is an amide or hydrazide, then both enzymes are inhibited. The inhibitory activity is reversible; the inhibitors are not hydrolyzed by the enzyme and the inhibition is noncompetitive with synthetic substrates of similar structure, suggesting that binding at the sites adjacent to the carboyl group of the amino acid analogue, 2-methylcarbazic acid, is important for this inhibition. The data further demonstrate the differences between pancreatic and granulocyte elastases.
In advanced osteoarthritis, all of the cartilaginous components are lost from the joint surface. Although mechanisms exist for proteoglycan degradation, there is not known to be any system for removal of the collagen. This study suggests that the loss of the collagen components may be a function of articular cartilage collagenase. The enzyme in normal human cartilage is bound to an inhibitor and appears to be present in very small amounts. Attempts to demonstrate collagenase activity in ground human articular cartilage or in its lysosomal fraction were unsuccessful. 7-Day cartilage tissue cultures also failed to demonstrate the presence of the enzyme; but the same culture fluid, incubated with trypsin, showed significant degradation of collagen, suggesting that trypsin destroyed the inhibitor. 7-Day culture fluids were then chromatographed on a heparin-charged Sepharose 4B affinity column that had been activated with cyanogen bromide. This removed the inhibitor, and the chromatographed fluid from osteoarthritic cartilage released 42% of the incorporated counts of the collagen substrate, whereas normal cartilage released 10.1% and a trypsin control, 6.4%. Electrophoresis of the degradation products of the enzyme-collagen complex incubated at 37 degrees C revealed breakdown was complete to small dialyzable fragments, while at 25 degrees C larger fragments were split off.
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Comparison of the rate and extent of penetration of test compounds from plasma into brain and muscle of the hagfish, Myxine glutinosa, indicates that the blood-brain barrier is poorly developed or absent in this species. We examined a series of hagfish brains in the light and electron microscope in order to relate the structure of the brain to the physiology of the blood-brain barrier and cerebrospinal fluid. The ventricular system consists of an ependymal cell-lined central canal extending from the spinal cord to the midbrain and two or more ependymal cell-lined cavities located more rostrally. A preoptic and an infundibular recess were present in the diencephalons of all brains and were isolated from each other and from the primary ventricular system. Since a typical choroid plexus could not be identified, this suggests that cerebrospinal fluid must be formed entirely by brain in this species. Cerebral capillaries differ significantly from those of other vertebrates in possessing large numbers of cytoplasmic vesicles and in the relative rarity of tight junctions between endothelial cells. These capillaries do not, therefore, appear to be morphologically specialized for barrier functions.
Section of the medial collateral and both cruciate ligaments combined with resection of the medial meniscus in rabbit knees caused instability and during the ensuing six months these knees showed progressive histological changes similar to those of human osteoarthritis. Biochemical analysis of the cartilage from such knee joints demonstrated a decrease in proteoglycan, an increase in acid phosphatase, and increases in the rates of synthesis of protein and glycosaminoglycan. These findings, which are quite consistent with those in human osteoarthritis, suggest that this animal model may be of value in the study of the pathogenesis and treatment of human disease.
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A questionnaire was developed for use with a large sample of passengers travelling in British Rail stock on a cross-section of main line routes serviced by London Midland Region. The questionnaire was distributed to a stratified random sample of 1500 passengers-covering both male and female travellers in five different carriage types. The aim of the study was to determine the improvements passengers would most like to see in existing carriage design, and generally what they felt about the quality of their environment. The questionnaire included sections covering personal and travel details, a check list of conceivable improvements, and the use of the semantic differential technique for obtaining passengers' impressions and perceptions. The findings allowed comparisons to be made between the different carriage interiors and resulted in recommendations for the possible modification of certain carriage designs.
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