Biomedical subjects

S S Matharu

Publications and source records attributed to S S Matharu.

9 recordsLinked to original sources

PubMed1996

Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds.

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

Acrylamides↗

PubMed1988

Synthesis and oral antiallergic activity of carboxylic acids derived from imidazo[2,1-c][1,4]benzoxazines, imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles.

4H-Imidazo[2,1-c][1,4]benzoxazine-2-carboxylic acid (3) was found to possess potent activity in the IgE-induced rat passive cutaneous anaphylaxis model which may be predictive of clinical antiallergic activity. Compared to disodium cromoglycate (DSCG, 1), 3 was less active following iv administration but unlike DSCG showed very significant oral activity. To explore the structural requirements for this activity, a range of tricyclic compounds was prepared and their activities were measured. Individual 2-carboxylic acids derived from imidazo[1,2-a]quinolines, imidazo[1,2-a]quinoxalines, imidazo[1,2-a]quinoxalinones, pyrrolo[1,2-a]quinoxalinones, pyrrolo[2,3-a]quinoxalinones, and imidazo[2,1-b]benzothiazoles showed iv activities up to 10(3) times as potent as DSCG and many of them showed significant oral activity. From these, imidazo[1,2-a]quinoxaline-2-carboxylic acid 114 has been chosen for further development.

Animals↗

PubMed1988

(Imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones and related compounds as potential nonsedative anxiolytics.

Several series of heterocyclic carboxylic esters were found to be active in the benzodiazepine receptor binding assay, a typical example being ethyl 7-ethyl-5-methoxyimidazo[1,2-a]quinoline-2-carboxylate (4b) with an IC50 of 150 nM. The corresponding phenylmethanone 5d was more potent with an IC50 of 14 nM and was orally active in animal models thought to predict anxiolytic effects. The synthesis of a large number of compounds resulted in the optimization of this activity in a series of (imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones of which compounds 7e, 8b, 8h, 8j, and 8k were equipotent with chlordiazepoxide while exhibiting reduced anticonvulsant activity, little or no muscle relaxation, and negligible sedative effects.

Animals↗

PubMed1980

Presentation of cancer to hospital as 'acute abdominal pain'.

In a survey of 5675 patients presenting to five hospitals in England, Scotland and Denmark with acute undiagnosed abdominal pain, 106 patients later proved to have intraabdominal cancer. The risk of cancer was age-dependent: amongst patients over 50 years with 'non-specific' pain the risk of cancer was 10 per cent. The commonest primary cancer site (in 57 cases, 53.8 per cent) was the large bowel. Most cancers neither perforated nor obstructed: 73 patients merely presented with a short history of unexplained abdominal pain. Of those patients with cancer presenting with 'unexplained' pain, half (37/73, 50.7 per cent) left hospital without a diagnosis of cancer having been made. Subsequently, a computer-aided system was constructed to discriminate (in patients over the age of 50) between those with unexplained acute abdominal pain who did and did not have cancer. Overall accuracy was 84.7 per cent in 138 cases. The most helpful clinical features in making this discrimination are listed. It is suggested (a) that cancer is now a relatively common cause of acute abdominal pain, (b) that the diagnosis is frequently difficult and (c) that urgent screening of all patients over 50 with non-specific acute abdominal pain may be warranted.

Abdomen, Acute↗

PubMed1979

Pharmacologically active sulfoximides: 5-hexyl-7-)S-methylsulfonimidoly) xanthone-2-carboxylic acid, a potent antiallergic agent.

The antiallergic activity of some xanthone derivatives containing a sulfoximide substitutent has been investigated. While 2-(S-methylsulfonimidoyl)xanthone itself was found to be inactive, a series of 7-(S-methylsulfonimidoly)-xanthone-2-carboxylic acids showed good levels of activity in the passive cutaneous anaphylaxis screen. N-Substituted sulfoximide derivatives were, without exception, less active than the corresponding unsubstituted compounds. The activity of the 7-(S-methylsulfonimidoyl)xanthone-2-carboxylic acids could be enhanced by the introduction of an alkyl or alkoxy substituent at C-5. As a result of these studies, 5-hexyl-7(S-methylsulfonimidoyl)xanthone-2-carboxylic acid has been selected for further investigation as an antipasthmatic agent.

Animals↗

PubMed1979

The penetrability of cephazolin into the subcutaneous fat and skeletal muscle of ischaemic lower limbs with atherosclerotic disease.

Seventeen patients with atherosclerotic disease, who were undergoing arterial reconstruction or amputation of the lower limb, had 2 g cephazolin injected per-operatively in two equal doses by intramuscular and intravenous routes. Samples of subcutaneous fat and skeletal muscle from the ischaemic leg, and serum were collected during the operation for assay of cephazolin content. The mean cephazolin levels in the serum, skeletal muscle and subcutaneous fat were found to be well above the minimum inhibitory concentrations required for most important Gram-positive and Gram-negative pathogens.

Adipose Tissue↗

PubMed1979

Sampling gastro-enterologists' opinions--an OMGE study.

This study describes a pilot project to sample gastroenterologists' opinions on a variety of interesting and controversial topics. At the Madrid World Congress, a sample of delegates were asked to respond to a questionnaire distributed at the meeting itself. A total of 224, representative of those attending by discipline and by geographical area, did so. The results were analysed in two days and presented to the Congress within 72 hours. Amongst the findings were several of interest. Vagotomy is now the most common operation for (elective) duodenal ulcer surgery. Three-quarters of those responding prescribe high-fibre diet for chronic diverticular disease. Over 80% routinely prescribe sulphazalazine for patients with ulcerative colitis--even in remission. The most useful mode of detection of gastro-intestinal cancer is now felt to be endoscopy, even ahead of double contrast radiology. The results should be interpreted with caution, although the survey represents findings in over 200 hospitals. The principle of an on-the-spot rapid attitude survey has been established as feasible. It is proposed to repeat the exercise on a wider scale at the next World Congress in Stockholm in 1982.

Attitude of Health Personnel↗

PubMed1978

A study on tissue concentrations of cephradine achieved in patients with peripheral vascular disease.

The levels of cephradine were measured in serum, voluntary muscle and subcutaneous fat samples collected from 30 patients during surgical operations for peripheral vascular disease. Cephradine 2 g was administered in two equal doses by intramuscular and intravenous routes before each operation. The mean levels found in the serum and muscle were well above the minimum inhibitory concentrations required for most important Gram-positive and Gram-negative pathogens, in contrast to the relatively low mean level found in subcutaneous fat.

Adipose Tissue↗

PubMed1977

Synthesis and antitussive activity of aminotetra- (and -hexa-) hydrodibenzofurans.

The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with that of codeine, was found in the 4alpha-amino series. The 4-methylpiperazin-1-ylpropionamide (28) was found to be the most active of the compounds synthesized and was equipment with codeine. The effects of structural modification upon antitussive activity were investigated in numerous analogues but no enhancement of activity was achieved over that of 28.

Animals↗