ABSTRACT
The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.
Subject(s)
Enzyme Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Metalloendopeptidases/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Humans , Hydroxamic Acids/adverse effects , Hydroxamic Acids/pharmacokinetics , Middle Aged , Pilot Projects , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
The matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent enzymes which are known to degrade the protein components of extracellular matrix. In addition, MMPs and related enzymes can also process a number of cell surface cytokines, receptors, and other soluble proteins. In particular we have shown that the release of the pro-inflammatory cytokine, tumor necrosis factor-alpha, from its membrane-bound precursor is an MMP-dependent process. MMPs are expressed by the inflammatory cells which are associated with CNS lesions in animal models of multiple sclerosis (MS) and in tissue from patients with the disease. MMP expression will contribute to the tissue destruction and inflammation in MS. Drugs which inhibit MMP activity are effective in animal models of MS and may prove to be useful therapies in the clinic.
Subject(s)
Metalloendopeptidases , Multiple Sclerosis/enzymology , Multiple Sclerosis/immunology , Tumor Necrosis Factor-alpha , Animals , Humans , Metalloendopeptidases/antagonists & inhibitors , Metalloendopeptidases/physiology , Multiple Sclerosis/pathology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/physiologyABSTRACT
The matrix metalloproteinases (MMPs) are a group of enzymes which have the ability to degrade extracellular matrix. They also cleave non-matrix proteins such as myelin basic protein and alpha 1-antitrypsin and they are able to process tumour necrosis factor-alpha (TNF) to its mature form. We have cloned, expressed and purified human macrophage metalloelastase (EC 3.4.24.65), an MMP recognised for its ability to degrade elastin, but whose substrate specificity has not yet been defined. With the exception of type I collagen this enzyme degraded all matrix proteins tested, namely: type IV collagen, type I gelatin, fibronectin, laminin, vitronectin and proteoglycan. It also degraded myelin basic protein, cleaved alpha 1-antitrypsin and released TNF from a pro-TNF fusion protein. Thus, in common with several other MMPs, macrophage metalloelastase has a broad substrate range which extends beyond that of elastin alone.
Subject(s)
Metalloendopeptidases/metabolism , Myelin Basic Protein/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Cell Line , Chondrosarcoma , Collagen/metabolism , Collagenases/metabolism , Gelatinases/metabolism , Humans , Kinetics , Matrix Metalloproteinase 1 , Matrix Metalloproteinase 12 , Metalloendopeptidases/isolation & purification , Mutagenesis, Site-Directed , Point Mutation , Rats , Recombinant Fusion Proteins/metabolism , Recombinant Proteins/metabolism , Substrate Specificity , Swine , Tetradecanoylphorbol Acetate/pharmacology , Tumor Cells, CulturedABSTRACT
Matrix metalloproteinases (MMPs) are a group of enzymes responsible for the degradation of interstitial connective tissue and basement membrane. The coding sequences for five of the human MMPs, viz. interstitial collagenase, 72 kDa gelatinase, stromelysin-1, matrilysin and 92 kDa gelatinase, were cloned and expressed in Chinese hamster ovary cells, and the proteins purified. The enzymes were compared for their ability to digest myelin basic protein, the major extrinsic membrane protein of central nervous system myelin. The most active on this substrate was 72 kDa gelatinase, followed by stromelysin-1; interstitial collagenase, matrilysin and 92 kDa gelatinase were of comparable but lesser activity. Production of these enzymes by glia or infiltrating inflammatory cells could therefore contribute to demyelination in neuroinflammatory disease.
Subject(s)
Demyelinating Diseases/metabolism , Metalloendopeptidases/metabolism , Myelin Basic Protein/metabolism , Animals , CHO Cells , Cricetinae , HumansABSTRACT
To test the efficacy of chlorproguanil prophylaxis, 156 malaria-free schoolchildren in the coastal region of Kenya were allocated at random to receive either 7.5 mg chlorproguanil daily, 50 mg chlorproguanil weekly, 100 mg proguanil daily, or 100 mg calcium lactate weekly (placebo). The children were followed up daily for 169 d, by which time Plasmodium falciparum parasitaemia had occurred in 92% of the placebo group, 31% of the daily proguanil group, 38% of the daily chlorproguanil group and 55% of the weekly chlorproguanil group. There was significant reduction (P < 0.001) in the risk of parasitaemia in all the groups receiving chemoprophylaxis. Daily chlorproguanil and daily proguanil were equally effective, and significantly more effective than weekly high dose chlorproguanil. No significant toxicity was reported or observed. Thus daily chlorproguanil 20 mg/60 kg is a cheap and effective alternative to proguanil for chemoprophylaxis.
Subject(s)
Malaria, Falciparum/prevention & control , Proguanil/analogs & derivatives , Proguanil/administration & dosage , Child , Drug Administration Schedule , Humans , Treatment OutcomeABSTRACT
156 coastal schoolchildren participated in a placebo controlled trial. All the children were treated with chloroquine 25mg/kg over 3 days plus single dose pyrimethamine-sulfadoxine and then randomised to receive one of four regimens:- A:7.5 mg chlorproguanil daily; B: 50 mg chlorproguanil weekly; C: 100mg proguanil daily; D: 100 mg Calcium lactate weekly. The children were followed up daily for 169 days for P.falciparum parasitaemia. Each 'terminal' event for the construction of life table; was treated with single dose pyrimethamine-sulfadoxine and the child removed from the trial. At the end of the study; 34/37 children had suffered a terminal event in the placebo group compared to 12/39 in the daily proguanil 100 mg group; 15/39 in the daily chlorproguanil 7.5 mg group and 22/40 in the weekly chlorproguanil 50 mg group. Life table analysis found a significant reduction (P is greater than 0.001) in the risk of malaria in all the chemoprophylactic groups compared to the placebo group. Daily proguanil also gave greater protection than weekly chloroproguanil (P greater than 0.05); but there was no difference between daily proguanil and daily chlorproguanil (P less than 0.1). Daily chlorproguanil 7.5 mg; has a lower cumulative dose; greater in vitro activity and increased intracellular concentration of the metabolite. Compared to proguanil and increased intracellular concentration of the metabolite. Therefore; daily proguanil has significant potential as another chealp; effective; nontoxic chemoprophylactic addition to vector avoidance measures
Subject(s)
Drug Evaluation , Malaria/prevention & control , Plasmodium falciparumABSTRACT
Halofantrine hydrochloride given to 46 Kenyan children with falciparum malaria at 10 mg/kg for two doses, and to 60 other children at 8 mg/kg for three doses, resulted in rapid parasite clearance, mean parasite clearance times being 45.4 h and 54.8 h, respectively. In-vitro chemosensitivity tests showed that most infections were due to chloroquine-resistant parasites, and that parasite maturation was inhibited by considerably lower concentrations of halofantrine than of chloroquine.
Subject(s)
Antimalarials/administration & dosage , Chloroquine/therapeutic use , Malaria/drug therapy , Phenanthrenes/administration & dosage , Administration, Oral , Adolescent , Animals , Antimalarials/therapeutic use , Child , Child, Preschool , Clinical Trials as Topic , Drug Administration Schedule , Drug Evaluation , Drug Resistance , Female , Follow-Up Studies , Half-Life , Humans , Infant , Kenya , Malaria/blood , Malaria/epidemiology , Malaria/urine , Male , Phenanthrenes/therapeutic use , Plasmodium falciparum , Time FactorsABSTRACT
The conditions under which blood pressures (BPs) are recorded are critical, and it has been demonstrated several times that BPs measured in the home are lower than those measured in the clinic. However, these comparisons are based on home BPs measured by the patients or their friends and relatives and clinic BPs measured by doctors and nurses. To our knowledge, no comparison of home and clinic BPs measured by the same observer has been reported, and we present the results of such a study which is the first to demonstrate higher BPs in the home environment, perhaps reflecting the unacculturated nature of the study population.
