The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topic... more The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains, and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP Plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient has been developed. We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. The data were consistent with the concept that heparin increased the clinical activity of the DHEP Plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP Plus medicated plaster. Efficacy studies showed that the DHEP Plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. The benefit/risk assessment of DHEP Plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing wide... more Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and in...
The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 ... more The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protecti...
Oral or parenteral administration of lithium salts considerably increased the gastric fluid volum... more Oral or parenteral administration of lithium salts considerably increased the gastric fluid volume in rats, effectively preventing the hemorrhagic effects of oral or parenteral aspirin and other nonsteroid anti-inflammatory drugs on the gastric mucosa in cold-stressed and fasted animals and in fasted arthritic rats. The doses of Li+ which were totally protective in normal rats, though active, were much less protective in the arthritic animals. Thiocyanate salts reduced the gastrotoxicity of these drugs only in normal (i.e., nonarthritic) rats.
The proton-secreting parietal cell is shown, from recent evidence, to be the principal focus for ... more The proton-secreting parietal cell is shown, from recent evidence, to be the principal focus for the actions of aspirin (and related drugs) in damaging the gastric mucosa. It is suggested that the selective damage to the parietal cells is due to the ph gradient favouring a high rate of aspirin uptake and subsequent entrapment of drug anions inside these cells. This concept may serve as a useful basis for developing procedures to minimize the gastric damage by aspirin and related acidic drugs.
Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interr... more Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interrelated, mechanisms. They vary in ulcerogenic activity in different regions of the GI tract. These differences in ulcerogenicity of NSAIDs are due to (a) differing kinetics of absorption in various regions of the GI tract, intracellular distribution within the mucosal cells, and systemic availability, and (b) quantitative and qualitative differences in the biochemical or physiologic systems affected by the drugs. In the stomach, where acid/pepsin influence the ulcerogenic effects of most NSAIDs, prostaglandin (PG)-dependent and PG-independent factors are responsible for the ulcerogenicity of NSAIDs. PG-dependent factors can include the influences of PGs on mucus-bicarbonate secretion, regulation of acid secretion, and blood flow. Recent evidence suggests that CO inhibition may, by diversion of arachidonate, cause enhanced production of vasoconstrictor peptidoleukotrienes and oxyradicals produced by the lipoxygenase pathway, and this may contribute to the genesis of vascular and other mucosal changes induced by NSAIDs. Non-PG-dependent effects of NSAIDs include (a) physical effects of the acidic molecules on surface mucosal cell membranes and mucus, (b) oxyradical production, (c) cytotoxic effects on parietal cells, and (d) inhibitory effects on mucus synthesis, mitochondrial ATP production, cyclic nucleotide production, and a range of other cellular metabolic effects influencing mucosal metabolism and cellular regeneration. In the intestinal tract, two major factors influence the ulcerogenicity of NSAIDs: their capacity to undergo enterophepatic recirculation and the presence of bacteria, which may in part contribute to a immunoinflammatory changes.
The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topic... more The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains, and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP Plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient has been developed. We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. The data were consistent with the concept that heparin increased the clinical activity of the DHEP Plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP Plus medicated plaster. Efficacy studies showed that the DHEP Plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. The benefit/risk assessment of DHEP Plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing wide... more Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and in...
The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 ... more The intestinal ulcerogenic activity of the weak prostaglandin synthesis inhibitor drug Wy-41,770 [5H-dibenzo(a,d)-cyclohepten-5-ylidine] was contrasted with the potent synthesis inhibitor, indomethacin, in rats to establish the relationship of inhibition of prostaglandin synthesis to the intestinal damage. Wy-41,770 induced superficial erosions only in the cecum 26 hr after a single oral dose of 250 or 500 mg/kg of the drug, progressing to ulcers after 5 days dosing with ultrastructural evidence of bacteria in the mucosa. Indomethacin (5 or 10 mg/kg po) induced mucosal erosions in the ileum, initially at 26 hr progressing to ulcers after 5 days. Fewer bacteria were seen in the ileal mucosa of indomethacin-treated rats. Both drugs reduced prostaglandin E in those regions of the intestine coincident with the known accumulation of these drugs at sites of mucosal injury. Site-specific intestinal damage from these 2 drugs is associated with inhibition of the synthesis of mucosal-protecti...
Oral or parenteral administration of lithium salts considerably increased the gastric fluid volum... more Oral or parenteral administration of lithium salts considerably increased the gastric fluid volume in rats, effectively preventing the hemorrhagic effects of oral or parenteral aspirin and other nonsteroid anti-inflammatory drugs on the gastric mucosa in cold-stressed and fasted animals and in fasted arthritic rats. The doses of Li+ which were totally protective in normal rats, though active, were much less protective in the arthritic animals. Thiocyanate salts reduced the gastrotoxicity of these drugs only in normal (i.e., nonarthritic) rats.
The proton-secreting parietal cell is shown, from recent evidence, to be the principal focus for ... more The proton-secreting parietal cell is shown, from recent evidence, to be the principal focus for the actions of aspirin (and related drugs) in damaging the gastric mucosa. It is suggested that the selective damage to the parietal cells is due to the ph gradient favouring a high rate of aspirin uptake and subsequent entrapment of drug anions inside these cells. This concept may serve as a useful basis for developing procedures to minimize the gastric damage by aspirin and related acidic drugs.
Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interr... more Non-steroidal anti-inflammatory drugs (NSAIDs) induce GI damage by multiple, in some cases interrelated, mechanisms. They vary in ulcerogenic activity in different regions of the GI tract. These differences in ulcerogenicity of NSAIDs are due to (a) differing kinetics of absorption in various regions of the GI tract, intracellular distribution within the mucosal cells, and systemic availability, and (b) quantitative and qualitative differences in the biochemical or physiologic systems affected by the drugs. In the stomach, where acid/pepsin influence the ulcerogenic effects of most NSAIDs, prostaglandin (PG)-dependent and PG-independent factors are responsible for the ulcerogenicity of NSAIDs. PG-dependent factors can include the influences of PGs on mucus-bicarbonate secretion, regulation of acid secretion, and blood flow. Recent evidence suggests that CO inhibition may, by diversion of arachidonate, cause enhanced production of vasoconstrictor peptidoleukotrienes and oxyradicals produced by the lipoxygenase pathway, and this may contribute to the genesis of vascular and other mucosal changes induced by NSAIDs. Non-PG-dependent effects of NSAIDs include (a) physical effects of the acidic molecules on surface mucosal cell membranes and mucus, (b) oxyradical production, (c) cytotoxic effects on parietal cells, and (d) inhibitory effects on mucus synthesis, mitochondrial ATP production, cyclic nucleotide production, and a range of other cellular metabolic effects influencing mucosal metabolism and cellular regeneration. In the intestinal tract, two major factors influence the ulcerogenicity of NSAIDs: their capacity to undergo enterophepatic recirculation and the presence of bacteria, which may in part contribute to a immunoinflammatory changes.
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