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In organ culture experiments, the induction of pemphigus acantholysis is known to be blocked by the addition of serine proteinase inhibitors. Recently, nontoxic synthesized low molecular weight proteinase inhibitors have been clinically available for the treatment of disseminated intravascular coagulation and pancreatitis. To determine if these drugs are useful aids to treat patients with pemphigus, we examined the effect of omega-guanidino ester analogues, i.e., 1) gabexate mesilate, 2) camostat mesilate, and 3) nafamostat mesilate, on experimental pemphigus acantholysis in both organ culture and neonatal BALB/c mice. Furthermore, the effect of plasma natural proteinase inhibitors (alpha-1-proteinase inhibitor) isolated from human plasma was similarly examined. Results revealed that synthesized low molecular weight inhibitors (drugs) were able to inhibit the induction of acantholysis in organ culture system, but had little or no effect on lesion formation in the neonatal mouse system. By contrast, alpha-1-proteinase inhibitor could completely inhibit acantholysis formation in mice. These findings implied a possible new therapeutic approach using proteinase inhibitors for patients with pemphigus.

In conscious rats with cannulated pancreatic ducts, the synthetic trypsin inhibitor camostat (400 mg/kg) was instilled into the stomach once daily on 5 consecutive days. Each camostat administration stimulated the secretion of juice, bicarbonate, and protein. From day 2 to day 5, basal protein secretion measured before the daily instillation of camostat was increased, whereas basal secretion of volume and bicarbonate remained unchanged. The secretory responses to camostat increased up to day 3 of treatment without further change on days 4 and 5. In response to acute camostat instillation, parallel secretion of enzymes was found. Within 1 day, however, a change in the composition of secreted enzymes was observed. After 3 days, the percentage of amylase in pancreatic juice decreased by approximately 50%, whereas the relative amount of proteinases and the specific activity of phospholipase A2 doubled. The alteration of protein patterns in pancreatic juice parallels the effect on enzymes stored in the gland. The results demonstrate that adaptation of enzyme secretion in the exocrine pancreas occurs after a short period of treatment with camostat. Because this compound stimulated protein, volume, and bicarbonate secretion, it is suggested that other factors in addition to cholecystokinin may be involved in this adaptation process.

Adler G, Mullenhoff A, Bozkurt T, Goke B, Koop I, Arnold R. Comparison of the effect of single and repeated administrations of a protease inhibitor (camostate) on pancreatic secretion in man. Scand J Gastroenterol 1988, 23, 158–162In the present study pancreatic secretion and plasma cholecystokinin (CCK) levels were analysed in eight volunteers after daily ingestion of the serine protease inhibitor camostate for 5 days. This was compared with the effect of a single intraduodenal dose of camostate. Prolonged administration of camostate for 5 days had no effect on basal and stimulated pancreatic secretion and plasma CCK. A single dose of camostate completely inhibited enzymatic activity of trypsin and chymotrypsin and stimulated volume, amylase, and lipase secretion but induced an only slight and insignificant increase in plasma CCK. After the ingestion of a test meal, camostate did not influence stimulated enzyme secretion and increased plasma CCK. We concluded that the intraduodenal perfusion of camostate...

Oral administration of the proteinase inhibitor camostate to rats results in a characteristic regulation of pancreatic enzyme synthesis and release. These effects are thought to be mediated by an endogenous cholecystokinin release in answer to camostate feeding. An additional direct effect of the compound could be exerted directly on the acinar cell. We evaluated in the present study whether the acute or chronic influence of camostate alters the basal or cerulein-stimulated enzyme release from isolated rat acini. Neither basal nor cerulein-induced (10(-12) to 10(-8) M) amylase release from acini of non-pretreated donor rats were influenced in the presence of 5, 50, or 500 microM camostate. After oral feeding of camostate (200 mg/kg b.wt. daily) over 5 days pancreatic growth occurred. In experiments with acini obtained from the camostate-pretreated rats highly significant reductions of the cerulein-induced amylase release were found as compared to controls. Our findings exclude a direct effect of camostate on the secretory process of pancreatic acinar cells. However, after repeated oral pretreatment of donor rats a "desensitization" of acini against cerulein stimulation occurs. This latter effect is ascribed to elevated endogenous cholecystokinin which was released in response to camostate feeding.

The entry of the coronavirus SARS-CoV-2 into human lung cells can be inhibited by the approved drugs camostat and nafamostat. Here we elucidate the molecular mechanism of these drugs by combining experiments and simulations. In vitro assays confirm that both drugs inhibit the human protein TMPRSS2, a SARS-Cov-2 spike protein activator. As no experimental structure is available, we provide a model of the TMPRSS2 equilibrium structure and its fluctuations by relaxing an initial homology structure with extensive 330 microseconds of all-atom molecular dynamics (MD) and Markov modeling. Through Markov modeling, we describe the binding process of both drugs and a metabolic product of camostat (GBPA) to TMPRSS2, reaching a Michaelis complex (MC) state, which precedes the formation of a long-lived covalent inhibitory state. We find that nafamostat has a higher MC population than camostat and GBPA, suggesting that nafamostat is more readily available to form the stable covalent enzyme-substrate intermediate, effectively explaining its high potency. This model is backed by our in vitro experiments and consistent with previous virus cell entry assays. Our TMPRSS2-drug structures are made public to guide the design of more potent and specific inhibitors.

Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown. Design Retrospective observational case series. Setting Patient treated in ICU of University hospital Gottingen, Germany. Patients Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU. Interventions Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group). Measurements and main results Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation. Conclusions The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.