Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model. METHODS: A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days. RESULTS: In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines. CONCLUSIONS: This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Which has the least immunity depression during postoperative analgesia--morphine, tramadol, or tramadol with lornoxicam?

BACKGROUND: Analgesics are commonly used to provide pain relief after surgery. These drugs produce some extended depression of immunity. A prospective randomized controlled trial was designed to observe expressions of T-lymphocyte subsets (CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+)), natural-killer cells (CD3(-)CD16(+)CD56(+)), and activated T-lymphocytes (CD3(+)CD25(+)) of patients undergoing gastric cancer surgeries and receiving patient-controlled intravenous analgesia (PCIA). METHODS: Forty-five patients undergoing elective gastric cancer surgeries under general anesthesia were randomly allocated into 3 groups. Group I received PCIA using morphine after surgery, group II using tramadol, and group III using tramadol with lornoxicam. The analgesic efficacy was evaluated by visual analog scale (VAS) and Bruggrmann comfort scale (BCS). Expressions of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were measured as percentages of total lymphocytes by flow cytometer at 5 time points. RESULTS: There was no significant difference in analgesic efficacy and the baselines of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) in all groups. Compared with the baseline, CD3(+)CD8(+) had no changes in all groups at any time point. Ninety minutes after incision, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were lower in all groups (P<0.05). 24 h after surgery, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) were lower in group I and group II (P<0.05); meanwhile CD3(+), CD3(+)CD4(+), and CD3(+)CD25(+) returned to the baseline but CD3(-)CD16(+)CD56(+) was still low (P<0.05) in group III. 48 h after surgery, CD3(+), CD3(+)CD4(+), CD3(-)CD16(+)CD56(+), and CD3(+)CD25(+) returned to the baseline in group II and group III, but not in group I (P<0.05). 72 h after surgery, CD3(+), CD3(+)CD4(+), CD3(+)CD4(+)/CD3(+)CD8(+) returned to the baseline, but CD3(+)CD25(+) and CD3(-)CD16(+)CD56(+) were still low in group I (P<0.05). CONCLUSION: PCIA using lornoxicam with tramadol has the same good analgesic efficacy and less immunity depression than PCIA using morphine or tramadol.

Antigenic characterization in ampiroxicam-induced photosensitivity using an in vivo model of contact hypersensitivity.

Ampiroxicam (APX), a prodrug of piroxicam (PXM), has been reported to induce photosensitivity. Antigenic characterization of these photosensitivities, however, is still insufficient. The purpose of the present study was to elucidate further mechanism of photosenstivity induced by APX and PXM using an in vivo model of contact hypersensitivity in guinea pigs. Animals sensitized with ultraviolet-A (UVA)-irradiated 1% APX showed positive reaction in the patch testing to UVA-irradiated 1% APX and 1% thiosalicylate (TOS), while they were negative in challenge with UVA-irradiated 1% PXM, non-irradiated APX and PXM, whereas none of UVA-irradiated or non-irradiated APX and PXM showed positive patch test reaction in animals sensitized with UVA-irradiated 1% PXM or control vehicles. Animals sensitized with 1% TOS were successfully challenged by 1% TOS and cross-reacted with UVA-irradiated 1% APX; however, they failed to react with UVA-irradiated PXM, non-irradiated APX and PXM. Indeed, the in vitro study revealed that the concentration of APX was easily reduced by the increase of UVA irradiation dose, as compared with that of PXM. Interestingly, absorption spectrum of UVA-irradiated APX was similar to that of TOS, which is thought to be an active hapten of PXM. In the present study, we succeeded in the development of a novel animal model reflecting the clinical observations. Furthermore, these results suggested that contact hypersensitivity induced by UVA-irradiated APX is developed by photoproducts of APX itself, but not by the biotransformation of APX to PXM.

Piroxicam has at least two epitopes for contact photoallergy.

We have demonstrated previously in guinea pigs that the induction of photocontact sensitivity to piroxicam (PXM) also induces a state of cross-reactive contact hypersensitivity to two compounds having structurally related elements, thimerosal (TMS) and thiosalicylate (TOS). The present study was conducted to determine whether oral administration of TOS would desensitize guinea pigs previously photosensitized with PXM. At the same time, the spectrum of reactivities against these compounds and against tenoxicam (TXM) which resembles only piroxicam was assessed by appropriate sensitizing and eliciting protocols. As expected, animals photosensitized to PXM developed reactivities against all four compounds, PXM and TXM (photosensitivity) and TMS and TOS (contact sensitivity). By contrast, photosensitization with TXM induced cross-reactivity only against PXM. Moreover, the induction of contact sensitivity against TMS or TOS induced photosensitive cross-reactivity to PXM, but not to TXM. Finally, the oral administration of TOS produced a transient desensitization only for TMS and TOS. These results suggest that photosensitization with PXM induces two distinct reactivities. The first reactivity cross-reacts with TMS and TOS and is suppressible with orally administered TOS. The second cross-reacts only with TXM and is not suppressible with oral TOS. We conclude that PXM acquires at least two distinct immunogenic epitopes when exposed to UVA irradiation.

Photosensitivity to piroxicam: absence of cross-reaction with tenoxicam.

We studied 2 groups of patients. One group of 10 patients had a photosensitive eruption to piroxicam. Another group of 24 patients had positive patch test reactions to thimerosal and thiosalicylic acid and had never taken piroxicam or tenoxicam. Patients were patch tested with thimerosal 0.1% pet., thiosalicylic acid 0.1% pet., salicylic acid 2.0% pet., piroxicam 1 and 5% pet. and tenoxicam 1 and 5% pet. Photopatch tests were also performed with piroxicam and tenoxicam. All 10 patients with photosensitivity to piroxicam had positive patch tests to thimerosal and thiosalicylic acid and 9 of them had positive photopatch tests to piroxicam. 20 out of 24 patients with positive patch tests to thiosalicylic acid also had positive photopatch tests to piroxicam. All the patients tested with salicyclic acid were negative. Out of the 29 patients with positive photopatch tests to piroxicam, none reacted to tenoxicam. In countries with a high incidence of contact sensitivity to thimerosal/thiosalicylic acid, the use of piroxicam should be avoided and replaced by tenoxicam, a drug without reported photosensitivity.