Pharmacokinetic profile of piroxicam beta-cyclodextrin, in rat plasma and lymph.

1. The absorption of piroxicam into the blood of rats is significantly slower after oral administration of piroxicam beta-cyclodextrin than of free piroxicam. 2. The pharmacokinetic profiles of piroxicam in rat lymph were very similar in both groups. 3. Bioavailability of piroxicam in plasma is higher after treatment with the inclusion product than with free piroxicam. On the other hand, bioavailability in lymph is higher when free piroxicam is administered.

Effect of piroxicam beta-cyclodextrin complex on experimental inflammation.

1. The effectiveness of the inclusion product of piroxicam with beta-cyclodextrin was compared to that of free piroxicam on inflammatory reactions by using three experimental inflammatory models in rats. 2. The inclusion compound showed anti-inflammatory effects similar to those of simple piroxicam on granuloma tissue formation and arthritis induced by complete Freund adjuvant. 3. In carrageenin-induced pleurisy, the piroxicam beta-cyclodextrin reduced leukocyte mobilization more intensely than non-complexed piroxicam. 4. These results suggest that beta-cyclodextrin is a useful tool for improving the efficacy of piroxicam.

Edematogenic responses induced by Bothrops jararaca venom in rats: role of lymphocytes.

The intraplantar injection of Bothrops jararaca venom (Bjv) caused an edematogenic response in the rat which was of rapid onset, and reached a peak in about 60 min. The response was markedly attenuated in animals rendered leucopenic by the administration of amethopterin. This inhibition was partially reverted when leucopenic rats were given i.v. suspensions of lymphocytes. Suspensions of neutrophils were ineffective. If the animals were submitted to an experimental obstruction of the thoracic duct, which leads to specific lymphocytopenia, similar inhibition of the edematogenic response was observed. These results suggest that lymphocytes can directly influence the development of the edema induced by Bothrops jararaca venom.

Lymphatic mast cell response and effect of compound 48/80 on popliteal lymph node reaction in rats following intracutaneous injection of Staphylococcus aureus.

To investigate the significance of mast cells in the popliteal lymph node during the development of an inflammatory response, rats were inoculated with 12 x 10(7) colony-forming units of Staphylococcus aureus in the hind foot pad. Numerical changes in mast cells were then measured in the corresponding popliteal lymph node. Six days after inoculation, despite the enlargement of the responding lymph node, a marked decrease in granulated mast cell number, relative to the contralateral node, was observed in the cortical and medullary compartments. Popliteal lymph nodes from rats treated with compound 48/80 and then inoculated with S. aureus showed a higher cortical and medullary hypertrophic response and a significant increase in degranulated/weakly basophilic mast cell number in the lymph node tissue. The findings suggest that (1) Staphylococcus aureus induces a reduction in granulated mast cell number in the cortical and medullary compartments of regional lymph nodes; (2) pretreatment with compound 48/80 appears to contribute to the lymphoid cell proliferation and the hypertrophic response of lymph nodes induced by S. aureus; and (3) granulated mast cells have a regulatory role on lymphoid cell proliferation.

Miconazole as inflammatory agent--I. Cellular and pathophysiological effects.

1. Subcutaneous injection of miconazole into the rat paw evoked an acute, circumscribed and long-lasting inflammation. 2. Miconazole edema presented two defined phases of rapid swelling. 3. Miconazole edema was antagonized by chlorpheniramine, dexamethasone and phenylbutazone. 4. This edema was 1.5-2 times more intense than edema due to econazole. 5. It is suggested that miconazole paw edema might be useful in the process of screening anti-inflammatory drugs.

Lymphatic transport of salicylates in dogs.

1. Pharmacokinetic parameters were determined for acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma and lymph following the intravenous or oral administration of a water-soluble preparation of lysine-acetylsalicylic acid to dogs. 2. By both routes of administration, ASA but not SA, tended to be deposited in lymph, as indicated by the ratio between the area under the concentration-time curve constructed for the parent compound and its metabolite in lymph and plasma. 3. A reduced conversion of ASA to SA by esterases in lymph, and lymphatic absorption of ASA following the oral administration might be factors responsible for the accumulation of the compound in the lymphatic system. 4. It is suggested that the lymphatic system might serve as a temporary reservoir compartment for ASA.

Endocrine disorders render rats hyporeactive to non-steroidal but not to steroidal anti-inflammatory drugs.

The effect of cortisol (10 and 20 mg kg-1 day-1, sc), indomethacin (2 and 4 mg kg-1 day-1, po) and piroxicam (10 and 20 mg kg-1 day-1, po) on the proliferative component of inflammation was investigated in normal, diabetic, adrenalectomized and diabetic-adrenalectomized rats using the cotton pellet test. Whereas cortisol was equally effective in preventing granulation tissue formation in all groups of animals, indomethacin and piroxicam were much less active in animals with hormonal dysfunctions. Indomethacin and piroxicam reduced thymus weight of normal and diabetic animals as much as cortisol. This was taken to be a strong indication of the effect of these non-steroidal drugs on the adrenal cortex leading to increased secretion of adrenal corticosteroids. We conclude that at least part of the anti-inflammatory effect of indomethacin and piroxicam, in the present experiments, can be ascribed to the release of endogenous corticosteroids. This would explain the decreased sensitivity of adrenalectomized animals to the non-steroidal anti-inflammatory drugs used. An additional component, however, seems to be necessary for the full expression of the anti-inflammatory effect of these drugs, since diabetic animals were also less responsive to them. When both components were absent, as in diabetic-adrenalectomized animals, indomethacin and piroxicam were practically devoid of an anti-inflammatory effect.

The inflammatory responses of rats depleted of lymphocytes or with an artificial obstruction of the thoracic duct.

Rats selectively depleted of lymphocytes by chronic drainage from the thoracic duct during a 3-day period presented a marked lymphopenia, and decreased responses to carrageenin injected into one of the hind paws. The intensity of the inflammatory responses in thse animals was restored by the i.v. administration of suspensions of viable or lysed lymphocytes, collected from the spleen or lymph of normal animals. A spontaneous reversal of the depressed responses to carrageenin was observed 40 days after the period of lymph drainage, when lymphocyte counts were again normal in blood. If highly inbred rats were used, the i.v. injection of syngeneic lymphoid cells was equally effective in restoring the inhibityed inflammatory responses resulting from lymphocyte depletion. Artificial obstruction of the thoracic duct, with interruption of lymphocyte recirculation, was followed by decreased lymphocyte counts in blood and severely depressed inflammatory responses to carrageenin. This unresponsive state was corrected as the animals recuperated, probably coincidentally with the development of collateral lymph channels and as the temporarily disturbed blood picture returned to normal. It is concluded that lymphocytes can participate in the development of non-immune inflammation through the release of pro-inflammatory factors. This release is independent of previous sensitization of the cells.

The proinflammatory function of lymphocytes in non-immune inflammation: effect of steroidal and non-steroidal anti-inflammatory agents.

Leucopenia rendered rats unresponsive to various inflammatory stimuli. The intensity of the inflammatory response in such animals was restored by i.v. administration of suspensions of lymphocytes, but not of granulocytes. This restorative effect was blocked by both steroidal and non-steroidal anti-inflammatory drugs. Utilizing carrageenin to induce inflammatory responses in the rat's paw, the effect of these drugs on lymphocytes was observed in two circumstances. First, following incubation of the cells with the drugs in concentrations not exceeding the peak plasma levels estimated for these substances in man or laboratory animals; the effect of the drugs seemed selective, since anti-histamine and anti-serotonin agents, as well as amethopterin, were devoid of action. Second, when lymphocytes were collected from rats previously treated with the various anti-inflammatory agents, injected 6-hourly during periods of 18 and 36 h, respectively, for steroidal and non-steroidal anti-inflammatory substances. The total amounts given were lower than those required to produce consistent anti-inflammatory effects in normal animals, when the drug was given as a single dose before injection of the irritant. It is concluded that the pro-inflammatory function of lymphocytes in non-immune inflammation can be blocked by steroidal and non-steroidal anti-inflammatory agents.