Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate.

Male hypogonadism is often treated by testosterone (T) replacement therapy such as oral administration of the ester prodrug, testosterone undecanoate (TU). However, the systemic exposure to T following oral TU is very low due to esterase-mediated metabolism, particularly in the small intestine. The aim of this work was to examine the esterase-inhibitory effect of natural fruit extract of strawberry (STW) on the intestinal degradation of TU as a potential approach to increasing the oral bioavailability of T. Herein, the hydrolysis of TU was assessed in fasted state simulated intestinal fluid with added esterase activity (FaSSIF/ES) and Caco-2 cell homogenates in the presence of STW extract. It is noteworthy that STW substantially inhibited the degradation of TU in FaSSIF/ES and Caco-2 cell homogenates at concentrations that could be achieved following oral consumption of less than one serving of STW fruit. This can significantly increase the fraction of unhydrolyzed TU in the intestinal lumen as well as in enterocytes. In addition, it was demonstrated that TU has high intestinal lymphatic transport potential as the association of TU with plasma-derived human chylomicrons was in the range of 84%. Therefore, oral co-administration of TU with STW could potentially increase the intestinal stability of TU and consequently the contribution of lymphatically delivered TU to the systemic exposure of T in vivo.

Baccharis dracunculifolia (Asteraceae) essential oil displays anti-inflammatory activity in models of skin inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Baccharis dracunculifolia (Asteraceae) is a commonly used plant in traditional medicine known as "alecrim-do-campo". Popularly it has been used as an immunostimulant, antibiotic, anti-inflammatory among other applications. So far, only a few studies have investigated the B. dracunculifolia anti-inflammatory effect and none has investigated the effectiveness of essential oil on skin diseases. AIM OF THE STUDY: The study aimed at evaluating the topical anti-inflammatory activity of B. dracunculifolia essential oil (BdEO) in mice models of acute and chronic skin inflammation. MATERIALS AND METHODS: BdEO was obtained from leaves and it was analyzed with Gas Chromatograph. Topical anti-inflammatory activity of BdEO (0.1, 0.3 and 1.0 mg/ear) was evaluated in Arachidonic Acid or TPA-induced acute and chronic skin inflammation in mice. Parameters such edema, cell migration and keratinocytes proliferation were evaluated. In addition, safety and a possible mechanism of action for BdEO essential oil were also investigated. RESULTS: Our results indicate that mainly terpenoids compounds compose BdEO. In addition, topical treatment with BdEO inhibited inflammatory parameters in both acute and chronic models of skin inflammation. This protective effect was associated with reduced edema formation, smaller cellular influx into the inflamed tissue and reduction of keratinocytes hyperproliferation. Although BdEO appears to exert its anti-inflammatory effect through a corticosteroid pathway, no local or systemic side effects were observed. CONCLUSION: Taken together, the present results showed that the essential oil obtained by hydrodistillation from B. dracunculifolia leaf samples exhibit remarkable topical anti-inflammatory properties. Therefore, our study demonstrated evidence for BdEO topical anti-inflammatory efficacy and safety, suggesting that it could be considered for developing of a new phytotherapeutic formulation as treatment for skin diseases.

Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis.

Although clinical outcomes for patients with rheumatoid arthritis (RA) have greatly improved with the use of biologic and conventional DMARDs, approximately 40% of patients do not achieve primary clinical outcomes in randomized trials, and only a small proportion achieve lasting remission. Over the past decade, studies in murine models point to the critical role of the lymphatic system in the pathogenesis and therapy of inflammatory-erosive arthritis, presumably by the removal of catabolic factors, cytokines and inflammatory cells from the inflamed synovium. Murine studies demonstrate that lymphatic drainage increases at the onset of inflammatory-erosive arthritis but, as inflammation progresses to a more chronic phase, lymphatic clearance declines and both structural and cellular changes are observed in the draining lymph node. Specifically, chronic damage to the lymphatic vessel from persistent inflammation results in loss of lymphatic vessel contraction followed by lymph node collapse, reduced lymphatic drainage, and ultimately severe synovitis and joint erosion. Notably, clinical pilot studies in patients with RA report lymph node changes following treatment, and thus draining lymphatic vessels and nodes could represent a potential biomarker of arthritis activity and response to therapy. Most importantly, targeting lymphatics represents an innovative strategy for therapeutic intervention for RA.

Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport.

Effect of beta-aescin extract from Chinese buckeye seed on chronic venous insufficiency.

The aim of this study was to explore the mechanism of domestic beta-aescin treating chronic venous insufficiency through observing its actions on the isolated canine saphenous venous tension, venous pressure, venous return and lymphatic return. The isolated canine spiral saphenous venous tension test was performed to detect the activity of the beta-aescin. Furthermore, in the condition of constant canine femoral artery perfusion kept in the extracorporeal circulation, we measured the changes of the canine femoral artery pressure, femoral artery flow and the lymphatic return flow after intravenous injection of the agent. The results showed that when beta-aescin was administrated at the dose between 5.0 x 10(-5)-5.25 x 10(-4) mol/L, it increased obviously the contractile tension of the venous to norepinephrine in a dose-dependent manner. With canine femoral artery perfusion kept constant, beta-aescin, whose doses were 50 mg and 100 mg, reinforced intently the canine femoral venous tension accelerated the rise of the venous pressure. These finding suggested that domestic betabeta-aescin extracted from Chinese Buckeye Seed had an effect on chronic venous insufficiency by strengthening the venous tension, increasing the venous pressure and promoting venous return and lymphatic return.

Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release.

Diamine oxidase (DAO) is abundantly expressed in mammalian small intestine catalyzing the oxidative breakdown of polyamines and histamine. The aim of this study was to determine the relationship between stimulation of intestinal diamine oxidase secretion with intestinal fat absorption and histamine release. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated and intraduodenal tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic DAO activity and protein secretion were analyzed by radiometric assay and Western blot, respectively. Lymphatic histamine concentration was measured by ELISA. Infusion of Liposyn II (4.43 kcal/3 ml) resulted in a ~3.5-fold increase in lymphatic DAO protein secretion and DAO activity, peaking at 1 h and lasting for 3 h. Liposyn II infusion also increased the lymphatic histamine release, a substrate for DAO. To determine the relationship of DAO release with histamine release, histamine was administered intraperitoneally (10 mg/kg) in fasting rats and resulted in a significant doubling in lymphatic DAO activity, supporting a link between histamine and DAO. In addition, ip administration of the histamine H4 receptor antagonist JNJ7777120 significantly reduced the Liposyn II-induced DAO output by 65.9%, whereas H(1) (pyrilamine maleate), H(2) (ranitidine), and H(3) (thioperamide maleate) receptor antagonists had little effect. We conclude that DAO secretion may contribute to the catabolism of histamine released during fat absorption and this is probably mediated through the histamine H(4) receptor.

Intestinal lymphatic transport of halofantrine in rats assessed using a chylomicron flow blocking approach: the influence of polysorbate 60 and 80.

The aim of the study was to examine the effects of polysorbate 60 and 80 on intestinal lymphatic transport of a poorly water-soluble compound, halofantrine, using a chylomicron flow blocking approach in rats. Male Sprague-Dawley rats were pretreated intraperitoneally with 3.0 mg/kg cycloheximide or saline. One hour later, rats were dosed with 6.7 mg/kg halofantrine in 0.4 or 1.0 g/kg polysorbate 60 or 80, 0.33 g/kg soybean oil or 0.33 g/kg soybean oil+1.0 g/kg polysorbate 80 by gavage, and plasma samples were collected. The fraction of halofantrine transported to the lymphatic system was determined as the difference between the bioavailability in saline-pretreated rats and cycloheximide-pretreated rats. No significant differences in halofantrine transport to the systemic blood and in the deduced lymphatic transport were observed between the two polysorbates, at the tested dosages. The lymphatic transport of halofantrine was the same whether dosing with polysorbate 60, polysorbate 80 or soybean oil; accordingly both surfactants can be used as lymphotropic carriers. Furthermore, there was a good correlation between the halofantrine transport to blood and lymphatics in the chylomicron flow blocking model and published results from the mesenteric lymph-cannulated model.

Fructus Schisandrae (Wuweizi) containing compound in modulating human lymphatic system - a Phase I minimization clinical trial.

BACKGROUND: Hepatitis B virus (HBV) infection afflicts Asia population and, in Hong Kong, about 10% was Hepatitis B surface antigen carrier. It is still one of the major issues under investigation. Herbal medicine KY88 composed of Fructus Schisandrae possessing immunomodulatory property was adopted by Chinese medicine practitioner for treatment of acute and chronic HBV infection. However, the underlying impact on host immune system is not fully understood. MATERIALS AND METHODS: Twenty-three healthy volunteers infected with HBV were taken peripheral venous blood from which the blood cells involved in simple host immunity was obtained. RESULTS: It was found that the circulating monocyte count significantly drop after 2weeks of KY88 therapy whereas the fall did not return back to baseline. Circulating white blood cell, neutrophil and lymphocyte, however, did not show obvious change upon commencement of KY88 therapy. CONCLUSION: It was postulated that reduction in circulating monocyte count may reduce the self-inflicted host immune injury to hepatocyte which may testify the hepatoprotective ability of the herb. But, the exact mechanism on how immunomodulatory properties of the herbal medicine protect chronic HBV carriers from liver injury remains a myth.

Suppression of postprandial hypertriglyceridemia in rats and mice by oolong tea polymerized polyphenols.

Oolong tea-polymerized polyphenols (OTPP) are characterized polyphenols produced from semi-fermented tea (oolong tea). In the present study, we evaluated the suppressive effects of oolong tea extract and OTPP on postprandial hypertriglyceridemia in rats and mice. Lymphatic recovery of triglycerides in rats cannulated in the thoracic duct was delayed by the administration of oolong tea extract at 100 and 200 mg per head, and more effectively than with green tea extract. OTPP delayed lymphatic triglyceride absorption at 20 mg/head, though (-)-epigallocatechin gallate (EGCG) did not do so at the same dose. OTPP also suppressed postprandial hypertriglyceridemia after administration of olive oil in mice. The area under the curve (AUC) of plasma triglycerides was significantly decreased, by 53% and 76%, in the 500 and 1,000 mg/kg OTPP groups respectively, as compared with the control group. These results suggest that OTPP is responsible for the suppression of hypertriglyceridemia by ingestion of oolong tea.

[Effects of ligustrazine injection on lymph circulation in rats with acute microcirculation disturbance].

OBJECTIVE: To explore the interferential effect of ligustrazine injection (LI) on lymph circulation in rats with acute microcirculation disturbance (AMD). METHODS: Sixteen Wistar male rats were divided into experimental and control groups. AMD was done by Dextran 500 injection from jugular vein and effects of LI on lymph circulation were observed in these rats by lymphatology methods. RESULTS: During AMD phase, the contractility of mesenteric lymphatic (ML) , the intestinal lymph flux, lymphocytes out put were obviously decreased, and there was little monocytes in the lymph fluid, but the lymph fluid viscosity was increased. After treatment of LI, the contractility of ML, the intestinal lymph flux, lymphocytes out put was obvious increased. There was a lot of monocytes in the lymph fluid and the lymph fluid viscosity was decreased. There were signifcant difference compared with control group (P < 0.05). CONCLUSION: LI can influence the recovery of AMD though enhancing the contractility of ML and the transport function of lymph circulation and decreasing lymph fluid viscosity.

Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats.

Tea catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), have been shown to be epimerized to (-)-catechin (C), (-)-gallocatechin (GC), (-)-catechin gallate (CG), and (-)-gallocatechin gallate (GCG), respectively, during heat treatment. In this study, we examined the effect of tea catechins rich in ECG and EGCG and heat-treated tea catechins rich in CG and GCG on postprandial hypertriacylglycerolemia in rats. Both tea catechins and heat-treated tea catechins suppressed postprandial hypertriacylglycerolemia. Lymphatic recovery of (14)C-trioleoylglycerol in rats cannulated in the thoracic duct was delayed by the administration of tea catechins and heat-treated tea catechins. Tea catechins and heat-treated tea catechins had the same effect on all variables tested. These catechin preparations dose-dependently inhibited the activity of pancreatic lipase in vitro. When purified catechins were used, only those with a galloyl moiety inhibited the activity of pancreatic lipase. These results suggest that catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by slowing down triacylglycerol absorption through the inhibition of pancreatic lipase. Because postprandial hypertriacylglycerolemia is a risk factor for coronary heart disease, our results suggest that catechins with a galloyl moiety may prevent this disease.

[The effects of extracts from Herba Lagopsis on lymph microcirculation of acute blood stasis rats].

OBJECTIVE: To observe the effects of the extracts from Herba Lagopsis (HLE) on lymph microcirculation of acute blood stasis rats. METHODS: The acute blood stasis model was made by iv dextran (10 ml/kg) within 1 min. After 6 minutes, HLE(1.0g/kg) was given intravenously to the treatment group and the same volume of NS was done in the normal control group. The changes of contractility of mesenteric micro-lymphatics (ML) was observed by using a vital microscope with TV recorder. RESULTS: HLE could markedly improve the ML spontaneous constraction frequency, lymphatics constractive activity (Index I), total lymphatics constractive activity (Index II) and lymphatics dynamics (L. D-Index) (P < 0.05 approximately 0.01). CONCLUSION: HLE played an important role in lymph microcirculation of acute blood stasis rats.

Green tea extract inhibits the lymphatic absorption of cholesterol and alpha-tocopherol in ovariectomized rats.

Evidence indicates that green tea consumption lowers the serum level of cholesterol (CH). This study was conducted to determine whether green tea lowers the intestinal absorption of CH and other lipids in ovariectomized (OX) rats. OX rats with lymph duct cannulae were infused at 3.0 mL/h for 8 h via an intraduodenal catheter with a lipid emulsion containing (14)C-cholesterol ((14)C-CH) and alpha-tocopherol (alphaTP) without (GT0) or with green tea extract standardized to 42.9 mg (GT1) or 120.5 mg (GT2) of total catechins in PBS (pH 6.5). Green tea extracts dose-dependently reduced (P < 0.05) the lymphatic absorption of (14)C-CH. The cumulative absorptions of (14)C-CH in rats infused with GT0, GT1 and GT2 were 36.3 +/- 1.1, 20.7 +/- 4.3 and 4.8 +/- 4.1% dose, respectively. The percentage distribution of esterified CH did not differ between rats infused with GT0 and GT1 (80.2 +/- 2.3% vs. 79.0 +/- 1.7%), but was significantly lower in those given GT2 (69.1 +/- 6.8%). The absorption of alphaTP also was significantly reduced by GT1 (736.5 +/- 204.9 nmol, 20.8 +/- 5.8% dose) and GT2 (281.0 +/- 190.8 nmol, 7.9 +/- 5.4% dose) compared with GT0 (1048.8 +/- 174.9 nmol, 29.6 +/- 4.9% dose). The absorption of fat was significantly increased by GT1 (862.6 +/- 151.1 micromol) but lowered by GT2 (557.9 +/- 252.2 micromol) relative to GT0 (717.7 +/- 39.1 micromol). The findings provide direct evidence that green tea has a profound inhibitory effect on the intestinal absorption of CH and alphaTP in OX rats. Whether the inhibitory effect of green tea extract is attributable to a specific catechin(s) and other components in green tea remains to be determined.

Study on the mechanism of regulation on the peritoneal lymphatic stomata with Chinese herbal medicine.

AIM: To study the mechanism of Chinese herbal medicine (CHM), the prescription consists of Radix Salviae Miltiorrhizae, Radix Codonopsitis Pilosulae, Rhizoma Atractylodis Alba and Rhizoma Alismatis, Leonurus Heterophyllus Sweet,etc on the regulation of the peritoneal lymphatic stomata and the ascites drainage. METHODS: The mouse model of live fibrosis was established with the application of intragastric installations of carbon tetrachloride once every three days; scanning electron microscope and computer image processing were used to detect the area and the distributive density of the peritoneal lymphatic stomata; and the concentrations and NO in the serum were measured and analyzed in the experiment. RESULTS: Two different doses of CHM could significantly increase the area of the peritoneal lymphatic stomata, promote its distributive density and enhance the drainage of urinary ion such as sodium, potassium and chlorine. Meanwhile, the NO concentration of two different doses of CHM groups was 133.52+/-23.57 micromol/L and 137.2+/-26.79 micromol/L respectively. In comparison with the control group and model groups (48.36+/-6.83 micromol/L and 35.22+/-8.94 micromol/L, P<0.01),there existed significantly marked difference, this made it clear that Chinese herbal medicine could induce high endogenous NO concentration. The effect of Chinese herbal medicine on the peritoneal lymphatic stomata and the drainage of urinary ion was altered by adding NO donor(sodium nitropurruside,SNP) or NO synthase (NOS) inhibitor (N(G)-monomethyl-L-arginine, L-NMMA) to the peritoneal cavity. CONCLUSION: There existed correlations between high NO concentration and enlargement of the peritoneal lymphatic stomata, which result in enhanced drainage of ascites. These data supported the hypothesis that Chinese herbal medicine could regulate the peritoneal lymphatic stomata by accelerating the synthesis and release of endogenous NO.

Pharmacological targets of drugs employed in chronic venous and lymphatic insufficiency.

Numerous compounds acting on the venous system have been developed over the last 50 years, including and often associating flavonoids, pycnogenols, saponosides, nucleosides and bilobatides. Some products have proved highly successful such as Cyclo 3 Fort (Fabroven), Phlebodril, made of ruscus extract (flavonoids, saponins), hesperidin-methyl-chalone and ascorbic acid. This presentation is an attempt to classify the scientifically proven mechanisms of such substances. All selected substances have been tested in clinical trials for their action on the symptoms of chronic venous insufficiency (CVI), leg pain and edema. As the distensibility of the leg veins is the main pathological factor determined by plethysmogaphy, it was at first thought that leg pain would be related to it. But observations have shown that this factor is often unrelated to the enlargement of the veins but rather to a whole chain of factors. The effects of different drugs on venous distensibility, rheological disorders, the prevention of wall dystrophy and action on the microcirculation are examined.

Total triterpenic fraction of Centella asiatica in chronic venous insufficiency and in high-perfusion microangiopathy.

Total triterpenic fraction of Centella asiatica (TTFCA) is effective in improving venous wall alterations in chronic venous hypertension and in protecting the venous endothelium. TTFCA is active on connective tissue modulation, improves the synthesis of collagen and other tissue proteins by modulating the action of fibroblasts in the vein wall, and stimulates collagen remodeling in and around the venous wall. This is due to the modulating action of TTFCA on fibroblasts as shown by experiments on the growth of human embryonal fibroblasts. TTFCA has a moderate in-vitro and in-vivo stimulating effect on collagen synthesis and, at higher dosages, an inhibition on the synthesis of collagen and acid mucopolysaccharides. Studies have indicated the role of TTFCA on the synthesis of specific venous wall elements by cell cultures of human embryonal fibroblasts. The tissue-stimulating action is shown by the increased collagen production independent from the stimulation of cell proliferation (this differentiates the action of TTFCA from cell growth factors). TTFCA is active on the microcirculation in venous and diabetic microangiopathy. Signs and symptoms of venous hypertension and edema are improved by treatment. The remodeling on collagen synthesis could be one of the possible mechanisms of actions of TTFCA in the remodeling of echolucent (soft; therefore, with risk of thrombosis and embolization) plaques at the carotid and femoral bifurcation. This compound is safe and well tolerated. In conclusion, several actions of TTFCA in vascular diseases makes the use of this compound very interesting in venous and arterial problems.

Improvement of macromolecular clearance via lymph flow in hamster gingiva by topical warming and massage.

The lymphatic system is very important for macromolecular clearance in various tissues, especially in the gingiva. However, the kinetics of macromolecular clearance via the lymph flow in the gingiva are poorly understood. The aim of this study was to investigate whether thermal or mechanical stimulation affects macromolecular clearance via the lymph flow in the gingiva. Carbon black suspension was injected into the mandibular gingiva of anesthetized hamsters and its drainage into cervical lymph nodes was examined. Clearance of 14C-methylated bovine albumin and tritiated water from the gingiva and their drainage into submandibular lymph nodes and blood was quantified. The effect of topical warming or massage on clearance of 14C-methylated albumin from the gingiva during a 15 min period was examined. In addition, the influence of neurochemical antagonists on the stimulatory effect of topical warming on albumin clearance was investigated. Submandibular lymph nodes were clearly delineated by carbon black 10 min after the injection. More radiolabeled albumin appeared in submandibular lymph nodes than in serum, while more tritiated water appeared in serum. Topical warming (45 degrees C, 2 min) and warming plus massage (with a silicon rubber brush, 20 s) decreased the radiolabeled albumin in the gingiva 15 min after the injection. There was less radiolabeled albumin in the gingiva after gingival warming plus massage than after warming. Previous injection of HOE140 or propranolol into the gingiva diminished the stimulatory effect of topical warming on albumin clearance. It was concluded that topical warming plus massage improves macromolecular clearance via the lymph flow in hamster gingiva.

Influence of ochratoxin A and an extract of artichoke on the vaccinal immunity and health in broiler chicks.

The combined effect of ochratoxin A (at diet levels of 130, 305 and 790 ppb) and penicillic acid was studied in 100 broiler chicks. Serological investigations revealed significantly lower haemagglutination inhibiting antibody titers in the experimental chicks immunized with vaccine against Newcastle disease. A statistically significant decrease of the body weight and the relative weight of lymphoid organs as well as a significant increase of the relative weight of kidneys and liver were seen. The main degenerative changes were observed in the proximal convoluted tubules in kidneys and slight degenerative changes were found in the hepatocytes. Degenerative changes and depletion of lymphoid cells were observed in the bursa Fabricii, thymus, spleen and Peyer's patches of intestinal mucosa. Serum analyses revealed significant decreases of the total protein and cholesterol, and significant increases of the uric acid and glucose. Haematological analyses showed a slight anaemia, leucocytosis and slightly decompensated metabolic acidosis. A statistically significant protective effect of 5% total water extract of artichoke on humoral immune response (increase of haemaglutination inhibiting antibody titer), relative organ weight as well as on pathomorphological, haematological and biochemical changes induced by ochratoxin A, was established.

Tirilazad mesylate--effects of the 21-aminosteroid on the lymphoid system of laboratory animals: a comparison with the glucocorticoid methylprednisolone.

Four-week toxicity studies with the 21-aminosteroid tirilazad mesylate were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys to support development of the drug for use in various clinical syndromes of injury to the central nervous system of humans. As the immune system is involved in many of the obvious side effects of glucocorticoids used currently for this indication, particular attention was directed to the lymphoid system; results were contrasted with similar data from studies with methylprednisolone, a classical glucocorticoid. Administration of tirilazad mesylate to rats, dogs and monkeys for 4 weeks had no effects at the highest doses tested on parameters assessed, including absolute peripheral blood lymphocyte counts, thymus or adrenal weights, circulating levels of cortisol, or lymphocyte proliferation response to phytohemagglutinin-P. Germinal centers in lymphoid tissues from dogs given high doses of tirilazad contained small numbers of macrophages with vacuolated cytoplasm but no other changes; lymphoid tissues in rats and monkeys given tirilazad were morphologically normal. Administration of methylprednisolone for a similar duration in rats and dogs at high dose levels was associated with increased death rates due to bacterial infections, markedly decreased peripheral blood lymphocyte counts and weights of thymus and adrenal glands, and prominent lymphoid atrophy as well as decreased circulating levels of cortisol. Female dogs infused for 10 days with a high dose of methylprednisolone had depression of the in vitro proliferation response of peripheral blood lymphocytes to phytohemagglutinin-P.