Study of the Effects of Cordia myxa Fruit Extract on Induced Animal Model of Depression in Male Rats.

Depression is one of the most common mental illnesses. Herbal medications such as ginseng and peony have recently gained popularity in treating depression due to their safety, efficacy, and cost-effectiveness. Therefore, the present study aimed to evaluate the actions of Cordia myxa (C. myxa) fruit extract on the model of chronic unpredictable mild stress (CUMS) and antioxidant enzymes system in male rats' brains. Sixty male rats were divided into six groups (n=10). Group 1 (control) was neither exposed to CUMS nor received any treatment, while group 2 was exposed to CUMS for 24 days with normal saline treatment for 14 days, group 3 was exposed to CUMS for 24 days and received 10 mg/kg fluoxetine daily on day 10 for 14 days, and group 4, 5, and 6 were exposed to CUMS for 24 days and received C. myxa extract (125, 250, and 500 mg/kg, respectively) on day 10 for 14 days. The antidepressant effect of fluoxetine and C. myxa extract was evaluated using a forced swim test (FST). At the end of the experiments, animals were sacrificed by decapitation; and antioxidant enzyme levels, catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assays kits (ELISA) on rats' brain tissues. All groups subjected to CUMS showed a significant rise in duration of immobility on the tenth day compared to day zero. The CUMS showed a decrease in antioxidant enzyme levels, and groups treated with extract showed significant rise in enzyme levels (SOD and CAT) compared to group 2. According to this recent study, C. myxa may have an antidepressant-like action.

New photosensitizers for photodynamic therapy: combined effect of metallopurpurin derivatives and light on transplantable bladder tumors.

A series of metallopurpurins was tested for their photodynamic activity against transplantable N-[4-(5-nitro-2-furyl)-2-thiazoyl]formamide-induced urothelial tumors growing in male Fischer CDF (F344/CrlBR) rats. Histological examination of tumors in animals treated with the metallopurpurins and red light (greater than 590 nm, 360 J/cm2) revealed tumor necrosis 24 h after completion of therapy. Control tumors showed no histological change. In 30-day tumor regrowth studies, 70% of animals treated with the metallopurpurin derivative SnET2 were free of tumors while 50% of the animals treated with the free-base purpurin ET2 were free of tumor. Metallopurpurins have intense absorptions in the red region of the visible spectrum, a region with good tissue penetration. The metallopurpurins are easily prepared from the corresponding purpurins with a high degree of purity. This study demonstrates the potential of these photosensitizers for photodynamic cancer therapy.

Morphological study of the combined effect of purpurin derivatives and light on transplantable rat bladder tumors.

Purpurin derivatives, a group of synthetic photosensitizers, were tested for their photodynamic activity against transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced urothelial tumors growing in male Fischer 344 rats. Histological examination of tumors in animals treated with the purpurin derivatives and red light (greater than 590 nm, 360 joules/cm2) revealed tumor cell necrosis 24 h after completion of therapy. Control tumors showed no histological change. Purpurins have a major absorption peak in the red region (greater than 650 nm) of the visible spectrum, a region with good tissue penetration, and purpurins can be synthesized with a high degree of purity. This study demonstrates the potential of purpurin derivatives as photosensitizers for photodynamic cancer therapy.

Histological study of the effect of hematoporphyrin derivative photodynamic therapy on the rat jejunum.

Hematoporphyrin derivative photodynamic therapy is evolving as a local treatment for neoplastic disease. The emphasis of previous research has been on the determination of mechanisms of tumoricidal activity and defining the tumoricidal porphyrin component in hematoporphyrin derivative. The effect of hematoporphyrin derivative photodynamic therapy on normal tissue has received little attention. In the following study we examined the morphological changes of normal rat intestine exposed to hematoporphyrin derivative and light. In this model a segment of rat jejunum was exposed to red light (greater than 590 nm; 360 J/cm2) 24 or 72 h after the i.v. administration of hematoporphyrin derivative (5 or 10 micrograms/g body weight). Control groups received either no treatment, hematoporphyrin derivative only, or light only. Four h after treatment, intestinal segments were removed and examined by light microscopy. Segments treated with hematoporphyrin derivative and light showed extensive sloughing of the mucosa and submucosa with sparing of the muscular and serosal layers. It appears that hematoporphyrin derivative photodynamic therapy is capable of causing mucosal and submucosal damage to normal rat jejunum at these doses of light and hematoporphyrin derivative.

Jejunal blood flow after exposure to light in rats injected with hematoporphyrin derivative.

Experiments were performed to determine the effect of hematoporphyrin derivative (HPD) photodynamic therapy on blood flow to normal rat intestine. A segment of rat jejunum was exposed to red (greater than 590 nm) light (200 mW/cm2) 24 h after the i.v. administration of HPD. Blood flow to the light exposed segment was determined using the radioactive microsphere technique while blood flow to an adjacent light shielded segment of intestine served as an internal control. Animals were divided into six groups of six each: Group I, no HPD, no light; Group II, light, no HPD; Group III, HPD (20 micrograms/g body weight), no light; and Group IV, HPD (20 micrograms/g body weight), light. Blood flow in these four groups was determined 10 min after completion of a 30-min exposure to light. Only in Group IV was there a statistically significant decrease (P less than 0.005) in blood flow to the segment treated with HPD and light. In Groups V [HPD (20 micrograms/g body weight), light] and VI [HPD (10 micrograms/g body weight), light] blood flows were determined 24 h after exposure to light. In both of these groups there was also a significant (P less than 0.05) decrease in blood flow in the segment treated with HPD and light. This study demonstrates that normal intestinal blood flow can be disrupted by HPD photodynamic therapy.

Blood flow in transplantable bladder tumors treated with hematoporphyrin derivative and light.

Following hematoporphyrin derivative (HPD) photochemotherapy, blood flow to transplantable N-[4-(5-nitro-2-furyl)-2-thia-zolyl] formamide-induced urothelial tumors was determined by a radioactive microsphere technique using either 103Ru or 141Ce. Two tumors were implanted s.c. on the abdominal wall of Fischer 344 weanling rats. HPD (10 mg/kg body weight) was administered 24 hr prior to phototherapy (red light, greater than 590 nm; 360 J/sq cm). One of the two tumors was shielded from light exposure and served as an internal control. Blood flows were determined in control animals that received no treatment (Group 1), HPD only (Group 2), or light only (Group 3). In Groups 4 and 5, animals received the combination of HPD and light but differed in the time interval between treatment and blood flow determinations (10 min and 24 hr, respectively). Only blood flow to tumors treated with HPD and light showed a significant decrease (p less than 0.05) when compared with their internal controls both at 10 min (Group 4) and 24 hr (Group 5) after completion of phototherapy. These studies suggest that disruption of tumor blood flow may be an important mechanism of action of this method of cancer therapy.

Aspirin blocks binding of photosensitizer SnET2 into human serum albumin: implications for photodynamic therapy.

Tin etiopurpurin dichloride (SnET2) is one of the photosensitizers under investigation to be used in photodynamic therapy of prostate cancer. The drug is delivered intravenously, transported in vivo by liposomes and plasma proteins and localized within the prostate. SnET2 exists in two tautomeric forms (I - closed ring, II - open ring) with I converting spontaneously into the more energetically stable form II at physiological pH. Up to approximately 50% of the drug can be carried by serum albumin, although this association can increase photo-bleaching and diminish the drug efficiency. Molecular modeling and force field calculations indicate that Sudlow Site I in human serum albumin (HSA) is the most probable binding site for both forms of SnET2, with the porphyrin moiety nestling between domains IIA and IB, and the esterolytic side group oriented toward domain IIIA of HSA. Other drugs, including aspirin, bind to the same part of HSA. SnET2 does not bind to HSA when pre-incubated with aspirin, which confirms that its place of binding to this protein must be located near Lys199. This observation could be exploited to improve photo-efficiency of SnET2 by finding drugs that could compete with the photosensitizer for binding into Sudlow Site I of HSA.

St. John's wort may ameliorate 2,4,6-trinitrobenzenesulfonic acid colitis off rats through the induction of pregnane X receptors and/or P-glycoproteins.

It is reported that deficiencies of the pregnane X receptor (PXR) and P-glycoprotein (P-gp), the latter of which is encoded by the MDR1 gene, are important factors in the pathogenesis of inflammatory bowel disease (IBD). It is also known that the activation of PXR is protective of IBD due to the mutual repression between PXR and nuclear factor kappa B (NF-κB) expression and because NF-κB was reported to play a pivotal role in the pathogenesis of ulcerative colitis. The goal of this study was to investigate whether St. John's wort (SJW) and spironolactone (SPL), both known to have strong inducing effects on cytochrome P 450 (CYP) enzymes as well as PXR and P-gp, have ameliorating effects on 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis of rats through induction of PXR and/or P-gp. Wistar albino rats (250 - 300 g) were divided into control and TNBS-colitis groups. Each group was then divided into a) control (saline), b) SJW (300 mg/kg p.o. bid), and c) SPL (80 mg/kg p.o.) groups. Drugs were given for 7 days. Both treatments ameliorated the clinical hallmarks of colitis, as determined by body weight loss and assessment of diarrhea, colon length, and bowel histology. Plasma levels of NF-κB, tumour necrosis factor-alpha (TNF-α) and tissue myeloperoxidase (MPO) activity, as well as the oxidative stress markers that increased during colitis, decreased significantly after both treatments. The PXR and P-gp expression in the intestinal tissues was diminished in the colitis group but increased after drug treatments. Both drugs appeared to have significant antioxidant and anti-inflammatory effects and ameliorated the TNBS colitis of the rats, most likely through their PXR- and P-gp-inducing properties.

Salvage external beam radiotherapy for clinical failure after cryosurgery for prostate cancer.

PURPOSE: To investigate the role of external beam radiotherapy (EBRT) as salvage treatment of prostate cancer after cryosurgery failure. METHODS AND MATERIALS: Between 1993 and 1998, 6 patients underwent EBRT with curative intent for local recurrence of prostate cancer after cryosurgery. All 6 patients had biopsy-proven recurrence and palpable disease on digital rectal examination at the time of EBRT. The median follow-up was 34 months (range 8-46). The median prostate-specific antigen level was 2.3 ng/mL (range 0.8-4.1). No patient had evidence of metastatic disease. Two patients received hormonal therapy before beginning EBRT. No patient received hormonal therapy after EBRT completion. The median elapsed time between cryosurgery and EBRT was 3 years (range 1.5-4). The median delivered dose was 66 Gy (range 62-70.2) using a 10-MeV photon beam. An in-house-developed three-dimensional treatment planning system was used to plan delivery of the prescribed dose with conformal radiotherapy techniques. RESULTS: After EBRT, all patients had complete resolution of palpable disease. Four patients (66%) were disease free at the time of the last follow-up. Two patients developed biochemical failure as defined by the American Society for Therapeutic Radiology and Oncology consensus definition. One of these patients had a prostate-specific antigen level of 97 ng/mL before cryosurgery. No patient developed distant metastasis during follow-up. Two patients (33%) developed proctitis; 1 case resolved with Rowasa suppositories and 1 required blood transfusion. CONCLUSIONS: Our preliminary results suggest that EBRT can render a significant number of patients biochemically free of disease and can cause complete resolution of clinically palpable disease after initial cryosurgery. The results also showed that EBRT can be given without excessive morbidity. EBRT should be considered as a treatment option in these potentially curable cases.

Synthesis and in vivo photodynamic activity of some bacteriochlorin derivatives against bladder tumors in rodents.

Bacteriochlorins have been suggested as potential photosensitizers for use in photodynamic therapy. We have shown that bacteriochlorin-like macrocycles can be generated through cyclization of either 5,10- or 5,15-bis[(ethoxycarbonyl)vinyl]porphyrins; however, the resulting products are rapidly decomposed on exposure to air. More stable systems can be generated by Diels-Alder reactions between dienophiles such as dimethyl acetylenedicarboxylate or tetracyanoethylene, and vinylporphyrinones. Although spectroscopic properties of these latter products resemble those of porphyrinones rather than bacteriochlorins, in vivo studies using the N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced rat bladder tumor (AY-27) transplanted into Fisher CDF (F344)/CrlBr rats demonstrated a powerful photodynamic response.

New sensitizers for photodynamic therapy: controlled synthesis of purpurins and their effect on normal tissue.

Purpurins are a class of porphyrin derivative that have been shown to have good in vivo cytotoxicity to N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) induced rat bladder tumors (AY-27) implanted into Fisher 344 rats. The synthesis of purpurins from etioporphyrin I and coproporphyrin I proceeds in high yield and with a high degree of regioselectivity. Product formation can be rationalized in terms of relief of steric strain about the periphery of the purpurin macrocycle. The effect of therapeutic light doses using the rat footpad model suggests that, at therapeutic sensitizer doses, normal tissue damage is within acceptable limits, particularly for metalated purpurins.

Diels-Alder adducts of vinyl porphyrins: synthesis and in vivo photodynamic effect against a rat bladder tumor.

Benzoporphyrin derivatives have been proposed as potential photosensitizers for photodynamic therapy. We have prepared a number of benzoporphyrin derivatives and tested their effect, in combination with red light, on the N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) induced rat bladder tumor (AY-27) transplanted into Fischer CDF(F344)/CrlBr rats. Tetracyanoethylene (TCNE) adducts showed very little activity, which may be attributable to their poor tumor uptake or to chemical instability of the adduct under physiological conditions. However, dimethyl acetylenedicarboxylate (DMAD) adducts tested showed greater cytotoxic effect than hematoporphyrin derivative and similar activities to metallopurpurins when tested under the same protocol.

Enhanced skin allograft survival after photodynamic therapy. Association with lymphocyte inactivation and macrophage stimulation.

It has been found previously that peritoneal exposure to hematoporphyrin derivative (HpD) photodynamic therapy (PDT) can induce systemic immunosuppression of contact hypersensitivity. We have now found that HpD-PDT also significantly prolongs survival of murine skin allografts. Normal A/J mice transplanted with BALB/c skin rejected the grafts within 10 +/- 0.9 days. Recipient mice treated 24 hr previously with HpD-PDT rejected skin allografts at 16 +/- 1.2 days. HpD alone or irradiation alone had no effect on skin graft survival, nor did HpD-PDT administered shortly after grafting. Flow cytometric analyses showed a nearly complete depletion of peritoneal lymphocytes 3 days after HpD-PDT. Lymphocyte levels were normal in the spleen, an organ not directly targeted by the PDT treatment, but the cells were totally unresponsive to Con A and LPS mitogens. Conversely, peritoneal HpD-PDT caused a striking enhancement in macrophage function as measured by phagocytosis of antibody-coated sheep erythrocytes. Humoral immunity to hen egg-white lysozyme was not significantly changed by HpD-PDT. These results demonstrate that HpD-PDT causes systemic immunosuppression of cellular immunity which, in turn, allows prolonged survival of allografts. Humoral immunity appears to remain largely unaffected by HpD-PDT and macrophages become activated, suggesting that this therapy might be more effective in specifically targeting T cell-mediated immunity than current immunosuppressive treatments.

Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.

BACKGROUND: Tacrolimus has been shown to have a less adverse effect on the lipid profiles of transplant patients when the drug is started as induction therapy. In order to determine the effect tacrolimus has on lipid profiles in stable cyclosporine-treated renal transplant patients with established hyperlipidemia, a randomized prospective study was undertaken by the Southeastern Organ Procurement Foundation. METHODS: Patients of the 13 transplant centers, with cholesterol of 240 mg/dl or greater, who were at least 1 year posttransplant with stable renal function, were randomly assigned to remain on cyclosporine (control) or converted to tacrolimus. Patients converted to tacrolimus were maintained at a level of 5-15 ng/ml, and control patients remained at their previous levels of cyclosporine. Concurrent immunosuppressants were not changed. Levels of total cholesterol, triglycerides, total high-density lipoprotein, low-density lipoprotein (LDL), very-low-density lipoprotein, and apoproteins A and B were monitored before conversion and at months 1, 3, and 6. Renal function and glucose control were evaluated at the beginning and end of the study (month 6). RESULTS: A total of 65 patients were enrolled; 12 patients failed to complete the study. None were removed as a result of acute rejection or graft failure. Fifty-three patients were available for analysis (27 in the tacrolimus group and 26 controls). Demographics were not different between groups. In patients converted to tacrolimus treatment, there was a -55 mg/dl (-16%) (P=0.0031) change in cholesterol, a -48 mg/dl (-25%) (P=0.0014) change in LDL cholesterol, and a -36 mg/dl (-23%) (P=0.034) change in apolipoprotein B. There was no change in renal function, glycemic control, or incidence of new onset diabetes mellitus in the tacrolimus group. CONCLUSION: Conversion from cyclosporine to tacrolimus can be safely done after successful transplantation. Introduction of tacrolimus to a stable renal patient does not effect renal function or glycemic control. Tacrolimus can lower cholesterol, LDL, and apolipoprotein B. Conversion to tacrolimus from cyclosporine should be considered in the treatment of posttransplant hyperlipidemia.

Dobutamine echocardiography for prediction of ischemic events in heart transplant recipients.

The purpose of this study was to assess the use of dobutamine stress echocardiography in predicting cardiac events in heart transplant recipients. Dobutamine echocardiography was performed in 63 consecutive heart transplant recipients, 52 males and 11 females ranging in age from 12 to 77 years (mean 54), undergoing routine yearly evaluation. Twenty-one patients had abnormal wall motion at baseline or during dobutamine infusion. Over a mean follow-up of 8 months (range 4 to 14), there were six major cardiac events: five occurred among patients with abnormal echocardiography study results; only one event occurred in a patient with a normal echocardiography result. These data suggest that normal wall motion during dobutamine echocardiography identifies a subset of heart transplant recipients at low risk for development of cardiac events, whereas an abnormal study result serves as an important predictor of subsequent cardiac events.

Acute vascular rejection of the coronary arteries in human heart transplantation: pathology and correlations with immunosuppression and cytomegalovirus infection.

Prior studies of vascular rejection in transplanted human hearts have stressed the importance of accelerated coronary arteriosclerosis (chronic vascular rejection). We, however, have had four patients with sudden onset of acute heart failure within 90 days of transplantation who have died without significant myocardial interstitial rejection or the concentric intimal thickening with dense collagen that is typical of chronic vascular rejection. In contrast, the coronary arteries in our patients had a prominent lymphocytic infiltrate, a loosely organized intimal thickening composed of smooth muscle cells, and extensive endothelial injury. We believe that these changes define acute vascular rejection of the coronary artery. In 14 transplanted hearts obtained consecutively, at autopsy or at a second transplant procedure, graft failure was caused by acute coronary vascular rejection in six cases and by chronic coronary vascular rejection in one case. The remaining seven patients showed no evidence of vascular rejection and died primarily of sepsis. Cytomegalovirus (CMV) disease was present in 6 of 7 patients with vascular rejection, of which 43% were CMV-negative recipients of hearts from CMV-positive donors. The adoption of a triple-drug protocol, in which azathioprine was added to cyclosporine and prednisone, reduced the incidence of acute vascular rejection from 27% to 8%. We conclude that acute coronary vascular rejection may be initially seen as global cardiac ischemia in the absence of significant interstitial myocardial rejection. Further, acute vascular rejection should be pathologically distinguished from chronic vascular rejection, although both are probably stages in the natural history of immune-mediated vascular injury.

Atheromatous changes in expanded polytetrafluoroethylene grafts.

Expanded polytetrafluoroethylene (PTFE) has shown promise as an arterial and venous subsitute. Experimental and clinical reports on its use as a vascular prosthesis have documented excellent tissue incorporation with the development of a thin neointimal lining. We have recovered three PTFE grafts within which atheromatous changes of the neointimal were discovered on pathological examination. Anatomic location, radiographic findings, and special stains differentiated these changes from suture-line neointimal hyperplasia. Two of the three grafts were placed as angioaccess conduits for chronic hemodialysis. The potential for accelerated atherogenesis in chronic renal failure and repeated needle punctures of the grafts may have been contributory factors in these patients. These findings suggest that further evaluation is necessary to determine if PTFE allows for optimal neointimal healing or if, in fact, expanded PTFE has atherogenic potential.

Evaluation of an immunoisolation membrane formed by incorporating a polyvinyl alcohol hydrogel within a microporous filter support.

An immunoisolation membrane formed by incorporating a high water content polyvinyl alcohol (PVA) hydrogel into a microporous polyether sulfone (PES) filter has been investigated in this study. The PVA hydrogel is formed in situ within the filter pores via glutaraldehyde (GA) crosslinking under acidic conditions. The tortuous nature of the microporous filter pores securely anchors the embedded hydrogel to provide excellent structural integrity. The high void fraction of the PES filter support (>80%) and high water content of the PVA hydrogel (>85% water by weight) allow excellent solute transport rates, while an appropriate level of glutaraldehyde crosslinking supplies the required molecular size selectivity. In vitro permeability measurements made with solutes covering a wide range of molecular sizes demonstrate high transport rates for small nutrient molecules with rapidly diminishing permeabilities above a molecular weight of approximately 1,000 Dalton. Implantation experiments show that the membrane properties are not deleteriously affected by prolonged in vivo exposure or common sterilization techniques. Thus, this hybrid hydrogel/filter membrane system offers a promising approach to the immunoisolation of implanted cells.

Tracer technique to measure in vivo chemical transport rates within an implantable cell transplantation device.

An in vivo tracer technique that uses radiolabeled insulin as the tracer molecule has been developed to assess the rate of chemical transport between the cell transplantation chamber of an implantable bioartificial device and the host's circulatory system. The device considered here employs site-directed neovascularization of a porous matrix to induce capillary growth adjacent to an immunoisolated cell implantation chamber. This device design is being investigated as a vehicle for therapeutic cell transplantation, with the advantages that it allows the cells to perform their therapeutic function without the danger of immune rejection and it avoids damaging contact of blood flow with artificial surfaces. A pharmacokinetic model of the mass transport between the implantation chamber, the vascularized matrix, and the body has been devised to allow proper analysis and understanding of the experimental tracer results. Experiments performed in this study have been principally directed at evaluation of the tracer model parameters, but results also provide a quantitative measure of the progression of capillary growth into a porous matrix. Measured plasma tracer levels demonstrate that chemical transport rates within the implanted device increase with the progression of matrix vascular ingrowth. Agreement between the fitted model curves and the corresponding measured concentrations at different levels of capillary ingrowth demonstrate that the model provides a realistic representation of the actual capillary-mediated transport phenomena occurring within the device.

Small bilateral renal cell carcinomas.

A case of multicentric bilateral small renal cell carcinomas is presented. The two largest tumors were detected by computerized tomography (CT) and the diagnosis confirmed by ultrasound and fine needle biopsy.