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C E Freise

Publications and source records attributed to C E Freise.

At least 19 recordsLinked to original sources
PubMed1998

Risks associated with conversion of stable patients after liver transplantation to the microemulsion formulation of cyclosporine.

BACKGROUND: Neoral is a microemulsion formulation of cyclosporine that has a better pharmacokinetic profile than the standard formulation (Sandimmune). To prove the safety of converting stable liver transplant patients from Sandimmune to Neoral, we conducted a prospective trial involving 54 patients. METHOD: The average time from transplantation to conversion was 48.5+/-21.6 months. Thirty of 54 patients (55%) required a dose reduction during the study for various reasons. Five of 30 patients had the first dose reduction because of increased levels of cyclosporine. Seven patients required more than one dose reduction. RESULTS: Sixteen patients suffered serious adverse events. Six patients had a biopsy-proven rejection. Four of 6 patients had trough cyclosporine levels within 20% of baseline value immediately before developing rejection. CONCLUSION: Converting patients from the standard formulation to the microemulsion formulation of cyclosporine seems to expose stable patients to unnecessary risks.

Adolescent↗
PubMed1996

Hepatotoxins and liver transplantation decrease pulmonary metastases in rats with hepatoma.

Results following liver transplantation for hepatocellular carcinoma have been dismal, attributed largely to recurrent disease locally or at distance sites. Undetected micrometastases or tumor that embolizes at the time of liver transplant from manipulation of the liver may account for these recurrences. A model and treatment protocol were developed to address this clinical problem. The protocol is modeled on the concept of bone marrow transplantation for leukemia. Hepatotoxins that are lethal to both normal hepatocytes and hepatoma cells are administered followed by liver transplantation to "rescue" the failing liver. The feasibility of this protocol was examined in a rat model. Male Buffalo rats were injected with 1 million Morris hepatoma MH-7777 cells intravenously at Day 0 as a model for micrometastatic disease. Three treatment groups were established. Group 1 received no treatment. Group 2 received 5% dextrose in water (D5W) followed by a syngeneic orthotopic liver transplant (OLTX). Group 3 received the hepatotoxin pyrazofuin (10 mg/kg) followed by OLTX. Animals were followed to Day 35, at which time they were sacrificed and examined for evidence of pulmonary metastases and quantitation of nodules with India ink insufflation. There was a significant decrease in the number with pulmonary nodules as well as the number of animals with pulmonary metastatic disease in the pyrazofurin-treated group compared with groups 1 and 2 (4.8 +/- 4.0 nodules/animal vs 45.2 +/- 11.2 nodules/animal--no treatment and 60.8 +/- 21.4 nodules animal--D5W/OLTX group) These data indicate that this model is reliable for examining metastatic hepatoma and that pyrazofurin is effective in preventing hematogenous micrometastases of hepatoma cells. Other hepatotoxins and the effect of allogeneic transplantation and immunosuppression could be examined in this model.

Amides↗
PubMed1996

Liver transplantation improves survival of rats bearing hepatoma-3924A.

There was interest in developing a rat model of hepatocellular carcinoma with tumor dissemination that would respond to liver transplantation. Thus, a model of intrahepatic hepatoma implantation with micrometastases was developed by modifying a previously reported technique in the ACI rat. The pattern of tumor growth permits surgical resection with liver transplantation if done early in the course of disease. In addition, this model results in a reproducible rate of pulmonary metastatic disease. The pulmonary metastatic rate (number of rats developing pulmonary metastases) was 45.5% (n = 11) 2 weeks following intrahepatic tumor implantation and rose to 100% at the fifth week (n = 7). To examine the long-term outcome of animals with tumor, 46 animals were followed until death or 100 days after tumor implantation. Of these animals, 67.4% died from tumor within 100 days, all with pulmonary metastases. Several of the animals that were followed long term had advanced liver tumor as well, with intraperitoneal spread and ascites. To evaluate the effect of orthotopic liver transplantation (OLTX) in this model, syngeneic OLTX was performed 16 days after intrahepatic tumor implantation (n = 11). OLTX improved the 100-day survival of the recipients from 32.6% (control group) to 80.0% (P < 0.05). None of the long-term survivors had evidence of tumor on postmortem examination. The mechanisms responsible for decreased metastases following syngeneic liver transplantation are being investigated. The influence of immunosuppression, more advanced stage of tumor at the time of OLTX, and chemotherapeutic agents on this survival benefit could be be investigated with this model.

Animals↗
PubMed1995

Increased efficacy of CSA following rearterialization in the rat OLTX model.

Many investigators presently use a rat orthotopic liver transplant (OLTX) model without rearterialization of the graft. Rearterialization has been demonstrated to have a variable effect on the rejection response in various strain combinations. However, there are little data on the effects in a model with immunosuppression. The influence of rearterialization on the efficacy of cyclosporine (CSA) in such a model was examined, with the hypothesis that rearterialization may alter the rejection response and efficacy of cyclosporine. OLTX was performed between adult male D Agouti rats and Lewis rats. Rearterialization was performed between the recipient and donor celiac axis, and CSA was delivered at 1 mg/kg/day by continuous infusion for 14 days postoperatively. Treatment groups consisted of no rearterialization/no CSA, rearterialization/no CSA, no rearterialization/CSA, and rearterialization/CSA. Survival time and histology of liver grafts were measured. Rearterialization itself did not prolong survival in this strain combination (median survival no rearterialization/no CSA is 11 days versus median survival rearterialization/no CSA is 10 days). The addition of CSA at this dose without rearterialization also did not prolong survival (median survival no rearterialization/CSA is 15.5 days). The combination of CSA with rearterialization did prolong survival significantly (median survival rearterialization/CSA is 22 days; P < 0.05 versus the other three groups). The mechanism of this increased efficacy is unknown, but may involve altered MHC antigen expression, altered metabolism of CSA, decreased toxicity of CSA, or decreased nonspecific inflammation in the rearterialized grafts.

Animals↗
PubMed1994

The increased efficacy and decreased nephrotoxicity of a cyclosporine liposome.

A potential approach to avoid the complications of systemic immunosuppression is to deliver immunosuppressive agents locally to the site of the allograft. Liposomes are phospholipid particles that allow delivery of drugs preferentially to the reticuloendothelial system. Since the liver is a primary component of the RES, we hypothesized that liposome technology could be utilized to deliver immunosuppressive agents locally to a transplanted liver, thereby avoiding the complications of systemically delivered immunosuppression. We evaluated this hypothesis with a prototypic cyclosporine liposome in a rat model. Pharmacokinetic studies of this liposome indicated earlier clearance from the systemic circulation and increased hepatic uptake relative to the standard intravenous form of CsA. Decreased nephrotoxicity was also shown in an ischemic kidney model in the rat. The immunosuppressive efficacy of this liposome was also tested in a rat liver transplant model. There was a significant increase in survival compared with standard intravenous CsA when both drugs were administered at a dose of 1.75 mg/kg/day for seven days posttransplant (P < .05, CsA liposome-treated versus CsA/saline-treated). There were no demonstrable early toxic effects or late toxic effects observed with follow-up to 100 days. These data indicate that CsA liposomes have potential for use as an immunosuppressive agent with increased efficacy and decreased nephrotoxicity relative to the commercially available form of intravenous CsA. This improved therapeutic index of a locally targeted drug may lead to fewer complications attributed to systemic immunosuppression.

Animals↗
PubMed1993

Nonoperative management of biliary leaks after orthotopic liver transplantation.

Specific therapy should be instituted expeditiously once the diagnosis of a biliary leak has been made in patients who have undergone orthotopic liver transplantation. Controversy exists over whether to use nonoperative or operative management. The results of 325 consecutive orthotopic liver transplants in 297 adult and pediatric recipients were reviewed. The biliary tract was reconstructed using a choledochocholedochostomy anastomosis (254/325 or 78%) or a Roux-en-Y choledochojejunostomy anastomosis (71/325 or 22%). The incidence of biliary leaks was 23% (74/325). Overall, only 3% (10/325) of the orthotopic liver transplant recipients required operative repair of a biliary leak. Biliary leaks occurring in patients with Roux-en-Y choledochojejunostomy anastomoses (9/71 or 13%) commonly required operative repair (6/9 or 67%), whereas leaks that occurred in patients with choledochocholedochostomy anastomoses (65/254 or 26%) seldom required operative repair (4/65 or 6%). All choledochojejunostomy leaks occurred at the anastomosis, whereas choledochocholedochostomy leaks occurred either at the anastomosis (17/254 or 7%) or the T-tube insertion site (45/254 or 18%). Our study confirms that in centers with proficient endoscopic and interventional radiologic support, resolution of biliary leaks in orthotopic liver transplant patients can be achieved with nonoperative management.

Adolescent↗
PubMed1993

Acute liver rejection: evaluation with cell-directed MR contrast agents in a rat transplantation model.

Enhancement patterns with gadolinium (4s)-4-(4-ethoxybenzyl)-3,6,9-tris (carboxylatomethyl)-3,6,9-triazaundecandioic acid (EOB) diethylenetriaminepentaacetic acid (DTPA), a hepatocyte-directed magnetic resonance (MR) contrast agent, and superparamagnetic iron oxide particles (SPIO), a Kupffer cell-directed contrast agent, were compared at MR imaging in rat models of allogeneic and syngeneic liver transplantation. Light and electron microscopy were performed to monitor the morphologic changes in these livers and revealed typical findings in acute rejecting liver (allogeneic transplants) and normal architecture in syngeneic transplants. Liver enhancement with Gd-EOB-DTPA at MR imaging was delayed and prolonged with transplantation, and even more with rejection, but the level of enhancement when compared with that of control rats remained unaffected. Uptake of SPIO was decreased in the acutely rejecting livers but was normal in the syngeneic transplantation model. Enhanced MR imaging with cell-directed contrast agents depicted decreased phagocytotic activity in acute transplant rejection and enabled the excretory function of hepatocytes to be monitored. Additionally, Gd-EOB-DTPA may be applied advantageously for detection of focal lesions in transplanted livers.

Acute Disease↗
PubMed1993

Major histocompatibility complex class I deficiency prolongs islet allograft survival.

Because of islet allograft rejection, nonimmunosuppressed pancreatic islet allotransplantation has been unsuccessful for the treatment of type I diabetes. The role of major histocompatibility complex class I antigen expression on islet allograft survival was evaluated with the use of mice homozygous for a beta 2-microglobulin gene disruption. These mice express little if any functional major histocompatibility complex class I antigen. When these major histocompatibility complex class I-deficient islets were used as donors in an allogenic murine transplantation model, islet allograft survival was markedly prolonged. These results demonstrate a major importance for the alloresponse directed against major histocompatibility complex class I antigen.

Animals↗
PubMed1991

Wound healing after anorectal surgery in human immunodeficiency virus-infected patients.

Medical records of 52 human immunodeficiency virus (HIV)-infected patients who underwent a total of 80 anorectal operations from January 1985 to January 1990 were retrospectively reviewed to determined whether anorectal surgical wounds healed in HIV-infected patients and the mean survival time of these patients after surgery. Twenty-four operations were performed in asymptomatic HIV-infected patients, 19 in HIV-infected patients with persistent lymphadenopathy, and 37 in patients with acquired immunodeficiency syndrome. Wounds healed in 49 patients (94%). The mortality rate 30 days after surgery was 2%. There were no major complications. The mean survival time of HIV-infected patients after surgery was 15 months. We conclude that anorectal surgical wounds heal in most HIV-infected patients and that the survival time after surgery of HIV-infected patients with anorectal disease justifies appropriate surgical treatment.

Abscess↗
PubMed1991

Demonstration of local immunosuppression with methylprednisolone in the sponge matrix allograft model.

This study evaluated the effect of locally delivered methylprednisolone on the systemic and local immune response in the sponge matrix allograft model. Polyurethane sponges were coated with peritoneal exudate cells from DBA/2 (H-2d) or C57Bl/6 mice (H-2b) and placed subcutaneously in C57BL/6 recipients 24 hr later. Each mouse received both a syngeneic and an allogeneic sponge graft. Local immunosuppression was effected by placement on day 0 of cellulose/matrix pellets containing a preparation of increasing quantity of controlled release MP or by daily intrasponge injection of MP. Local immunosuppression was demonstrated by decreased cytotoxicity on day 12 in the allogeneic sponge receiving MP directly, as compared with the groups that received MP in the opposite syngeneic sponge or no MP. This effect was noted at a specific MP dose (0.5 mg/kg/day). Absolute numbers of precursor cytolytic cells and mature cytolytic cells (determined by limiting dilution analyses) infiltrating the allografts were also decreased in the sponges receiving MP directly, relative to the groups receiving MP in the opposite syngeneic sponge. Maintenance of systemic (in contrast to local) immunity was also demonstrated. Animals treated with local MP into a simultaneously placed syngeneic sponge or in whom no MP was delivered became sensitized to a synchronous DBA/2 sponge and rejected a subsequent DBA/2 skin graft in second-set fashion. Conversely, animals that received local MP into their synchronous DBA/2 sponge rejected a subsequent DBA/2 skin graft or a third-party graft with first-set kinetics. The presence of local MP at the initial graft site prevented the animals from becoming sensitized to the presented alloantigen but did not keep the animal from developing a rejection response to a third-party skin graft with first-set kinetics. It appears that delivery of MP locally to the site of antigen is an effective method to modulate alloreactivity. In addition, the sponge matrix allograft appears to be a useful model for studying local immunosuppression.

Animals↗