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Clinicians have been concerned that fractures do not heal properly in individuals exposed to bisphosphonate treatment, a treatment that strongly affects bone metabolism. The current study attempted to clarify the long-term effects of clodronate (dichloromethylene bisphosphonate) treatment on fracture healing in growing rats. Clodronate was administered subcutaneously twice a week in a dose of 2 mg/kg or 10 mg/kg. Physiologic saline served as a control. After 24 weeks of treatment, the tibiae were fractured, and the treatment was continued for another 4 weeks and 8 weeks. At both end points the cross-sectional areas of the callus, measured by peripheral quantitative computed tomography, were greater in the clodronate-treated rats than in controls, but there were no significant differences in bone mineral density. There were no significant differences between treatments in radiologic healing, histomorphometry, or in mechanical failure load of the callus with the exception of increased tensile stiffness at a dose of 2 mg/kg at 4 weeks. Clodronate treatment does not seem to prolong the fracture healing process, even when administered on a long-term basis before the fracture. Clodronate increases the size of the callus, but has only a minor effect on its biomechanical properties. The current results suggest that long-term clodronate treatment does not inhibit fracture healing.

Background: Bone loss has been reported as a complication after heart transplantation (HTx), and the increase in bone fractures is an effective problem. Treatment of osteoporosis has obtained mixed results. In this study we evaluate the effect of treatment with an oral bisphosphonate., Methods: Sixty-four patients with low mineral density 6 months after HTx were randomized as follows: Group A received oral clodronate (1600 mg/day in two divided doses), and Group B received placebo. Every patient was also treated with 2000 mg/day of oral calcium carbonate. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at the lumbar spine, 1/3 and 1/10 of the distal nondominant forearm before and after 12 months of treatment. Laboratory tests were performed at 3, 6, and 12 months of treatment., Results: All patients demonstrated manifest bone loss 6 months after HTx compared with normal non-HTx controls (P=0.0001). After 1 year of clodronate therapy, BMD at the lumbar spine increased from 0.77+/-1.4 g/cm(2) to 0.86 g/cm(2) (P=0.02). Laboratory tests did not show any significant variation, except for the bone isoenzyme of alkaline phosphatase, which showed a significant decrease after 1 year of treatment. The incidence of new fractures was 9.3% in the placebo group and 0% in the clodronate group. Therapy was well tolerated without impact on graft function., Conclusions: One year of clodronate therapy induced a significant increase in BMD at the lumbar spine in our HTx patients. Treatment was well tolerated without onset of new bone fractures.

To evaluate the penetration of cefepime in the inflamed pancreas, three doses of 50 mg/kg were administered intramuscularly at 8-h intervals after induction of acute necrotizing pancreatitis using intraperitoneal injection of DL-ethionine in 35 rabbits and in 33 controls. Animals were sacrificed and concentrations of cefepime were determined by a microbiological assay. Cefepime reached its peak concentrations 60 min after the last drug dose when mean values of 46.05 microg/ml, 22.34 microg/g and 34.74 microg/ml were found in serum, pancreas and bile, respectively, in rabbits with acute necrotizing pancreatitis and 45.19 microg/ml, 12.68 microg/g and 20.77 microg/ml respectively in controls. Tissue/serum ratios of cefepime were 0.48, 0.23, 0.15 and 0.09 at 60, 90, 120 and 180 min, respectively, after the last dose of cefepime in rabbits with acute necrotizing pancreatitis and 0.28, 0.18, 0.16 and 0.16, respectively at 60, 90, 120 and 180 min in controls. It is concluded that the administration of cefepime in rabbits with acute necrotizing pancreatitis resulted in pancreatic tissue levels well above the MIC90s of the common pathogens involved in pancreatic superinfection, so that its administration might be proposed for the therapy of superinfection following acute necrotizing pancreatitis in humans.

There are controversial in vitro data comparing the strength of the cellular immune response between allogeneic and xenogeneic stimulator/responder combinations. The present study therefore compares in vivo lymphocyte proliferation using heart transplantation (HTx) models in mice. Heterotopic HTx into BALB/c mice was performed using donor organs from mice (BALB/c and C57BL/6) or Lewis rats. Intraperitoneally given bromodeoxyuridine (BrdU) was incorporated into the DNA and was subsequently analyzed by flow cytometry. On postoperative days 3 and 5, proliferation of splenocytes, CD4(+) T-lymphocytes, and CD19(+) B-lymphocytes was significantly higher after xenogeneic than after allogeneic and isogeneic HTx. No significant difference was observed when proliferation of CD8(+) lymphocytes was determined. The increased in vivo proliferation after xenotransplantation may reflect an earlier and probably stronger cellular immune response compared to allogeneic transplantation. The higher CD4(+) lymphocyte proliferation underscores the importance of this cell population in xenograft rejection., (Copyright 2003 Wiley-Liss, Inc.)

Ten-year experience of treatment of 213 patients with trauma of the pancreas and 56 patients with trauma of the duodenum is analyzed. Combined injury of other organs was seen in 80% patients. Diagnostic policy included intraoperative revision in open abdominal trauma and dynamic observation with US, roentgenography, CT and laboratory tests in closed trauma wich doesn't require urgent surgery. The diagnosis was verified during laparoscopy and contrast duodenography. Surgical treatment results in patients with trauma of the pancreas depending on the variant of surgery are analyzed. The role of drug treatment of traumatic pancreatitis with 5-ftoruracil and octreotid is stressed. It is demonstrated that these principles allowed us to reduce complications rate to 11.7% and lethality to 6.7% from 71.7% and 37.0% respectively. It is established that suturing of duodenal wall on the decompressive nasoduodenal tube is effective within 6 hours after trauma. Later, for prophylaxis of suture insufficiency the duodenum must be switched off. Adequate drainage and depression of secretion with octreotid are very important for success of surgery. In this approach there were no cases of sutures insufficiency among 16 patients in the last 3 years.

The aim of the present work was to investigate the possibility of achieving buccal delivery of a problematic drug, acyclovir, from films based on chitosan hydrochloride (HCS) and polyacrylic acid sodium salt (PAA). At first, the ionic interaction between HCS and PAA in distilled water was investigated by means of rheological and turbidimetric analysis. Films containing 1 mg/cm2 of acyclovir and based on pure HCS and on HCS and PAA mixed in different ratios were prepared by casting technique. The films were subjected to hydration, rheological, mucoadhesion, drug release, "wash away," and permeation/penetration measurements. A commercial cream containing acyclovir and an aqueousacyclovir suspension were used as references. The addition of PAA to HCS produced a decrease in film hydration. Films based on HCS/PAA weight ratio close to interaction productstoichiometry were characterized by higher rigidity and better "wash away" properties with respect to the other films and the reference formulation. The worst mucoadhesive properties were shown by films based on mixing ratios close to interaction product stoichiometry. The addition of PAA to HCS produced a lowering in drug release profile. All the films examined promoted the permeation of acyclovir across porcine cheek epithelium when compared with acyclovir suspension and the commercial cream. The penetration enhancement properties were affected by the mixing ratio of the two polymers. The film based on 1/1.3 HCS/PAA weight ratio, besides possessing the best resilience properties on the mucosa, was also characterized by the highest permeation profile and, therefore, represents a promising formulation for buccal delivery of acyclovir.

The effectiveness of radiation and chemotherapy for breast cancer depends on individual response to drug-induced toxicity. The response can be evaluated by means of myelodepression. To this end, changes in leukocyte DNA level after ex vivo gamma radiation test were used as a criterion. Patients, aged 29-78, with tumors stage IIIB-IV received standard radiotherapy (50 Gy) or cyclophosphamide-methotrexate-5-fluorouracil (CMF). Clodronate alone was given to 26 patients and prior to a CMF course. The method proved prognostically effective since it revealed a significant inverse relationship between S-index and leukocyte nadir for both modalities. However, chemotherapy resulted in more pronounced leukopenia. With clodronate administration, the correlation was not significant. When clodronate was supplemented with CMF chemotherapy involved a significant relationship was observed between the two factors.

Background and Objective: Rituximab has shown a high activity in relapsed follicular lymphomas when given alone. Further on, phase-II-studies indicate that its addition to chemotherapy may improve the response rate substantially. However, so far, prospective randomized studies have not been available., Patients and Methods: In 1998 the GLSG started a multicenter trial in patients with relapsed or refractory indolent lymphoma or mantle cell lymphoma. A fludarabine-containing regimen (FCM) was chosen for salvage therapy, with fludarabine 25 mg/m(2)/d 1-3, cyclophosphamide 200 mg/m(2) d 1-3 and mitoxantrone 8 mg/m(2) d 1. A total of four courses, every 4 weeks were given. Patients were prospectively randomized for FCM alone or the immunochemotherapy with R-FCM (375 mg/m(2) one day before FCM) RESULTS: About 147 randomized patients 93 had follicular, 40 mantle cell and 14 lymphoplasmocytic/-cytoid lymphoma. Statistical analysis was performed by sequential testing and indicated for 94 fully evaluable patients a significant advantage for the R-FCM-arm, with an overall response rate of 83 % as compared to 58%, when treated with FCM alone (CR: 35 % vs. 13 %). Similar improvements of remission rate were detected in the different lymphoma subgroups, especially in MCL (OR: 65 % vs. 33 %). Both treatment options were associated with hematological toxicities of grade III and IV, but well tolerated; infectious complications were rare, with no difference between the two treatment groups., Conclusion: This prospectively randomized trial demonstrates for the first time a significant improvement of the combined immunochemotherapy related to the remission rate in patients with relapsed or refractory indolent lymphoma.

Purpose: To compare the safety and efficacy of intraoperative 5-fluorouracil (5-FU) or Intraoperative mitomycin C (MMC) in eyes undergoing primary trabeculectomy., Design: Prospective double-masked randomized clinical trial., Methods: One hundred fifteen eyes of 103 patients with uncontrolled intraocular pressure (IOP) despite maximally tolerated medical therapy or laser were prospectively randomized in a double-masked fashion to one of two treatment groups in a single institution setting. Subject's eyes underwent primary trabeculectomy with either topical 5-FU (50 mg/ml for 5 minutes) or topical MMC (0.2 mg/ml for 2 minutes). Primary outcome measures included the number of eyes achieving target pressures of 21, 18, 15, and 12 mm Hg at 6 and 12 months postoperatively. Secondary outcome measures included IOP, best-corrected visual acuity, complications, and interventions., Results: Of the 115 eyes, 57 received 5-FU while 58 received MMC. A target IOP of 21 mm Hg at 6 months was achieved in 53 of 56 (95%) eyes in the 5-FU group and 54 of 57 (95%) eyes in the MMC group (P = 1.00). At 12 months, 45 of 48 (94%) eyes in the 5-FU group met a target IOP of 21 mm Hg while 48 of 54 (89%) eyes in the MMC group did (P =.49). The most common complications in each group were persistent choroidal effusions and bleb leak., Conclusion: Our study suggests that intraoperative topical 5-FU is at least as effective as intraoperative topical MMC in reducing IOP of eyes undergoing primary trabeculectomy.

Purpose: To study the long-term results (1-14 years) of trabeculectomies with 5-fluorouracil injections that were successful at 1 year., Design: A retrospective noncomparative case series. INTERVENTION/PARTICIPANTS: We identified 87 patients (87 eyes) who had trabeculectomies with 5-fluorouracil injections from 1984 to 1989 that were successful at 1 year and had a follow-up range of 1.0 to 14.7 years (mean, 8.1, standard deviation of 4.4 years). All patients had previously failed glaucoma surgery (66.7%), cataract surgery (47.1%), or other diagnoses making them at high risk for failure., Main Outcome Measures: Successful control of intraocular pressure (IOP) was defined as IOP less than 21 mmHg or a reduction of 33% if preoperative pressure was less than 21 mmHg. Statistical analysis was performed using Kaplan-Meier life table analysis., Results: If an eye is considered successful by IOP at 1 year, the probability of successful control is 61% at 5 years, 44% at 10 years, and 41% at 14 years., Conclusions: Despite successful IOP control at 1 year, trabeculectomies with 5-fluorouracil injections show a continual loss of IOP control over time.

Chemotherapy has had limited success in the treatment of cancer over the years, due, in part, to the untoward toxicity of the therapeutic agent to normal cells. The design of tailor-made polymer conjugates provides a synthetic approach that can overcome some of the problems. Several synthetic polymer-based anticancer drug conjugates have entered clinical studies. This report reviews the chemistry, physicochemical properties, and therapeutic applications in cancer therapy of polymeric chemotherapeutic agents based on poly(L-glutamic acid). Targeted delivery of anticancer agents using poly(L-glutamic acid) as the drug carrier is also discussed with emphasis on the design of innovative polymeric constructs., (Copyright 2002 Elsevier Science B.V.)

To elucidate the relationship between 5-fluorouracil (5-FU) distribution and 5-FU-induced apoptosis and/or cell cycle arrest, microautoradiography was applied to murine intestinal crypts exposed to [14C] 5-FU by intravenous infusion. The histologic location of apoptotic cells in the crypt did not correlate to that of 5-FU. The temporal profiles of apoptotic and/or mitotic indexes corresponded to those of orally administered 5-FU in a previous study. Two cell cycle-related proteins, p21(WAF/Cip1) and bax, were also investigated in the present study. With time, p21(WAF/Cip1)-positive nuclei apparently migrated up the crypt. Bax-positive cytoplasm was observed throughout the crypt epithelial cells, accompanied by the occurrence of apoptosis, and remained until 48 h when the control level recovered. The findings demonstrate that 5-FU mainly exerts an apoptotic effect and/or cell cycle arrest by systemic exposure, and p21 and bax expression determine an individual cell's fate.

The objective of this study was to compare the efficacy of a combination of allopurinol (AL) and low-dose meglumine antimoniate (MA) with standard-dose MA in cutaneous leishmaniasis caused by Leishmania major. An open, controlled study was performed. Seventy-two patients were randomly selected from volunteers with cutaneous leishmaniasis living in a hyperendemic area. Exclusion criteria included pregnancy, nursing vs. gestation, age less than 5 years, and duration of disease of more than 4 months. Each patient received MA (60 mg/kg/day) or AL (20 mg/kg/day) plus low-dose MA (30 mg/kg/day) for 20 days, and was followed up for 30 days after cessation of treatment. The study was completed as planned in 66 patients. Complete healing occurred in 74.2% of patients in the MA group and in 80.6% of patients in the MA + AL group. No difference was found between the two groups with respect to side-effects. The combination of AL and MA increases the anti-leishmanial effects of antimoniate. In this study, it was confirmed that low-dose MA plus AL is as effective as high-dose MA in the treatment of cutaneous leishmaniasis caused by L. major.

Background: An increase in gut permeability can have serious consequences leading to sepsis and multiple organ failure. After lower torso ischemia an increase in gut permeability is seen in both animals and humans. There is proof that this can be modified by antioxidant supplementation., Methods: In this prospective, randomized study we have looked at the influence of a multiantioxidant supplementation regime, using allopurinol, vitamins E and C, mannitol and N-acetylcysteine, perioperatively. Twenty-two patients received standard treatment and 20 patients received supplementation. Gut permeability was determined using a double sugar test with lactulose and rhamnose., Results: A significant increase in gut permeability was found neither in the non-treatment group (p = 0.012) nor in the treatment group (p = 0.006) after 6 and 24 h. No difference was found between the group receiving antioxidants and the standard treatment group. p = 0.93 6 h post clamp; p = 0.97 24 h post clamp., Conclusion: In this study we have not found an influence of multiantioxidant supplementation on gut permeability after lower torso ischemia. Possible explanations for this negative result are being discussed., (Copyright 2002 S. Karger AG, Basel)

Using a syngeneic murine model, we investigated the therapeutic efficacy of combined gene therapy using adenoviral vectors expressing murine interleukin-2 (AdmIL-2) and Escherichia coli cytosine deaminase (AdCD). In a subcutaneous tumor model, tumor-bearing mice were treated with an intratumoral injection of adenoviral vectors and received an intraperitoneal administration of 5-fluorocytosine (5-FC). Only the mice treated with AdCD (2 x 10(8) pfu) and an intermediate dose of AdmIL-2 (1 x 10(6) pfu) survived significantly longer than mice treated with AdCD alone (P < 0.01). Moreover, 40% of these treated mice obtained complete remission from tumor-bearing status. The cytotoxicity of splenocytes obtained from the treated mice was related to the survival period. Tumor-specific cytotoxic T lymphocyte assay showed that the cell-mediated cytotoxic response was specific for parental tumor cells. In a hepatic metastasis model, mice treated with an intravenous administration of both AdCD (2 x 10(8) pfu) and an intermediate dose of AdmIL-2 (1 x 10(6) pfu) demonstrated the most significant reduction of metastatic foci and the longest survival following a 5-FC administration. These results suggest that gene therapy combined with AdmIL-2 and AdCD may be a promising strategy for clinical application and, in addition, that translation of combined gene therapy from murine models into the clinical setting will require careful attention to the variables of cytokine expression levels in the design of clinical trials and in the evaluation of treatment efficacy.

The prevalence of HIV-positive subjects in dialysis (hemodialysis and peritoneal dialysis) population varies from 0.13 to 0.36% in italian and french studies, respectively. Most drugs used in HIV therapy are primarily excreted by the kidney. In patients with renal insufficiency, careful dosage adjustment is mandatory to optimize drug exposure and reduce the risk for adverse events. We review the impact of peritoneal dialysis on the pharmacokinetics of antiviral drugs, and discuss on the dosage recommendations needed to achieve efficacy and avoid toxicity in patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD).

Aims: To evaluate a new delivery system of 5-fluorouracil (5-FU) using 5-fluorocytosine (5-FC) as a prodrug and cytosine deaminase induced in vitro and in vivo., Methods: Fibroblastic cells from rabbit Tenon's capsule were cultured. The cells were exposed to 5-FU and 5-FC with or without cytosine deaminase induced by recombinant adenovirus. In the in vitro study, cell proliferation and DNA synthesis were assessed by MTS, BrdU assay. The effect of 5-FC removal after the treatment of 5-FC and cytosine deaminase induction was also assayed. In the in vivo study cells with or without cytosine deaminase induction were transplanted into the subconjunctival space of mice, followed by eye drops of 1000 microg/ml of 5-FC three times a day. The mice were sacrificed at days 1, 5, and 10, then the cells transplanted were evaluated., Results: Cell proliferation was inhibited by exposure to 5-FU in a dose dependent manner; however, up to 1000 microg/ml of 5-FC did not affect cell proliferation. Cell proliferation was inhibited by exposure to 5-FC in a time dependent manner with induction of cytosine deaminase following infection of recombinant adenovirus. When 5-FC was removed 3 or 6 days after the treatment, the cells grew again. The effect was reproduced in the in vivo model of subconjunctival cellular proliferation although 5-FC was administrated as eye drops. There were no cases with corneal erosion., Conclusion: Cell proliferation was inhibited by co-exposure of 5-FC and cytosine deaminase. This new delivery system may merit controlled delivery of 5-FU after filtering surgery.

Background: We examined whether topical administration of a bisphosphonate clodronate could prevent alveolar bone loss in rats with experimental periodontitis., Methods: On day 0, elastic rings were placed around the cervix of the right and left maxillary first molars (M1) to induce inflammatory periodontitis. Fifty microl of clodronate solution at a concentration of either 0 (0.9% NaCl), 20, 40, or 60 mM was injected into the subperiosteal palatal area adjacent to the interdental area between M1 and M2 on either the left or right (experimental) side on days 0, 2, 4, and 6. The contralateral side served as a control and received 0.9% NaCl solution without clodronate. The animals were sacrificed on day 7., Results: Histological examination and determination of bone mineral density in the interdental alveolar bone area between M1 and M2 revealed that placement of an elastic ring caused severe vertical and horizontal bone resorption on the control side, while the topical administration of clodronate significantly prevented such alveolar bone loss. The number of osteoclasts on the experimental side was decreased compared with the control side. Furthermore, many of the osteoclasts on the experimental side were detached from the surface of the alveolar bone and had degenerated appearances, such as rounded shapes and a loss of polarity., Conclusions: These results suggest that topical administration of clodronate may be effective in preventing osteoclastic bone resorption in periodontitis.

Purpose: To observe the long term success of antimetabolites used in glaucoma filtering surgery in eyes with high risc of failure., Material and Method: Two groups of patients undergone trabeculectomy with the use of antimetabolites 5-Fluorouracil (5-FU) and Mitomycin C (MMC) are included in this retrospective study. 5-FU was administered postoperatively 1-10 times in the dose of 5 mg/ml in subconjunctival injection on 32 eyes. Follow up time ranged from 8 months to 9 years. Mitomycin C was administered intraoperatively in the dose of 0.2 mg/ml, on subconjunctival sponge with application time from 3 to 5 minutes on 15 eyes. Follow up time ranged from 7 month to 4.5 years., Results: Intraocular pressure (IOP) before operation with the use of 5-FU was in average 28.8 mmHg (22-50 mmHg) at the end of therapy with 5-FU was 17.6 mmHg (10-30 mmHg) and in the last examination was on average 19.5 mmHg (14-28 mmHg). IOP before operation with the use of MMC was in average 30.3 mmHg (22-40 mmHg), the seventh day after administration of MMC 12.7 mmHg (6-20 mmHg) and in the last examination was in average 18 mmHg (9-28 mmHg). During the long term observation of IOP values in the 5-FU group there was 79.2% success and in the MMC group there was 83.3% success (IOP up to 20 mmHg with or without therapy). Decrease of IOP was statistically significant., Conclusion: Antimetabolites improve the success of filtering surgery in high risc glaucomas. The long term follow up shows that failure of filtration in these types of glaucomas is still a serious clinical problem.

Intestinal intraepithelial lymphocytes (i-IEL) expressing CD8 alpha are located in the intestine and may confer protection against invasion of intestinal microflora. We found that mice rendered deficient in CD8 alpha molecules by homologous recombination were susceptible to 5-fluorouracil (5-FU)-induced lethality accompanied by translocation of members of the enterobacteria. The number of i-IEL was greatly reduced on day 6 after 5-FU administration in both CD8 alpha(+/-) mice and CD8 alpha(-/-) mice, whereas the recovery of the level of i-IEL thereafter was significantly impaired in CD8 alpha(-/-) mice compared with that in CD8 alpha(+/-) mice. The ability of i-IEL to produce gamma interferon in response to immobilized T-cell receptor (TCR) alpha beta or TCR gamma delta monoclonal antibodies was significantly lower in CD8 alpha(-/-) mice than in CD8 alpha(+/-) mice. Transfer of CD8(+) i-IEL conferred significant protection against 5-FU-induced lethality in CD8 alpha(-/-) mice. The results suggest that CD8(+) i-IEL play an important role in protection against 5-FU-induced lethality with translocation of Enterobacteriaceae.

The central mechanisms underlying diabetes-associated impotence are currently unknown. This study utilized immunolesion techniques to eliminate hindbrain catecholaminergic projections to the medial hypothalamus which have been reported to be glucoresponsive. The immunolesioned male rats had an attenuated feeding response to glucoprivic challenge. Furthermore, these lesioned rats had significantly attenuated penile reflexes. Northern blot analyses of hypothalamic oxytocin mRNA expression showed a significant increase; however, neuropeptide Y mRNA expression did not. These results suggest that hindbrain catecholaminergic neurones may alter the expression of hypothalamic neuropeptides that stimulate penile erections based upon glucoregulatory signals from the periphery.

Objective: Interleukin-6 (IL-6) and its soluble receptor (sIL-6R) stimulate osteoclast formation and activity. The primary cell abnormality in Paget's disease of bone (PDB) involves osteoclasts. Pagetic osteoclasts overproduce IL-6 and IL-6 receptor in vitro. In vivo, IL-6 serum levels are very high in the acute phase of PDB. The aim of this study was to evaluate the modification in the serum levels of IL-6, sIL-6R and osteotropic hormones (parathormone, 25OHD3 and 1,25(OH)2D3) as a in long-term response to clodronate treatment in patients with PDB., Methods: 16 patients (8 females) with polyostotic PDB were studied. IL-6, sIL-6R and osteotropic hormones serum levels were evaluated in active PDB and after clodronate treatment (300 mg injected intravenously for 5 consecutive days). The sequential changes in total alkaline phosphatase (tALP) serum levels were used to assess the maximal pharmacological response to treatment., Results: In untreated pagetic patients, mean serum levels of IL-6 (3.20+/-1.18 pg/ml) and sIL-6R (35.02+/-8.33 ng/ml) were significantly increased. Serum osteotropic hormone levels fell within the normal range. Eight weeks after treatment, the maximal pharmacological response to clodronate was associated with a significant reduction of sIL-6R serum levels in all patients, without a significant variation in serum IL-6 and osteotropic hormone levels. Moreover, we observed a correlation between lower sIL-6R serum levels before clodronate therapy and complete remission of PBD, defined as a decrease of tALP serum levels within the normal range., Conclusion: The decrease in serum sIL-6R levels could be one of the molecular mechanisms that play a role in the clinical response to clodronate treatment in PDB.

Background: The majority of chemotherapeutic agents are administered at fixed doses that are close to those maximally tolerated., Material and Methods: This review is based on current knowledge about the metabolism of thiopurines and the clinical implications of genetic polymorphism in thiopurine-S-methyltransferase (TPMT)., Results: Intracellularly thiopurines, e.g. 6-MP, are anabolized to cytotoxic 6-thioguanine nucleotides (6-TGN) that are incorporated into DNA and RNA. A competing pathway is S-methylation of 6-MP and its initial nucleotide metabolites by TPMT. In childhood acute lymphocytic leukaemia, high erythrocyte concentrations of 6-TGN correlate with the degree of leukopenia and a good prognosis, while low concentrations appear to be associated with higher risk of relapse. In most populations studied, approximately 10% have intermediate TPMT activity and 1/300 lacks TPMT activity due to one or two mutant TPMT alleles, respectively., Interpretation: Phenotyping or genotyping may be used to identify patients as deficient or intermediate thiopurine metabolizers. This suggests that they should receive a profound or moderate reduction in dosage to avoid haematopoietic toxicity.

Purpose: To estimate the prevalence and identify factors related to late-onset transconjunctival aqueous oozing and point leak from functioning blebs after trabeculectomy with 5-fluorouracil (5-FU) or mitomycin C., Design: Cross-sectional study., Setting: The study took place at the outpatient clinic of the Department of Ophthalmology, University of Tokyo Graduate School of Medicine (Tokyo, Japan). Four hundred three consecutive patients (403 eyes) with functional blebs at least 3 months after previously performed trabeculectomy were examined between December 1997 and February 1998. The Seidel test was performed with extended observation up to 15 seconds. Oozing was identified as transconjunctival aqueous egress without interruption of the conjunctival tissue or aqueous stream on the bleb wall. Logistic regression analyses of oozing and point leak in 331 eyes with an avascular area were performed using independent variables, including age, gender, glaucoma diagnosis, prior incisional surgery, antimetabolite use, combined cataract surgery, postoperative follow-up period, intraocular pressure (IOP), concurrent glaucoma therapy, bleb size, and avascular area size., Results: Of 403 eyes, 48 eyes (11.9%) had oozing and 8 eyes (2.0%) had point leak. Intraocular pressure was significantly lower and an avascular area was more frequent in eyes with oozing or leak than in eyes without (P <.001). Logistic regression analysis revealed that oozing was significantly more common after use of 5-FU than mitomycin C (P =.024), whereas point leak was associated with a larger avascular area (P =.045)., Conclusions: After trabeculectomy with antimetabolites, transconjunctival oozing is much more frequent than point leak. Oozing was significantly associated with the use of 5-FU and point leak with a larger avascular area in the bleb.

Endocrinological assessment of male reproductive toxicity was carried out in SD-Slc male rats treated with 5-FU (0, 20, 30 mg/kg/day) orally for 2-week or 4-week term. Serum hormone levels including GnRH, FSH, LH, prolactin, total and free testosterone, inhibin B, pro-alpha C, and activin A were determined as well as histopathological examination of the reproductive organs. The 5-FU treated groups showed histopathological changes in the testis such as degeneration of seminiferous epithelium. An obvious decrease in serum testosterone level was observed with a reduced organ weight of the seminal vesicle and prostate. However, no significant changes were noted in serum LH or FSH levels, nor in the morphological examination of the Leydig cells. Decreased serum levels were noted in activin A and prolactin. An increased serum level was noted in GnRH and pro-alpha C whose synthesis is regulated by FSH. Serum inhibin B levels showed a tendency toward decreasing with morphological change (vacuolation) in Sertoli cells. These results indicated that male reproductive toxicity induced by 5-FU would be augmented by decreased serum prolactin and testosterone levels as well as a decreased function of Sertoli cell, in addition to the direct cytotoxic effects on germ cells. It is suggested that these endocrinological changes related to male reproductive toxicities can be detected even in the 2-week-treated study.

Background: 5-Fluorouracil, an antimetabolic agent, improves the success rate of trabeculectomies by inhibiting subconjunctival fibrosis. However, complications may be associated with early postoperative use. We investigated the outcome of needling revision with delayed subconjunctival 5-fluorouracil in failing filtering blebs after a trabeculectomy in patients with medically poorly controlled glaucoma., Methods: We performed needling revision with subconjunctival 5-fluorouracil injection 5.0 +/- 4.0 weeks after trabeculectomy with failing filtering blebs in 25 eyes of 24 patients. The diagnoses of these patients were primary angle-closure glaucoma (4), primary open-angle glaucoma (4), post-cornea-graft glaucoma (8), traumatic glaucoma (5), neovascular glaucoma (3) and pseudophakic glaucoma (1)., Results: Total success was achieved in 21 eyes (84%) including complete success in 10 (40%) and qualified success in 11 (44%) after 3.2 +/- 1.2 needling revisions over an average 8.3 +/- 7.0-month follow-up period from the last needling revision. The mean intraocular pressure was 16.0 +/- 8.4 mmHg in the last visit compared with 26.0 +/- 8.1 mmHg before the procedure. Major complications were transient hypotony (1), transient corneal epithelial defect (13) and hyphema (3)., Conclusions: This study supports the efficacy and safety of the delayed use of 5-fluorouracil with needling revision for managing failing filtering blebs following a trabeculectomy.

Purpose: To evaluate the efficacy of an intracapsular ring releasing 5-fluorouracil (5-FU) in preventing posterior capsule opacification (PCO) in rabbit eyes., Setting: Center for Research on Ocular Therapeutics and Biodevices, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA, and Chu Morvan, Department d'Ophtalmologie, University of Brest, France., Methods: Seventeen rabbits were divided into 3 groups: Group 1, 6 rabbits (6 eyes), had phacoemulsification only (control group); Group 2, 6 rabbits (6 eyes), had phacoemulsification with implantation of an open-loop hydrogel intracapsular ring; Group 3, 5 rabbits (5 eyes), had phacoemulsification with implantation of a ring with sustained release of 0.25 microg/h of 5-FU for 9 days. All eyes were followed for 8 weeks before enucleation. Capsular bag shrinkage and the position of the intracapsular ring were assessed, and central and peripheral PCO was evaluated for intensity and area by stereomicroscopy from a posterior (Miyake-Apple) view. The residual equatorial lens epithelial cells (LECs) were counted by the same observer in histological sections. Transmission electron microscopy (TEM) of the cornea, capsular bag, and retina was done to evaluate the toxicity of 5-FU., Results: No significant difference was seen in the degree of capsular bag shrinkage in the 3 groups. The intracapsular ring was decentered in 2 eyes (1 each in Groups 2 and 3). There was a statistically significant difference (P <.05, Student t test) between Group 1 and Groups 2 and 3 in the area and intensity of central PCO. There was no difference between Groups 2 and 3 in the intensity of central PCO. No evidence of 5-FU toxicity to intraocular structures (cornea, capsular bag, and retina) was demonstrated on TEM analysis., Conclusion: Implantation of an intracapsular ring may prevent central PCO after cataract surgery by mechanically blocking LEC migration toward the central visual axis. The potential pharmacological effect of 5-FU in PCO prevention was not demonstrated.

Objective: To determine whether induction of pancreatic necrosis and islet proliferation by d,l-ethionine has potential for treating dogs with beta-cell insufficiency., Design: Eighteen mixed breed dogs of both sexes were given d,l-ethionine at 100 mg/kg three times weekly for 2 weeks; 6 dogs were euthanased at 2, 14 and 28 d after the last dose., Methods: Clinical signs during administration and recovery were assessed. Routine biochemical analyses were performed before each ethionine dose and then once weekly. Faecal samples were examined weekly for malassimilated nutrients and blood. Blood coagulation screening tests (OSPT and APTT) were determined on four dogs after ethionine administration. Intravenous glucose tolerance tests were conducted before the first and after the last ethionine dose and then fortnightly. All dogs were necropsied and pancreas, liver, kidney and jejunum were examined microscopically., Results: During ethionine administration all animals displayed vomiting, inappetence, diarrhoea (often with blood), weight loss and depression. Three dogs were euthanased prematurely due to severe illness, but those allowed to recover were eating and brighter 7 d after cessation of ethionine administration. Serum concentrations of TLI, amylase and lipase increased initially, then decreased, during administration but retumed to normal during recovery. Concentrations of ALT, ALP, unconjugated and conjugated bilirubin increased during administration then decreased slowly. Histological examination revealed hepatic lipidosis and necrosis, but no renal or jejunal lesions. In most dogs, faecal examination demonstrated increased undigested starch and muscle, as well as increased digested and undigested fat, during ethionine administration or early during the recovery period, suggesting transient malassimilation. APTT was unchanged but OSPT was prolonged in all dogs. There was no impairment of insulin secretion or glucose intolerance and C-peptide concentrations were unaffected. Immediately after ethionine administration there was delayed insulin degradation and by day 43 there was evidence of increased insulin sensitivity., Conclusion: d,l-ethionine administration in dogs appeared not to interfere with insulin secretion, but caused clinical signs and laboratory changes indicative of pancreatic exocrine necrosis, severe hepatobiliary disease and transient malassimilation. Pancreatic and hepatic dysfunction was severe but clinical recovery occurred after ethionine administration ceased. The severe side-effects observed with d,l-ethionine should preclude its potential use for treating diabetes mellitus in dogs.

There has been a dramatic change in the therapeutic approach to patients with Paget's disease of bone over the last 40 years. In the 1960s, only symptomatic therapy could be given, with control of pain the main objective. Analgesics and nonsteroidal anti-inflammatory drugs were the most commonly used agents. From 1968 onwards, antiosteoclastic agents became available, including calcitonin, plicamycin (mithramycin) and etidronate (etidronic acid), a first-generation bisphosphonate. Limitations with these agents, including potentially deleterious effects on bone mineralization with etidronate (etidronic acid), has cleared the way for increasingly potent second- and third-generation bisphosphonates, including clodronate (clodronic acid), pamidronate (pamidronic acid), alendronate (alendronic acid) and risedronate (risedronic acid). Even more potent bisphosphonates will become available in the near future. With the newer bisphosphonates, there is some hope for long-term remission (if not definitive healing) of pagetic lesions, as well as prevention of long-term complications in both symptomatic and asymptomatic patients. Thus, indications for therapy have been extended to include younger patients to prevent bone deformity of the limbs and skull, leading to secondary osteoarthritis, facial deformities and potentially to sarcoma transformation; as well as to elderly patients to prevent bone fragility, leading to fracture, and pagetic vascular steal syndromes. The increased potency and longer duration of action of newer bisphosphonates more than compensates for their marginally increased cost compared with older bisphosphonates.

Results of pancreatoduodenal resections were analyzed in 124 patients. All the patients were divided into 3 groups. The most common complication of pancreatoduodenal resections were shown to be postoperative pancreatitis resulting in incompetence of the pancreatodigestive anastomosis. The patients of the first group received traditional therapy. In the patients of the third group the application of a combined medicamentous prophylactics with Sandostatin and Verapanil allows the incidence of postoperative pancreatitis to be decreased from 35.4% noted in the first group to 18.4%.

Purpose: To report successful treatment of a case of ocular leishmaniasis with combined stibogluconate and allupurinol., Method: A 32-year-old physician developed a non-tender reddish chalazion like lesion in his right lower lid, associated with conjunctivitis and nodular episcleritis. Biopsy of the lesion in his eyelid and conjunctiva disclosed a dense inflammatory response including histiocytes containing typical leishmania organisms., Result: Therapy with stibogluconate, both intralesional and intramuscular, was initiated with some improvement. However recurrence of the lesion occurred. Systemic retreatment with combined stibogluconate and allupurinol led to complete healing of the lesion., Conclusion: Ocular leishmaniasis is a rare and potentially blinding disorder. Combined stibogluconate and allupurinol may be an effective therapy in such cases.

Purpose: Trabeculectomy is the procedure of choice for the surgical control of glaucoma, and is often augmented by intraoperative 5-fluorouracil application to reduce scarring. This study aims to assess the validity of this technique with a randomized placebo-controlled trial., Methods: Patients without risk factors for bleb failure other than previous drop use who were undergoing trabeculectomy surgery as their first ocular procedure were randomized to receive fluorouracil or placebo. The main outcome measures were intraocular pressure and bleb morphology., Results: Results from 40 eyes of 36 patients are presented; 23 eyes were treated with fluorouracil, and 17 eyes were treated with placebo. Mean intraocular pressure at 1 year and at the final follow-up examination was significantly lower than preoperatively, but was not different between fluorouracil and placebo groups. Kaplan-Meier survival analysis also failed to show any difference, though there was a trend toward better survival of an intraocular pressure of 16 mm Hg or lower. Bleb morphology was examined postoperatively in 24 patients, with no differences found between fluorouracil and placebo groups., Conclusions: No significant difference was found in trabeculectomy outcome between fluorouracil-treated and placebo-treated eyes. The study was too small to state definitively that no such difference exists, but suggests that any treatment effect is likely to be small.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Drainage devices are routinely placed in the eyes of patients with glaucoma to reduce intraocular pressure (IOP) by providing controlled outflow of fluid (aqueous humor) via a filtering bleb. However, the natural wound healing response often interferes with fluid outflow by thickening the walls of the bleb over time, so that these devices rarely remain functional for more than 5 years. We investigated the use of controlled release of an antimetabolite, 5-fluorouracil (5-FU), within glaucoma drains to determine if the wound healing response could be reduced and the useful life span of the device increased. Collagen plugs containing 1.125 mg of 5-FU were placed in the silicone tubes of modified Baerveldt glaucoma drains. Eight drains with 5-FU and eight drains without 5-FU were implanted in one eye each of 16 New Zealand white rabbits: the contralateral eyes served as unoperated controls. Results were evaluated in terms of IOP, fibrous capsule thickness, macrophage density. and presence of type III collagen surrounding the drain plate, 3 and 6 months after implantation. In general, eyes implanted with antimetabolite-containing drains demonstrated significantly lower values for all evaluated parameters at 3 months and lower or equal values at 6 months, compared with the eyes not receiving 5-FU and the unoperated controls, indicating improved IOP-lowering function, reduced bleb wall thickness, and earlier achievement of a steady-state wound healing response. All eyes remained healthy throughout the 6-month duration of the study with no cytotoxicity complications in any of the eyes. Thus, biodegradable plugs placed within the silicone tubes of glaucoma drains can safely deliver 5-FU to filtering blebs over time, which could prolong the functional life of the bleb by decreasing the thickness of the anterior fibrous capsule and permitting sufficient fluid outflow to reduce IOP to physiological levels.

Purpose: To compare the success rates of external dacryocystorhinostomy (EXT-DCR) with 5-fluorouracil (5-FU) augmented endonasal laser dacryocystorhinostomy (ENL-DCR) and to record the complications associated with 5-FU augmented ENL-DCR MATERIALS AND METHODS: This was a retrospective non-randomised study. Forty-one patients with primary acquired nasolacrimal duct obstruction underwent an EXT-DCR (19 patients) or an ENL-DCR (22 patients) over a 3-year period. A Holmium YAG laser (Ho:YAG) was used in the latter group of patients. Silicone tubes intubated in all patients were removed at three months. 5-FU was applied intraoperatively at the site of the ostium in the ENL-DCR patients. The median follow-up was 12 months (range 3-24 months) for the ENL-DCR group and 22 months (range 6-28 months) for the EXT-DCR group. The patency of the lacrimal system and the severity of epiphora were assessed at a final-review., Results: The median age of the EXT-DCR group was 77 years (range 53-87) and that of the ENL-DCR group was 71 years (range 23 to 84). There were 12 female patients in the former group and 19 in the latter. The percentage of success in the EXT-DCR group was 94.7% (95% confidence interval (CI) = 75.4-99.1) = ), and 63.6% in the ENL-DCR group (95% CI= 43.0-80.3). The confidence interval for the difference of 31.1% was 5.6-52.2. There was a statistically significant difference between the two groups, p=0.024 (Fisher exact test)., Conclusions: These data suggest that EXT-DCR provides better results than 5-FU augmented ENL-DCR. However, ENL-DCR is the procedure of choice in certain circumstances such as in elderly, frail or medically unfit patients. Our results of 5-FU augmented ENL-DCR compare favourably with other published series.

Background and Aims: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy., Methods: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities., Results: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity., Conclusions: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Purpose: There is a considerable body of literature relating to trabeculectomy; however, there are no data representative of the national experience of trabeculectomy in the United Kingdom (UK). The Department of Health funded a national survey of trabeculectomy to establish current practice patterns and the outcome of trabeculectomy in the National Health Service (NHS). In this paper we report variations in surgical technique and the national success rate of trabeculectomy., Methods: A cross-sectional survey was carried out of consultant ophthalmologists performing trabeculectomy in the NHS. Participants recruited their four most recent consecutive first-time trabeculectomy cases according to study eligibility criteria and data were collected by self-administered questionnaire., Follow-Up: 1 year post-trabeculectomy. Main outcome measure of success: final intraocular pressure (IOP) less than two-thirds the pre-operative IOP. Secondary outcome measures of success: final IOP less than 21 mmHg and visual field stability. Success was further defined as unqualified (excluding patients on anti-glaucoma medications at final follow-up) or qualified (including patients on anti-glaucoma medications at final follow-up). The relationship between variables characterising consultants' practice and main outcome measure was examined by chi-square test., Results: Clinical outcome data were available for 1240 (85.3%) cases. There were wide variations in operative technique. The mean post-operative IOP was 14.4 mmHg (95% CI 14.2-14.7), which is a mean reduction of 11.8 mmHg (95% CI 11.4-12.2). An unqualified success, in terms of the main outcome measure, was achieved in 66.6% of patients and a qualified success in 71.0% of cases. An unqualified success, in terms of a final IOP less than 21 mmHg, was achieved in 84.0% of cases and a qualified success in 92.0%. Visual fields were stable in 84.2%. Outcome was not related to consultants' specialist interest, level of activity, type of hospital or region., Conclusions: The success rates reported in this paper represent the national experience of first-time trabeculectomy for open angle glaucoma in the UK. The national success rate at 1 year compares favourably with many studies in the literature. This survey provides valid and clinically relevant measures of success for the production of guidelines and standards for audit at regional, local and individual level and a baseline for the comparison of new therapies.

The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 microL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes, the non-rigid preparation was the best. However, stabilization of the liposome membrane with cholesterol abolished the benefit of this non-rigid preparation. It was concluded that ultradeformable vesicles are promising agents for skin delivery of drugs.

The present study was designed to investigate the effect of the antimetabolite 5-fluorouracil (5-FU) on the capacity of the oral epithelium and the dental pulp to induce a mitogen-driven T-cell proliferation. Inbred Lewis rats were given 6 i.v. injections of 5-FU (30 mg/kg or 50 mg/kg) over a period of 8 days. Suspensions of oral epithelial and dental pulpal cells were prepared. The costimulatory capacity of the accessory cells from treated animals was monitored by their ability to induce a mitogen (ConA)-mediated proliferation of T cells isolated from regional lymph nodes of untreated animals. Accessory epithelial cells from rats treated with the high dose of 5-FU, but not the low dose, induced a decreased T-cell proliferation compared to controls. Accessory pulpal cells from rats, treated with 30 mg/kg or 50 mg/kg of 5-FU, induced a lower T-cell proliferation. When MHC class II molecule depleted T-cell suspensions from lymph nodes of 5-FU-injected animals were incubated with ConA, a significant proliferative response was observed. This finding correlated with an increase of MHC class II molecule expressing cells detected after incubation, although no such cells were observed immediately following the initial purification step of T cells. This finding demonstrates that the accessory cells could partly restore their expression of MHC class II molecules during incubation. The results of the study suggest that the function of immunocompetent cells of the oral mucosa and dental pulp is influenced by treatment with 5-FU and that the function of accessory cells of the pulp is affected more than the function of accessory cells derived from the oral mucosa.

Microparticles containing 5-fluorouracil (5-FU) were prepared using poly(DL-lactide-co-glycolide) with an oil-in-oil emulsion/solvent extraction technique. Particle characteristics including size distribution, 5-FU loading efficiencies, in vitro release and degradation were investigated. The dispersed phase was composed of PLG dissolved in dichloromethane, and the continuous phase was paraffin oil containing lecithin. 5-FU was successfully entrapped in the microparticles with trapping efficiencies up to 76%, loading level 10% w/v, and particle size 3 microm. Release profiles of 5-FU loaded microparticles were determined to follow a first-order-time relationship. An optimized preparation of 5-FU microparticles was achieved and was capable of controlling the release of 5-FU over 21 days with an in vitro delivery rate of 0.4 microg 5-FU/mg particles/day in the study. Preliminary animal studies indicated that the 5-FU loaded microparticles as an ocular delivery system showed no ocular toxicity and no significant inflammatory response in rabbits for 2 months. The 5-FU loaded microparticles approach, with PLG, might be a potential for the application of long-term delivery of hydrophilic drugs in the eye.

The healing process after glaucoma filtration is the main determinant of surgical failure and, even more important, the final intraocular pressure. The ability to fully control wound healing may ultimately give us the ability to set the intraocular pressure in the low teens for all patients undergoing glaucoma filtration surgery. The authors review the changes in how to use antimetabolites to improve safety, and many of the exciting new areas of progress, including growth factor neutralization and future molecular therapies to control wound healing.

The management of laryngeal and tracheal stenosis continues to challenge us, despite advances in surgical techniques and better understanding of the wound healing process. Injury to the airway mucosa is the inciting event, regardless of the cause of the stenosis. Mitomycin-C is an antineoplastic antibiotic that acts as an alkylating agent by inhibiting DNA and protein synthesis. It can inhibit cell division, protein synthesis, and fibroblast proliferation. Topical application of mitomycin-C (0.4 mg/mL) was used as an adjuvant treatment in the endoscopic laser management of laryngeal and tracheal stenosis in 15 patients. Fourteen patients (93%) have shown improvement of their airway and resolution of their preoperative symptoms. After a mean follow-up of 18 months, no complication was noted with regard to the application of mitomycin-C. This study gives promising findings on the efficacy and safety of mitomycin-C as an adjuvant treatment in the management of selected cases of laryngeal and tracheal stenosis.