Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2.

Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.

Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats.

To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-α), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-α) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats.

Glutamine and arginine improve permeability and tight junction protein expression in methotrexate-treated Caco-2 cells.

BACKGROUND & AIMS: Chemotherapy induces an increase of intestinal permeability that is partially related to an alteration of tight junction proteins, occludin and zonula occludens-1 (ZO-1). Protective effects of glutamine on intestinal barrier function have been previously shown but the effects of other amino acids remained poorly documented. Thus, we aimed to evaluate the effects of nine amino acids on intestinal permeability during methotrexate (MTX) treatment in Caco-2 cells. METHODS: Caco-2 cells were incubated in culture medium supplemented with glutamine, arginine, glutamate, leucine, taurine, citrulline, glycine, histidine or cysteine during 24 h and then treated with MTX (100 ng/ml). The dose of each amino acid was 16.6 fold the physiological plasma concentrations. Barrier function was assessed by transepithelial electrical resistance (TEER), FITC-dextran paracellular flux, occludin and ZO-1 expression and localization. Signaling pathways were also studied. RESULTS: Only glutamine, glutamate, arginine and leucine reversed the decrease of TEER observed after MTX treatment (P < 0.05). Interestingly, the addition of 6-diazo-5-oxo-1-norleucine, an inhibitor of glutaminase, blunted the effect of glutamine on MTX-treated cells (P < 0.05). Glutamine and arginine combination restored TEER and FITC-dextran flux to a similar extent than glutamine alone. In addition, pretreatment of Caco-2 cells with glutamine and arginine, alone or combined, differently limited the decrease of ZO-1 and occludin expression (P < 0.05) and the alteration of their cellular distribution, through c-Jun N-terminal kinase (JNK), Extracellular signal-regulated kinase (ERK) and nuclear factor kappa B (NF-κB) pathways. CONCLUSIONS: Glutamine prevented MTX-induced barrier disruption in Caco-2 cells. Arginine also had protective effects but in a lesser extent. The effect of glutamine and arginine should be evaluated in vivo.

5-Fluorouracil as chemoadjuvant for primary pterygium surgery: preliminary report.

PURPOSE: To investigate the safety and efficacy of intraoperative application of 5-fluorouracil as an adjuvant in primary pterygium surgery and to evaluate the effect of postoperative subconjunctival 5-fluorouracil injections on the recurrent pterygium. METHODS: Of 25 consecutive white patients, 28 eyes with primary pterygium underwent pterygium excision with intraoperative application of 5-fluorouracil (25 mg/mL for 3 minutes). The superior and inferior conjunctiva was approximated to cover the scleral bed within 1 mm of the limbus. Recurrence of pterygium was defined as postoperative fibrovascular growth more than 1 mm onto the cornea. Eyes with recurrence less than 2 mm were treated with subconjunctival 5-fluorouracil injections. RESULTS: After a mean follow-up of 14.1 +/- 3.9 months (mean +/- standard deviation), 7 recurrences (25%) were observed. All recurrences were detected within 12 months. In 4 of 7 recurrences, the fibrovascular growths were less than 2 mm. We, therefore, performed subconjunctival 5-fluorouracil injections. In 3 (75%) of 4 recurrences, the fibrovascular growths became atrophic. No serious complications were observed during and after the surgery. However, superficial punctate keratitis, pain, and hyperemia were detected in all patients in the early postoperative period. As a result, of 28 eyes, 4 (14%) had unacceptable cosmetic results and growing recurrences. CONCLUSIONS: This study suggests that intraoperative applications of 5-fluorouracil is both efficient and safe in the treatment of primary pterygium. Additionally, postoperative subconjunctival 5-fluorouracil injections may prevent the progression of fibrovascular tissue.

Irofulven, a novel inhibitor of DNA synthesis, in metastatic renal cell cancer.

Irofulven (6-Hydroxymethylacylfulvene, MGI-114) is the first of a new class of anticancer compounds the acylfulvenes which are derived from the natural product, illudin S. Irofulven is a potent anticancer agent with activity against a broad range of human tumors in vitro and in vivo. Irofulven covalently binds to DNA, inhibits DNA synthesis and induces apoptosis. Clinical activity has been observed in phase I studies. Because disease stabilizations were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of irofulven in this patient population. Twenty patients were accrued. Irofulven (11 milligrams per meter squared per day) was administered as a 5 minute intravenous infusion for 5 consecutive days, and response was evaluated every 8 weeks. There were no objective responses. The most common toxicities were nausea, emesis, and thrombocytopenia. Irofulven, at the dose and schedule administered in this trial, showed no effect in metastatic renal cell cancer.

Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 intraocular pressure control and complications.

BACKGROUND: Reduction of intraocular pressure (IOP) by 20-30% with glaucoma drainage surgery slows disease progression in normal tension glaucoma (NTG). It is not clear whether adjunctive antiproliferative agents are necessary or safe in eyes at low risk for scarring. METHOD: 86 eyes of 73 white NTG patients who had undergone a primary guarded fistulising procedure were reviewed. 25 eyes had no antiproliferatives, 36 had peroperative 5-fluorouracil (5-FU) and 25 had peroperative mitomycin C (MMC). Their postoperative IOPs, complications, and changes in visual acuity were recorded. RESULTS: Eyes that had no adjunctive antiproliferative less commonly maintained a 20-30% reduction in IOP (47.4% at 2 years) compared with either the 5-FU group (69.4%at 2 years, p=0.01) or the MMC group (64.9% at 2 years, p=0.04). Eyes that had adjunctive MMC more often had late hypotony (28%, p=0.02) and late bleb leak (12%, p<0.001). Eyes that had adjunctive MMC also more often had a two lines loss of Snellen visual acuity (39.8% by 2 years) compared with those that had adjunctive 5-FU (14.7% by 2 years), p=0.06. CONCLUSION: For NTG patients at low risk of scarring trabeculectomy with adjunctive peroperative 5-FU should maintain a suitable target IOP without the additional sight threatening complications seen with adjunctive MMC.

Methotrexate causes apoptosis in postmitotic endothelial cells.

Methotrexate (MTX) is a commonly used chemotherapy agent for a variety of cancers. However, therapeutic levels are associated with numerous untoward effects such as central nervous system damage in children with acute lymphoblastic leukemia. The purpose of this study was to determine if MTX caused injury to endothelial cells using cultured bovine pulmonary artery endothelial cells as a model. Light microscopy showed gaps between cells and reduced numbers of endothelial cells after exposure to MTX (10(-9) to 10(-5) M), a range consistent with therapeutic drug levels. Proliferation and viability of subconfluent and confluent MTX-treated endothelial cells were measured by colorimetric (MTS) assay. There was a significant decline in cell numbers in MTX-treated subconfluent (growing) cells cultured after 4 days of MTX exposure compared to controls, as expected. However, there was also an unexpected decline in cell numbers in MTX-treated postmitotic endothelial cells after 1, 3, and 4 days of drug exposure. This suggested that MTX induced endothelial cell death. Fluorescent ApoAlert Enhanced Annexin-V binding demonstrated apoptosis in endothelial cells after 1 day of MTX exposure. Apoptosis was confirmed by a DNA fragment assay. This is apparently the first report of MTX-induced apoptosis of postmitotic, cultured endothelial cells. The findings suggest that apoptosis may be one mechanism of MTX-induced injury to endothelial cells.

Late bleb leakage after trabeculectomy with 5-fluorouracil or mitomycin C.

OBJECTIVE: To determine the prevalence of late filtering bleb leakage after trabeculectomy performed with intraoperative adjunctive use of 5-fluorouracil (5-FU) or mitomycin C. DESIGN: Case series. SETTING: Private clinic in São Paulo. PATIENTS: Forty-seven consecutive patients (47 eyes) who had previously undergone trabeculectomy with intraoperative application of either 5-FU (25 mg/mL) or mitomycin C (0.2 mg/mL) and who had functioning filtering blebs. The patients who received 5-FU had advanced primary open-angle glaucoma without previous surgery; those who received mitomycin C had either previous failed filtering surgery or refractory glaucoma. All patients had been followed for at least 6 months. OUTCOME MEASURES: Slit-lamp appearance of bleb, bleb leakage, as determined with the Seidel test. RESULTS: None of the eyes had spontaneous bleb leakage. Ten (32.2%) of the 31 eyes that received 5-FU and 5 (31.2%) of the 16 eyes that received mitomycin C had induced bleb leakage. Thirty filtering blebs were classified as transparent, 10 as vascularized and 7 as ischemic. The rates of bleb leakage for the three groups were 46.7%, 0% and 14.3% respectively (p = 0.012). CONCLUSIONS: The importance of late bleb leakage in patients who receive intraoperative 5-FU or mitomycin C in predisposing these eyes to late complications, such as endophthalmitis and hypotony, needs to be evaluated.