Nucleoside chemistry represents an important research area for drug discovery, as many nucleoside analogs are prominent drugs and have been widely applied for cancer and viral chemotherapy. However, the synthesis of modified nucleosides presents a major challenge, which is further aggravated by poor solubility of these compounds in common organic solvents. Most of the currently available methods for nucleoside modification employ toxic high boiling solvents; require long reaction time and tedious workup methods. As such, there is constant effort to develop process chemistry in alternative medium to limit the use of organic solvents that are hazardous to the environment and can be deleterious to human health. One such approach is to use ionic liquids, which are 'designer materials' with unique and tunable physico-chemical properties. Studies have shown that methodologies using ionic liquids are highly efficient and convenient for the synthesis of nucleoside analogs, as demonstrated by the preparation of pharmaceutically important anti-viral drugs. This article summarizes recent efforts on nucleoside modification using ionic liquids.

Docetaxel is a microtubule inhibitor that has actions in the S and G(2)-M phase of the cell cycle. The pyrimidine trifluorothymidine (TFT) induces DNA damage and an arrest in the G(2)-M phase. TFT, as part of TAS-102, has been clinically evaluated as an oral chemotherapeutic agent in colon and gastric cancer. The aim of the present study was to determine the optimal administration sequence of TFT and docetaxel and to investigate the underlying mechanism of cytotoxicity. Drug interactions were examined by sulforhodamine B assays and subsequent combination index analyses, and for long-term effects the clonogenic assay was used. A preincubation with docetaxel was synergistic in sulforhodamine B (combination index 0.6-0.8) and clonogenic assays, and was accompanied by a time-dependent cell death induction (17-36%), the occurrence of polynucleation (22%), and mitotic spindle inhibition as determined by flow cytometry and immunostaining. Interestingly, administration of TFT followed by the combination displayed strong antagonistic activity, and was accompanied by less polynucleation and cell death induction than the synergistic combinations. Western blotting showed that the G(2)-M-phase arrest (25-50%) was accompanied by phosphorylation of Chk2 and dephosphorylation of cdc25c in the synergistic combinations. Together, this indicates that synergistic activity requires docetaxel to initiate mitotic failure prior to the activation of TFT damage signaling, whereas antagonism is a result of TFT cell cycle-arrested cells being less susceptible to docetaxel. Caspase 3 activation was low after docetaxel, suggestive of caspase-independent mechanisms of cell death. Taken together, our models indicate that combination treatment with docetaxel and TFT displays strong synergy when docetaxel is given first, thus providing clues for possible clinical studies.

Trifluorothymidine (TFT), a potent anticancer agent, inhibits thymidylate synthase (TS) and is incorporated into the DNA, both events resulting in cell death. Cell death induction related to DNA damage often involves activation of p53. We determined the role of p53 in TFT cytotoxicity and cell death induction, using, respectively, the sulforhodamine B-assay and FACS analysis, in a panel of cell lines with either wild type, inactive, or mutated p53. Neither TFT cytotoxicity nor cell death induction changed with TFT exposure in cell lines with wt, inactive or mutated p53. Conclusion: sensitivity to TFT is not dependent on the expression of wt p53.

Current treatment modalities for cancer combine cytotoxic drugs against DNA and novel targeted drugs affecting signal transduction pathways, which are required for growth progression and metastasizing tumors. Classical chemotherapeutic regimens for gastro-intestinal tumors include antimetabolites based on 5-fluorouracil (5FU), the platinum analog oxaliplatin and the topoisomerase inhibitor irinotecan. The thymidine analog trifluorothymidine (TFT) has been shown to bypass resistance pathways for 5FU derivatives (S-1, UFT, Xeloda) in model systems, while concurrent application with a thymidine phosphorylase inhibitor (TPI) increases the bioavailability of TFT, thereby potentiating the in vivo efficacy of TFT. The formulation TAS-102 is given orally in a 1.0:0.5 molar ratio (TFT:TPI). The formulation is dual-targeted due to the cytotoxic effect of TFT, which is enhanced by TPI, while TPI also exerts antiangiogenic effects by inhibiting thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor. Evidence is accumulating from in vitro and in vivo preclinical studies that these properties favor further combinations with other cytotoxic agents currently being used in the treatment of gastro-intestinal tumors. Also treatment with targeted agents will synergistically down-regulate signal transduction pathways responsible for growth and progression of tumors. In this review, we summarize the available information on (clinical) pharmacology, mechanisms of action, pharmacodynamic and pharmacokinetic properties, early clinical trials and future directions of the new potent combination drug TAS-102.

The mouse lymphoma assay (MLA) is the most widely used in vitro mammalian gene mutation assay. It detects various mutation events involving the thymidine kinase (Tk) gene in L5178Y/Tk+/--3.7.2C mouse lymphoma cells. Mutants are detected using a thymidine analogue that arrests the growth of cells containing a functional Tk gene. However, there are a number of potential test chemicals that are thymidine analogues, and there is a problem when using the MLA to evaluate the mutagenicity of these chemicals. Thymidine analogues are activated by Tk before eliciting their toxicity. Therefore, any pre-existing Tk-/- mutants may avoid the toxicity of the test chemical and obtain a growth advantage over the Tk+/- cells, increasing the Tk mutant frequency (MF) in the culture via a selection mechanism. This potential mutant selection effect needs to be distinguished from de novo mutant induction in order to properly evaluate the mutagenicity of these chemicals. Here we describe a simple MLA study design that can differentiate between the selection of pre-existing mutants and de novo mutant induction. Trifluorothymidine (TFT), a thymidine analogue and the selection agent normally used in the MLA, and 4-nitroquinoline-1-oxide (4-NQO), a potent mutagen, were used to treat cells from two different Tk+/- mouse lymphoma cell cultures with different background MFs (approximately 112 and 305x10(-6)). Both agents significantly increased the Tk MFs in both the normal and high background cultures (p<0.01). In 4-NQO-treated cultures, the induced MFs (MF of treated culture-MF of control) for the cultures with different background MFs were about the same (p>0.1), while in TFT-treated cultures, they were significantly different (p<0.01). In TFT-treated cultures, the fold-increases of MF (MF of treated culture/MF of control) for the cultures with different background MFs were about the same (p>0.1), while in 4-NQO-treated cultures, they were significantly different (p<0.01). This study confirms that, when de novo mutations are induced, the induced MF is the same for cultures with normal and artificially high background MFs. In situations where the increase in MF is due solely to selection of pre-existing mutants, the "induced" MF will be a multiple of the background MF and the magnitude of the increase of the induced MF will depend upon the magnitude of the background MF. Our results demonstrate that it is possible, using this experimental design, to distinguish between chemicals acting primarily via the selection of pre-existing Tk mutants and those inducing de novo mutants in the MLA.

BACKGROUND Adenovirus (Ad), associated with significant morbidity, has no topical treatment. A leading CTC compound (CTC-96), a Co(III) chelate, was found to have potent in vitro and in vivo antiviral efficacy against herpes viruses. In this study CTC-96 is being tested for possible anti-Adenovirus activity. METHODS The biological anti-adenovirus activity of CTC-96 in concentrations from 5 to 250 ug/ml, was evaluated initially by viral inactivation (viral exposure to CTC-96 followed by dilution and inoculation of cells), virucidal (viral exposure to CTC-96 and inoculation of cells without dilution) and antiviral (effect of CTC-96 on previously adsorbed virus) plaque assays on HeLa (human cervical carcinoma), A549 (human lung carcinoma) and SIRC (rabbit corneal) cells. After verifying the antiviral activity, New Zealand White rabbits were infected with Ad-5 into: 1) the anterior cul-de-sac scarifying the conjunctiva (Group "C+"); 2) the anterior cul-de-sac scarifying the conjunctiva and cornea (Group "CC+"); 3) the stroma (Group "CI+"). Controls were sham-infected ("C-","CC-","CI-"). Other rabbits, after "CC", were treated for 21 days with: 1) placebo, 9x/day ("-"); 2) CTC-96, 50 ug/ml, 9x/day ("50/9"); CTC-96, 50 ug/ml, 6x/day ("50/6"); CTC-96, 25 ug/ml, 6x/day ("25/6"). All animals were monitored via examination and plaque assays. RESULTS In vitro viral inactivation, virucidal and antiviral assays all demonstrated CTC-96 to be effective against Adenvirus type 5 (ad-5). The in vivo model of Ad keratoconjunctivitis most similar to human disease and producing highest viral yield was "CC". All eyes (6/6) developed acute conjunctivitis."CI" yielded more stromal involvement (1/6) and iritis (5/6), but lower clinical scores (area x severity). Infection via "C" was inconsistent (4/6). Fifty (50) ug/ml was effective against Ad-5 at 6x, 9x dosings while 25 ug/ml (6x) was only marginally effective. CONCLUSION CTC-96 demonstrated virucidal activity against Ad5 in tissue culture with HeLa, A549 and SIRC cell lines. Animal Model Development: 1)"CC" produced conjunctival infection with occasional keratitis similar to human disease;"CI" yielded primarily stromal involvement; 2)"C" consistently produced neither conjunctivitis nor keratitis.CTC Testing: 1) Conjunctivitis in all eyes; 2) Resolution fastest in "50/9"("50/9"."50/6">"25/6">"-"); 3) Efficacy in "50/6" was not statistically different than "50/9"; 4) Conjunctival severity was lower in treatment groups then controls; 5) Little corneal or intra-ocular changes were noted.

PURPOSE Trifluorothymidine (TFT) is a fluoropyrimidine that is part of the novel combination metabolite TAS-102, in which TFT is combined with a potent thymidine phosphorylase inhibitor (TPI). TAS-102 is currently tested as an orally chemotherapeutic agent in different schedules in a phase I study. In its monophosphate form, TFT can inhibit thymidylate synthase (TS) activity after binding to the TS-nucleotide binding site leading to dTTP depletion, and in its triphosphate form TFT is incorporated into DNA, eventually leading to DNA damage. In this in vitro study, we investigated whether TFT could potentiate cytotoxicity of the antifolate-based TS inhibitors AG337 (Nolatrexed), ZD1694 (Raltitrexed) and GW1843; and whether increased TS inhibition or DNA damage would be related to this result. METHODS The drug combinations were studied in colon cancer cell lines either grown at low or high folate conditions. Multiple drug effect analysis was performed after measuring growth inhibition when the drugs were combined (MTT Assay) and expressed as Combination Index (CI), where CI<0.9 indicates synergism, CI=0.9-1.1 indicates additivity and CI>1.1 indicates antagonism. Drug target analysis was performed using the TS in situ inhibition assay and the FADU DNA-damage assay. Cells were exposed to either the drugs alone or in combination to determine the effect on TS activity and DNA damage induction, respectively. RESULTS Three experimental procedures were used to test the interaction of the drugs: either one of the drugs was kept at a constant concentration (IC25) or two drugs were added in a 1:1 IC50-based molar ratio. The combinations of TFT with one of the antifolates in which one of the drugs was kept at a constant concentration were synergistic for all antifolates in WiDr/F cells, which grow in low folate medium (CI=0.6-0.8), but only additive to antagonistic for the cell lines growing in high folate medium: TFT-AG337: CI=0.9-2.3; TFT-ZD1694: CI=0.9-1.3; TFT-GW1843: CI=0.8-1.7. The procedure in which the two drugs were added in a 1:1 IC50-based molar ratio showed antagonism for all three combinations in all cell lines (CI>2.7). TS inhibition (14.3%) and DNA damage (8%) were more pronounced than expected (P<0.05) when TFT was combined with GW1843 in WiDr/F cells, in contrast to AG337 and ZD1694, which showed inhibiting effects as expected (additive). CONCLUSIONS The combination of TFT with the antifolates AG337, ZD1694 and GW1843 is mainly additive when the drugs are given simultaneously and this is mediated by an additive TS inhibition and DNA damage. The drug interaction may partly be dependent on the folate homeostasis since WiDr/F cells growing at low folate conditions show pronounced synergism in growth inhibition, two-sided TS inhibition and DNA damage, especially when TFT is combined with the tight-binding TS inhibitor GW1843.

The increase in the number and classes of antiviral agents that has occurred since the 1980s is remarkable. The rapid expansion in therapeutic options for previously untreatable illnesses challenges clinicians to gain familiarity and experience with these new drugs, especially with regard to their use in children. This article describes the clinical utilities, pharmacokinetics, and adverse effects of these new drugs to empower practitioners to use them appropriately.

Trifluorothymidine (TFT) can be phosphorylated by thymidine kinase (TK) to TFTMP which can inhibit thymidylate synthase (TS), resulting in depletion of thymidine nucleotides. TFT can be degraded by thymidine phosphorylase (TP) which can be inhibited by thymidine phosphorylase inhibitor (TPI). Using the TS in situ Inhibition Assay (TSIA) FM3A breast cancer cells were exposed 4 h or 24 h to TFT and 5-Fluorouracil (5FU). TS activity reduced to 9%(0.1 microM TFT) and 58%(1 microM 5FU) after 4 h exposure and to 6%(TFT) and 21%(5FU) after 24 h exposure. TPI did not affect TS inhibition by TFT. FM3A cells lacking TK or TS activity (FM3A/TK-) were far less sensitive to TFT compared to FM3A cells. Conclusion: TFT can be taken up and activated very rapidly by FM3A cancer cells, probably due to favourable TK enzyme properties, and TPI did not influence this.

PURPOSE Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing. METHODS Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial cauterization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment formulations of a given topical antiviral agent were combined. The proportion healed with 1 week of therapy, a scheduled follow-up day that approximated the average time of resolution with antiviral therapy, was selected as the primary outcome based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during antiviral therapy were developed by multivariate analysis of the Herpetic Eye Disease Study dataset. RESULTS After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial keratitis in 28 categories and 9 comparisons of geographic epithelial keratitis in 6 categories. For dendritic keratitis, idoxuridine was better than placebo at 7 days (combined odds ratio [OR], 3.59; 95% confidence interval [CI], 1.92-6.70), and at 14 days (OR, 4.17; 95% CI, 1.33-13.04), but pooling was limited by lack of homogeneity and low study quality. Direct comparisons at 1 week of treatment showed that trifluridine or acyclovir was significantly better than idoxuridine (OR, 3.12 and 4.56; 95% CI, 1.55-6.29 and 2.76-7.52, respectively), and indirect comparisons were also consistent with a clinically significant benefit. Vidarabine was not significantly better than idoxuridine in pooled treatment comparisons at 1 week (OR, 1.20; 95% CI, 0.72-2.00) but was better in 2 indirect comparisons (OR, 4.22 and 4.78; 95% CI, 1.69-10.54 and 2.15-10.65, respectively). At 14 days, trifluridine (OR, 6.05; 95% CI, 2.50-14.66), acyclovir (OR, 2.88; 95% CI, 1.39-4.78), and vidarabine (OR, 1.24; 95% CI, 0.65-2.37) were each better than idoxuridine. Trials of geographic epithelial keratitis also suggested that trifluridine, acyclovir, and vidarabine were more effective that idoxuridine. Other topical antiviral agents, such as bromovinyldeoxuridine, ganciclovir, and foscarnet, appeared equivalent to trifluridine or acyclovir. Oral acyclovir was equivalent to topical antiviral therapy and did not hasten healing when used in combination with topical treatment. Antiviral agents did not increase the speed of healing when compared to debridement but reduced the risk of recrudescent epithelial keratitis. The combination of physicochemical treatment with an antiviral agent seemed to be better than either physicochemical or antiviral treatment alone, but the heterogeneous cauterization and curettage techniques and the various treatment combinations limited valid quantitative summary effect measures. The combination of topical interferon with an antiviral agent was significantly better than antiviral therapy at 7 days (OR, 13.49; 95% CI, 7.39-24.61) but not at 14 days (OR, 2.36; 95% CI, 0.82-6.79). Finding apparent heterogeneity for some pooled estimates suggested that dissimilarities in patients, interventions, outcomes, or other logistical aspects of clinical trials occur across studies. CONCLUSIONS The available evidence on the acute treatment of presumed HSV epithelial keratitis demonstrates the effectiveness of antiviral treatment and shows the log-logistic healing curve of treated dendritic epithelial keratitis. Topical trifluridine, acyclovir, and vidarabine were significantly more effective than idoxuridine but similar in relative effectiveness for dendritic epithelial keratitis. Physicochemical methods of removing infected corneal epithelium are effective, but adjunctive virucidal agents are needed to avert recrudescent epithelial keratitis. Whether debridement in combination with antiviral therapy is more beneficial than antiviral chemotherapy alone appears likely but remains inconclusive. The combination of topical interferon with an antiviral agent significantly speeds epithelial healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response.

Trimethoprim, which has been widely available for several years in combination with sulphamethoxazole as co-trimoxazole, is now available for use alone in the treatment of acute uncomplicated urinary tract infections. Trimethoprim, which is active against a wide range of Gram-positive and Gram-negative aerobic bacteria, is readily absorbed by the oral route and is widely distributed in body fluids and tissues. In therapeutic trials, trimethoprim 200 to 400mg daily has been shown to be comparable in efficacy with co-trimoxazole, ampicillin 2g, cephalexin 2g, oxolinic acid 1.5g and nitrofurantoin 200mg daily in the treatment of acute urinary tract infection. Similarly, in long term prophylaxis of recurrent urinary tract infection, trimethoprim 100mg daily given as a single dose at night was comparable with nitrofurantoin 50 to 100mg, methenamine 1g, oxolinic acid 375mg or co-trimoxazole (80mg trimethoprim/400mg sulphamethoxazole) each given as a single daily dose. Emergence of acquired resistance has been infrequent during years of therapeutic use of co-trimoxazole. Nevertheless, results of serial laboratory surveys suggest that resistance to trimethoprim among enterobacteria is increasing. However, at present, there is no conclusive evidence that there will be a more rapid increase following the introduction of trimethoprim for use alone in the treatment of urinary tract infections. At the dosages used, trimethoprim has generally been well tolerated and in studies comparing it with co-trimoxazole overall, skin rashes and gastrointestinal upset have occurred less frequently with trimethoprim than with co-trimoxazole.

Zomepirac is an analgesic which is closely related chemically to the nonsteroidal anti-inflammatory agent, tolmetin. In short term studies mainly involving patients with acute pain of moderately severity, zomepirac was at least as effective as usual therapeutic doses of aspirin, codeine alone or with aspirin, phenacetin and caffeine, dextropropoxyphene with paracetamol, or orally administered pentazocine. Additionally, zomepirac may provide analgesia comparable to that with standard doses of intramuscular morphine in patients with acute pain of moderate intensity, but in severe pain states strong analgesics may be more appropriate. Zomepirac has also been studied in patients with chronic orthopaedic pain or osteoarthritic pain for up to several months, without the need for increased doses. It appears to be at least as effective as usual doses of aspirin when used in this way, with a lower incidence of some side effects such as gastrointestinal disturbances and hearing disorders. Preliminary studies suggest that zomepirac may also be effective in patients with chronic cancer pain who have not been previously maintained on strong analgesics, but further experience is needed to clarify its usefulness in this difficult treatment area.

Domperidone is a dopamine antagonist that does not readily enter the central nervous system. Given parenterally or orally it increases gastric emptying of liquids and increases lower oesophageal sphincter pressure in healthy subjects. The antiemetic and pharmacodynamic profile of domperidone is similar to that of metoclopramide, although domperidone has a lower propensity to cause extrapyramidal side effects. Domperidone effectively alleviates symptoms of chronic postprandial dyspepsia and nausea and vomiting due to a wide variety of underlying causes and in some studies has been superior to metoclopramide. Vomiting associated with the administration of moderately emetic cytotoxic drugs is controlled in the majority of patients. Alleviation of the dose-limiting peripheral side effects (nausea and vomiting) of the anti-Parkinsonian drugs bromocriptine and levodopa, enables a higher optimum dose, with consequent improvement in Parkinsonian symptoms. Domperidone does not aggravate the extrapyramidal side effects of neuroleptic drugs. Control of cytotoxic-induced, and postprandial nausea and vomiting in children has been achieved with domperidone without evidence of extrapyramidal side effects. Indeed, side effects have seldom occurred with therapeutic doses of domperidone.

Tinidazole, like the structurally-related drug metronidazole, was initially introduced for treating protozoal infections. However, both these nitroimidazole compounds are also active in vitro against most clinically important obligate anaerobes. Most of the clinical experience with tinidazole to date has involved prophylactic use to prevent postoperative anaerobic infection. Prospective placebo-controlled studies demonstrated that a single dose of tinidazole administered orally prior to elective colorectal surgery significantly reduced postoperative infection. Similarly, when given intravenously prior to appendectomy, tinidazole reduced the incidence of postoperative infection in some subgroups of patients. Although results of non-blinded studies with prophylactic tinidazole were encouraging when used in women undergoing gynaecological surgery (mainly hysterectomy), results from double-blind placebo-controlled studies in this situation have been somewhat equivocal. Thus, although the overall weight of evidence suggests that the drug is effective in this area of use, further study is needed to clarify its role in preventing anaerobic infection following gynaecological surgery compared with other antibiotics which can also be used for this purpose. Relatively few studies have been conducted with tinidazole in the treatment of established anaerobic infections, and this is an area needing further investigation. The drug is well tolerated when administered orally or intravenously.

Moxalactam (latamoxef) is a new synthetic oxa-beta-lactam antibiotic administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, is particularly active against Enterobacteriaceae and is resistant to hydrolysis by beta-lactamases. Moxalactam has moderate activity against Pseudomonas aeruginosa, but on the basis of present evidence can not be recommended as sole antibiotic treatment of known or suspected pseudomonal infections. Like the related compounds, the cephalosporins, moxalactam is effective in the treatment of complicated urinary tract infections and lower respiratory tract infections caused by Gram-negative bacilli. As moxalactam is also active against Bacteroides fragilis it has considerable potential in the treatment of intra-abdominal infections in patients with normal immunological mechanisms, as well as in immunocompromised patients, when used alone or in combination with other antibiotics. Likewise, its ready penetration into the diseased central nervous system, its high level of activity against Gram-negative bacilli, and the lack of necessity to monitor drug plasma concentrations, indicate its potential value in the treatment of neonatal Gram-negative bacillary meningitis. Further clinical experience is needed before it can be determined whether moxalactam alone can be used in the treatment of conditions for which the aminoglycosides are drugs of choice, but if established as equally effective, moxalactam has the advantage of being devoid of nephrotoxicity. Bleeding is a potentially serious problem, however, particularly in the elderly, malnourished and in the presence of renal impairment.

Acyclovir (aciclovir) is a nucleoside analogue antiviral drug related to cytarabine, idoxuridine, trifluridine and vidarabine. In common with these earlier antivirals, acyclovir is active against some members of the herpesvirus group of DNA viruses. The efficacy of topical acyclovir has been convincingly demonstrated in ocular herpetic keratitis, and in initial and primary initial genital herpes infection, but little or no clinical benefit was seen when non-primary initial genital infections were assessed separately. Acyclovir ointment demonstrated little benefit in recurrent genital herpes but topical acyclovir cream decreased the course of the infection by 1 to 2 days. Orally and intravenously administered acyclovir were beneficial in initial genital herpes infections, and oral therapy shortened the duration of recurrent infections by 1 to 2 days but did not ameliorate pain. In non-immunocompromised patients with recurrent herpes simplex labialis, generally little clinical benefit was seen with the use of topical acyclovir ointment even when therapy was initiated during the prodromal phase, while topical acyclovir cream effected small but significant improvements in the clinical but not the symptomological course of the disease. However, in immunocompromised patients, both intravenous and topical acyclovir shortened the clinical course of herpes simplex virus infections occurring mainly on the lips, oral mucosa and face, and prophylaxis with either oral or intravenous acyclovir suppressed the appearance of recurrent lesions from latent virus for the period of drug administration, but acyclovir did not eradicate latent herpesviruses. In non-immunocompromised patients, intravenous acyclovir was shown to decrease the acute pain of zoster, especially in the elderly, but postherpetic neuralgia was not ameliorated. When immunocompromised patients were studied, intravenous acyclovir inhibited the progression of zoster infections and shortened the healing time and duration of viral shedding in patients with cutaneous disseminated zoster. However, acute and post-herpetic pain were not significantly affected. Well designed controlled studies are underway to establish the efficacy of acyclovir in herpes simplex encephalitis and cytomegalovirus infections in immunocompromised patients, infections due to Epstein-Barr virus, and neonatal herpesvirus infections. Despite some aspects of the drug's use which require further clarification, acyclovir will make a major impact on the treatment of herpesviral infections. Barring unexpected findings with wider clinical use, it will become the agent of choice in several conditions.

Synopsis: Cefotaxime is a new 'third generation' semisynthetic cephalosporin administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the 'first' and 'second generation' cephalosporins. Although cefotaxime has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy for pseudomonal infections. However, cefotaxime has been effective in treating infections due to other 'difficult' organisms, such as multidrug-resistant Enterobacteriaceae. Like other cephalosporins, cefotaxime is effective in treating patients with complicated urinary tract and lower respiratory tract infections, particularly pneumonia caused by Gram-negative bacilli. High response rates have also been achieved in patients with Gram-negative bacteraemia. Although favourable clinical results have been obtained in patients with infections caused by mixed aerobic/anaerobic organisms (such as peritonitis or soft tissue infections), the relatively low in vitro activity of cefotaxime against Bacteroides fragilis may restrict its usage in situations where this organism is the suspected or proven pathogen. In preliminary studies, males and females treated with a single intramuscular dose of cefotaxime for uncomplicated gonorrhoea caused by penicillinase-producing strains of Neisseria gonorrhoeae responded very favourably. Encouraging results have also been reported in open studies in children including neonates, treated with cefotaxime for meningitis and various other serious infections. In some situations, cefotaxime has been given in combination with another antibiotic such as an aminoglycoside, but the merits of such a combination have not been clearly established. Whether cefotaxime alone is appropriate therapy for conditions previously treated with aminoglycosides (other than pseudomonal infections) also needs additional clarification, but if established as equally effective in such conditions cefotaxime offers potentially important clinical and practical advantages in its apparent lack of serious adverse effects and freedom from the need to undertake drug plasma concentration monitoring.

Zimelidine is a new antidepressant, which is structurally unrelated to the tricyclic and tetracyclic antidepressants. The pharmacological profile of zimelidine is different to that of other antidepressants in that it appears to owe the major part of its activity to the inhibition of serotonin uptake within the central nervous system. It appears that the demethylated metabolite, norzimelidine, may be responsible for most of the pharmacological activity. Studies to date suggest that zimelidine has overall efficacy comparable with that of amitriptyline, desipramine, maprotiline and doxepin in depressive illness, but at dosages which have achieved a similar overall clinical improvement zimelidine does not cause sedation, and anticholinergic side effects are mild and occur infrequently. Preliminary evidence suggests that zimelidine is effective against concomitant anxiety in depressed patients, and that it may also be useful in treating phobic anxiety. Zimelidine appears less likely to cause serious cardiotoxicity, in therapeutic dosages or an overdosage, than the tricyclic antidepressants, but it has not been studied in patients with cardiovascular disease. Sleep disturbance has occurred significantly more frequently during zimelidine therapy than during therapy with other sedative antidepressants, but whether this simply reflects the absence of sedation with zimelidine, or an effect on sleep as such, is presently unclear. Zimelidine appears to be effective and well tolerated in elderly patients. Thus, some aspects of the drug's profile (e.g. apparent low incidence of anticholinergic effects or drowsiness) may offer potential advantages in some patients; however, clinical experience with zimelidine to date has been limited, and further well designed studies are required to define the role of the drug more clearly in treating depressive illness compared with other antidepressants, and particularly to define whether some types of depression may respond more readily to zimelidine than to other antidepressants.

Ranitidine is a new histamine H2-receptor antagonist which, unlike cimetidine, does not contain an imidazole group. On a weight basis, ranitidine is 4 to 10 times more potent than cimetidine in inhibiting stimulated gastric acid secretion in humans. Therapeutic trials comparing ranitidine and cimetidine have demonstrated that ranitidine 150 mg twice daily is an effective alternative to cimetidine 1000 mg daily in 4 divided doses in increasing the rate of healing of duodenal and gastric ulcers over a period of 4 to 6 weeks. Ranitidine, given as a single 150 mg dose at night, decreases the incidence of ulcer recurrence. Preliminary studies in the Zollinger-Ellison syndrome and in patients intolerant of, or unresponsive to cimetidine, indicate that ranitidine controls the gastric hyperacidity and heals most ulcers, including those which failed to respond to months of treatment with cimetidine 1 to 1.6 g daily. Ranitidine, unlike cimetidine, has no antiandrogenic effects and does not alter hepatic metabolism of drugs. Ranitidine is well tolerated. Preliminary reports of the resolution of cimetidine-induced adverse effects following substitution of ranitidine, suggest that ranitidine may be of value in patients intolerant of cimetidine. However, wider clinical experience with ranitidine is needed to determine the clinical relevance of these reports.

Penbutolol is a non-selective beta-blocking drug with 'moderate' intrinsic sympathomimetic (partial agonist) properties, and a relatively narrow dose-response range. In many other aspects its pharmacological profile resembles that of propranolol. Significant beta-blockade, as demonstrated by reduction in heart rate during exercise in healthy subjects, persists for at least 24 hours after penbutolol administration, and thus the recommended dosage schedule in both hypertension and angina involves single daily doses (20 or 40mg daily) in most patients, with a divided dose (40mg twice daily) if a higher dose is needed. However, most angina prophylaxis studies to date have not been designed to clearly demonstrate that the beneficial effects of beta-blockade with a single dose of penbutolol extend throughout a 24-hour dosing interval. Further studies are needed to provide such evidence. As might be expected, penbutolol appears to be about as effective as usual doses of propranolol in both mild to moderate hypertension and in angina, but much of the clinical experience with the drug is in unpublished form and is thus somewhat difficult to evaluate in detail. The choice of a beta-blocking drug should be based on a knowledge of the characteristic pharmacodynamic and pharmacokinetic properties of the individual drugs within this group, and on careful consideration of how these properties might be used to benefit the individual patient. As is the case with most other beta-blocking drugs, penbutolol has some specific properties (e.g. relatively narrow dose-response range minimising the difficulty of dose titration, moderate intrinsic sympathomimetic activity) which may be used to advantage in certain patients.

Viral conjunctivitis is one of the most common disorders observed in ophthalmic emergency departments, yet no established treatment exists. Lately, antiviral medications have been introduced into clinical practice; however, a systematic review focusing on their use and effectiveness in the treatment of viral conjunctivitis has not been previously reported. We systemically reviewed the literature to identify studies where antiviral drugs were used to treat viral conjunctivitis. Currently, aciclovir, trifluridine and valaciclovir are commonly used as antiviral agents to treat herpesvirus infections. Cidofovir has been used successfully to treat some cases of adenoviral conjunctivitis, although toxicity has also been reported. The use of other medications, such as idoxuridine, has been minimized in clinical practice due to their high toxicity. Interestingly, most of the antiviral drugs developed are used to treat herpesvirus infections, while less progress has been made in the field of adenoviral infections. For other viral causes of conjunctivitis, no effective remedy is currently available, and treatment focuses on the relief of symptoms. Caution should be exercised when coadministering other pharmacological agents, such as corticosteroids, because of emerging adverse effects.

BACKGROUND Vaccinia virus keratitis (VACVK) is a complication of smallpox vaccination that can result in blindness. There are no Food and Drug Administration-approved treatments for VACVK, and vaccinia immunoglobulin (VIG) is contraindicated in isolated VACVK. We used a rabbit model of infection to compare several therapeutic options for VACVK. METHODS Rabbit eyes were infected with 10(5) plaque-forming units of the Dryvax strain of vaccinia virus and scored daily for 28 days using a modified MacDonald-Shadduck scoring system. Animals were treated for 10 days after the onset of keratitis with albumin, VIG, prednisolone acetate, trifluridine, or combinations thereof. Ocular viral titers and vaccinia-specific antibody titers were determined by plaque assay and enzyme-linked immunosorbent assay, respectively. RESULTS Treatment with intravenous VIG neither exacerbated nor ameliorated VACVK. Topical prednisolone acetate interfered with viral clearance, and ocular disease rebounded in prednisolone-treated groups. The most effective treatment was topical trifluridine alone. CONCLUSIONS We conclude that (1) VIG did not negatively affect the treatment of isolated keratitis,(2) topical corticosteroids should not be used for treating VACVK, and (3) treatment with topical trifluridine, with or without intravenous VIG, is the preferred therapeutic regimen for treating VACVK.

INTRODUCTION Ocular infection with herpes simplex virus (HSV) is usually acquired early in life, with 50% of people from higher and 80% from lower socioeconomic groups in the USA having antibodies by the age of 30 years. Attacks usually resolve spontaneously within 1-2 weeks, but 50% of people will experience a recurrence within 10 years. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with epithelial keratitis? What are the effects of treatments in people with stomal keratitis? What are the effects of interventions to prevent recurrence of ocular herpes simplex? What are the effects of interventions to prevent recurrence of ocular herpes simplex in people with corneal grafts? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS We found seven systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding oral aciclovir to topical corticosteroids plus topical antiviral treatment; adding topical corticosteroids to topical antiviral treatment; antiviral agents (topical); debridement; interferons (topical); and oral aciclovir.

BACKGROUND Blindness studies have shown that keratitis complicated by the use of traditional eye medications is a major factor of childhood blindness in developing countries. Most cases of such keratitis were presumably due to nutritional causes or bacterial infection. The patterns of outcome that are seen in hospitals may be different. OBJECTIVE To determine the clinical types of keratitis seen in children at a tertiary hospital and compare with other reports. METHOD A retrospective analysis was conducted using the records of children who presented with keratitis to the eye unit of the University College Hospital, Ibadan, Nigeria, over a three-year period from January 2003 to December 2005. Information obtained were the demographic data, the etiological type of keratitis and visual outcome of management. RESULT Ninety-five patients with keratitis seen during this three-year period were children. Of these, 47 (49.5%) patients had presumed herpes simplex keratitis; 78.9% of children with herpes simplex keratitis presented with combined epithelial and stromal disease; 21 (22.1%) had keratitis that was associated with a recent measles infection and protein calorie malnutrition. Fifteen (15.8%) had keratitis associated with phlyctenular keratoconjunctivitis, eight (8.4%) patients had bacterial/fungal keratitis, while four (4.2%) had vernal ulcers. Both the right and left eyes were affected in 47.6% and 52.4% of cases, respectively. Bilateral keratitis occurred in eight of the children with measles, and six patients with herpes simplex keratitis. Fifty-nine eyes had visual acuity recorded after the keratitis healed. Of these, the visual outcome was very poor in six (20.0%) eyes with herpes simplex keratitis and eight (100%) eyes with bacterial/fungal keratitis. All eyes with suppurative keratitis associated with measles developed dense corneal scars or were perforated. CONCLUSION Herpes simplex keratitis was the leading cause of keratitis in children seen at this tertiary hospital, and clinical presentations do not differ from those reported in other populations. Very poor visual outcome was associated with all types of keratitis except those with herpes keratitis. Blindness studies may underrepresent the burden of herpes simplex keratitis in the location of this study.

BACKGROUND Many clinical trials have been performed on the acute treatment of dendritic epithelial keratitis. Surveys of ocular antiviral pharmacology and of herpes simplex virus (HSV) eye disease have evaluated different interventions, but a systematic review of all comparative clinical studies has not previously been undertaken. OBJECTIVES The objective of this review was to compare the effects of various therapeutic interventions for dendritic or geographic HSV epithelial keratitis. SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) in The Cochrane Library (Issue 3, 2007), MEDLINE (1966 to September 2007), EMBASE (1980 to September 2007), LILACS (up to September 2007), SIGLE (1980 to September 2007), ZETOC (21 September 2007), BIOSIS (up to 2005), JICT-EPlus (up to 2005), Index Medicus (1960 to 1965), Excerpta Medica Ophthalmology (1960 to 1973), reference lists of primary reports and review articles, and conference proceedings pertaining to ocular virology. SELECTION CRITERIA This review included comparative clinical trials that assessed one-week or two-week healing rates of topical ophthalmic or oral antiviral agents and or physical or chemical debridement in people with active epithelial keratitis. DATA COLLECTION AND ANALYSIS The review author extracted data and assessed trial quality. Interventions were compared by the proportions of participants healed at seven days and at fourteen days after trial enrolment. MAIN RESULTS This review included data from 99 trials that randomised a total of 5363 participants. The topical application of vidarabine, trifluridine, acyclovir or ganciclovir resulted in a high proportion of participants healing within one week of treatment. Among these antiviral agents, no treatment emerged as significantly better for the therapy of dendritic epithelial keratitis. Insufficient placebo-controlled studies were available to assess debridement and other physical or physicochemical methods of treatment. Interferon monotherapy had a slight beneficial effect on dendritic epithelial keratitis but was not better than other antiviral agents. Interferon was very effective when combined with another antiviral agent such as trifluridine. AUTHORS' CONCLUSIONS Currently available antiviral agents are effective and nearly equivalent. The combination of a nucleoside antiviral with either debridement or with interferon seems to speed healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome of epithelial healing and should consider the effect of lesion size and other characteristics on treatment response.

Herpes simplex virus (HSV) keratitis is a common cause of ocular and visual morbidity. In this article, we systematically review published randomized clinical trials (RCTs) for HSV epithelial and stromal keratitis in order to establish a rational evidence-based foundation for treatment of these disorders. Articles for review were identified in the MEDLINE database from January 1, 1966, to May 30, 2006. Our review criteria stipulated that each study be performed in prospective, randomized, and double-blinded fashion, that it be controlled, and that it rely on specific clinical criteria for diagnosis and outcome. Of articles thus identified in the English language press, 38 articles met our review criteria, 30 for HSV epithelial keratitis and 8 (comprising 7 RCTs) for HSV stromal keratitis. From these studies, we concluded that the best evidence from treatment trials on HSV epithelial keratitis supports the use of topical trifluridine and topical or oral acyclovir, and suggests a possible additional benefit for topical interferon. The best evidence from RCTs for HSV stromal keratitis supports the use of topical corticosteroids given together with a prophylactic antiviral to shorten the duration of active HSV stromal keratitis, and the use of long-term suppressive oral acyclovir therapy to reduce the incidence of recurrent HSV keratitis.

BACKGROUND Many clinical trials have been performed on the acute treatment of dendritic epithelial keratitis. Surveys of ocular antiviral pharmacology and of herpes simplex virus (HSV) eye disease have evaluated different interventions, but a systematic review of all comparative clinical studies has not previously been undertaken. OBJECTIVES The objective of this review was to compare the effects of various therapeutic interventions for dendritic or geographic HSV epithelial keratitis. SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) in The Cochrane Library (Issue 3, 2006), MEDLINE (1966 to July 2006, week 3), EMBASE (1980 to 2006, week 30), LILACS (up to August 2006), SIGLE (1980 to March 2005), ZETOC (1 August 2006), BIOSIS (up to 2005), JICT-EPlus (up to 2005), Index Medicus (1960 to 1965), Excerpta Medica Ophthalmology (1960 to 1973), reference lists of primary reports and review articles, and conference proceedings pertaining to ocular virology. SELECTION CRITERIA This review included comparative clinical trials that assessed one-week or two-week healing rates of topical ophthalmic or oral antiviral agents and or physical or chemical debridement in people with active epithelial keratitis. DATA COLLECTION AND ANALYSIS The review author extracted data and assessed trial quality. Interventions were compared by the proportions of participants healed at seven days and at fourteen days after trial enrolment. MAIN RESULTS This review included data from 98 trials that randomised a total of 5211 participants. Compared to idoxuridine, the topical application of vidarabine, trifluridine, or acyclovir resulted in a significantly greater proportion of participants healing within one week of treatment. Among these latter three antiviral agents, no treatment emerged as significantly better for the therapy of dendritic epithelial keratitis. Insufficient placebo-controlled studies were available to assess debridement and other physical or physicochemical methods of treatment. Interferon monotherapy had a slight beneficial effect on dendritic epithelial keratitis but was not better than other antiviral agents. Interferon was very effective when combined with another antiviral agent such as trifluridine. AUTHORS' CONCLUSIONS Currently available antiviral agents are effective and nearly equivalent. The combination of a nucleoside antiviral with either debridement or with interferon seems to speed healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome of epithelial healing and should consider the effect of lesion size and other characteristics on treatment response.

This paper reviews the current concepts of viral classification, infection and replication. The clinical presentation of common oral viral infections encountered in the dental practice are discussed, including: herpes simplex virus types 1 and 2; Epstein-Barr virus; varicella-zoster virus; Coxsackie virus; human papilloma virus; and human immunodeficiency virus. The diagnosis, principles of management and pharmacological agents available for the treatment of oral viral infections are also discussed.

OBJECTIVE To evaluate the efficacy of multilayer amniotic membrane transplantation (AMT) combined with antivirus and corticosteroid drug to treat necrotizing herpes simplex stromal keratitis. METHODS Thirteen patients (13 eyes) of necrotizing stromal keratitis were referred to Shandong Eye Institute and Qingdao Eye Hospital between January 2003 and April 2004. The course of disease was 3 - 22 months (mean 15 months). Corneal inflammation persisted and corneal ulcer progressed despite topical and systemic antiviral treatment for over 1 weeks. Multilayer amniotic membrane transplantation was performed after excluding of bacterial and fungal infection by microbiologic studies including smears and cultures of necrotic corneal tissue and confocal microscope. Topical and systemic antiviral medications were given with adjuvant corticosteroid eyedrops postoperatively. We investigated the healing of corneal ulcer and improvement of stromal edema with slit lamp biomicroscope, the integrity of corneal defect with fluorescein staining, the migration of healthy corneal epithelial cells and transformation of amniotic membrane with confocal microscopy. All patients were followed up for 3 - 13 months (mean 10 months). RESULTS Corneal ulcer healed within 1 - 3 weeks postoperatively with negative fluorescein staining. Corneal stromal edema faded away within 1 month. Superficial amniotic membrane patches dissolved or shed on postoperative day 7 - 10, while the deeper grafts were adhered into the ulcer and fused with the surrounding fibroblasts. One of these grafts remained in situ more than 3 months. Confocal microscope examination indicated flat epithelial progenitor cells on the surface of residual amniotic membrane. Corneal transparence was achieved in 7 eyes, macula in 4 eyes and leucoma in 2 eyes 3 months after the operation. No recurrence of necrotizing stromal keratitis was occurred in 13 patients during the follow-up period. CONCLUSION Multilayer AMT combined with antivirus and corticosteroid treatment is an effective method to treat necrotizing herpes simplex stromal keratitis.

BACKGROUND Many clinical trials have been performed on the acute treatment of dendritic epithelial keratitis. Surveys of ocular antiviral pharmacology and of herpes simplex virus eye disease have evaluated different interventions, but a systematic review of all comparative clinical studies has not previously been undertaken. OBJECTIVES The objective of this review is to compare the effects of various treatments for dendritic or geographic herpes simplex virus epithelial keratitis. SEARCH STRATEGY Sources searched for relevant studies were the Cochrane Central Register of Controlled Trials - CENTRAL (which contains the Cochrane Eyes and Vision Group trials register),(Issue 3 2002), MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), LILACS (up to 2002), Index Medicus (1960 to 1965), Excerpta Medica Ophthalmology (1960 to 1973), reference lists of primary reports and review articles, and conference proceedings pertaining to ocular virology. SELECTION CRITERIA This review includes comparative clinical trials that assessed one-week and/or two-week healing rates of topical ophthalmic or oral antiviral agents and/or physical or chemical debridement in people with active epithelial keratitis. DATA COLLECTION AND ANALYSIS The reviewer extracted data and assessed trial quality. Interventions were compared by the proportions of participants healed at seven days and at fourteen days after trial enrollment. MAIN RESULTS This review includes data from 97 trials that randomised a total of 5102 participants. Compared to idoxuridine, the topical application of vidarabine, trifluridine, or acyclovir generally resulted in a significantly greater proportion of participants healing within one week of treatment. Among these three antiviral agents, no treatment emerged as significantly better for the therapy of dendritic epithelial keratitis. Insufficient placebo-controlled studies were available to assess debridement and other physical or physicochemical methods of treatment. Interferon monotherapy had a slight beneficial effect on dendritic epithelial keratitis, but not better than other antiviral agents, although interferon was very useful combined with debridement or with another antiviral agent such as trifluridine. REVIEWER'S CONCLUSIONS Currently available antiviral agents are effective and nearly equivalent. The combination of a nucleoside antiviral with either debridement or with interferon seems to speed healing. Future trials of the acute treatment of herpes simplex virus epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome of epithelial healing and should consider the effect of lesion size and other characteristics on treatment response.