The efficacy of adjunctive mitomycin C and/or anti-VEGF agents on glaucoma tube shunt drainage device surgeries: a systematic review.

PURPOSE: The effectiveness of mitomycin C (MMC) in trabeculectomy has long been established. The aim of this review is to evaluate the efficacy and safety of adjunctive agents in tube shunt drainage device surgery for glaucoma or ocular hypertension, since controversy still exists regarding their benefit. METHODS: We searched CENTRAL, PubMed, Embase, Web of Science, Scopus, and BASE for RCTs, which have used adjuvant antimetabolites-either MMC or 5-Fluorouracil (5-FU)-and/or anti-vascular endothelial growth factors (anti-VEGF) agents. The main outcome was IOP reduction at 12 months. RESULTS: Ten studies met our inclusion criteria. Nine used the Ahmed Glaucoma Valve (AGV) implant, while the double-plate Molteno implant was used in one study. Four studies used MMC. The remaining six studies used an anti-VEGF drug - either bevacizumab, ranibizumab or conbercept. Only one MMC-study reported a significant difference in the IOP reduction between groups at 12 months, favouring the MMC group (55% and 51%; p < 0.01). A significant difference was also reported by two out of five bevacizumab-studies, both favouring the bevacizumab group (55% and 51%, p < 0.05; 58% and 27%, p < 0.05), with the highest benefit seen in neovascular glaucoma cases, especially when panretinal photocoagulation (PRP) was also used. Neither ranibizumab nor conbercept were found to produce significant differences between groups regarding IOP reduction. CONCLUSION: There is no high-quality evidence to support the use of MMC in tube shunt surgery. As for anti-VEGF agents, specifically bevacizumab, significant benefit seems to exist in neovascular glaucoma patients, especially if combined with PRP.

In Vitro and In Silico Studies on Cytotoxic Properties of Oxythiamine and 2'-Methylthiamine.

It is important to search for cytostatic compounds in order to fight cancer. One of them could be 2'-methylthiamine, which is a thiamine antimetabolite with an additional methyl group at the C-2 carbon of thiazole. So far, the cytostatic potential of 2'-methylthiamine has not been studied. We have come forward with a simplified method of synthesis using commercially available substrates and presented a comparison of its effects, as boosted by oxythiamine, on normal skin fibroblasts and HeLa cancer cells, having adopted in vitro culture techniques. Oxythiamine has been found to inhibit the growth and metabolism of cancer cells significantly better than 2'-methylthiamine (GI50 36 and 107 µM, respectively), while 2'-methylthiamine is more selective for cancer cells than oxythiamine (SI = 180 and 153, respectively). Docking analyses have revealed that 2'-methylthiamine (ΔG -8.2 kcal/mol) demonstrates a better affinity with thiamine pyrophosphokinase than thiamine (ΔG -7.5 kcal/mol ) and oxythiamine (ΔG -7.0 kcal/mol), which includes 2'-methylthiamine as a potential cytostatic. Our results suggest that the limited effect of 2'-methylthiamine on HeLa arises from the related arduous transport as compared to oxythiamine. Given that 2'-methylthiamine may possibly inhibit thiamine pyrophosphokinase, it could once again be considered a potential cytostatic. Thus, research should be carried out in order to find the best way to improve the transport of 2'-methylthiamine into cells, which may trigger its cytostatic properties.

An Enzymatic Prodrug-like Route to Thio and Selenoamides.

6-Thioguanine (6TG) is a clinically used antitumor agent that was rationally designed as a DNA-targeting antimetabolite, but it also occurs naturally. 6TG is a critical virulence factor produced by Erwinia amylovorans, a notorious plant pathogen that causes fire blight of pome fruit trees. The biosynthesis of the rare thioamide metabolite involves an adenylating enzyme (YcfA) and a sulfur-mobilizing enzyme (YcfC), but the mechanism of sulfur transfer and putative intermediates have remained elusive. Through dissection and in vitro reconstitution of the thionation process using diverse substrates, we uncover an intermediate, prodrug-like thio-conjugate and elucidate the precise enzyme functions. YcfA not only adenylates GMP but also transfers the mercapto group of l-cysteine to the activated carbonyl. A designated C-S lyase (YcfC) then cleaves the resulting S-adduct to yield the thioamide. This pathway is distinct from canonical tRNA sulfur modifications and known enzymatic peptide thionations. By exploring a wide range of substrate surrogates, we exploited the tolerance of the enzyme pair to produce even a seleno analog. This study provides valuable insight into a previously unexplored area of bacterial thioamide formation and lays the groundwork for synthetic biology approaches to produce thioamide antimetabolites.

Modification of N-hydroxycytidine yields a novel lead compound exhibiting activity against the Venezuelan equine encephalitis virus.

Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in fighting infectious diseases. However, many of these agents are associated with important and potentially lethal off-target intracellular effects that limit their use. Based on the previous discovery of base-modified 2'-deoxyuridines, which showed high anticancer activity while exhibiting lower toxicity toward rapidly dividing normal human cells compared to antimetabolite chemotherapeutics, we hypothesized that a similar modification of the N4-hydroxycytidine (NHC) molecule would provide novel antiviral compounds with diminished side effects. This presumption is due to the substantial structural difference with natural cytidine leading to less recognizability by host cell enzymes. Among the 42 antimetabolite species that have been synthesized and screened against VEEV, one hit compound was identified. The structural features of the modifying moiety were similar to those of the anticancer lead 2'-deoxyuridine derivative reported previously, providing an opportunity to pursue further structure-activity relationship (SAR) studies directed to lead improvement, and obtain insight into the mechanism of action, which can lead to identifying drug candidates against a broad spectrum of RNA viral infections.

Purine antimetabolites associated Pneumocystis jirovecii pneumonia.

PURPOSE: To detect the possible safety signal of purine antimetabolites associated with Pneumocystis jirovecii pneumonia through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database. METHODS: A case/non-case retrospective disproportionality analysis was performed in the publicly available FAERS database using AERSmine (2004Q1-2021Q3). Four models were developed to explore the signal strength of PAs among different populations with possible confounding factors. Reporting odds ratio (ROR) and Proportional reporting ratio (PRR) was used as the data mining algorithm for the analysis. A value of ROR-1.96SE > 1 and PRR ≥ 2 with an associated X2 value of 4 or more was considered the threshold for a signal. RESULTS: A total of 7073 reports associated with Pneumocystis jirovecii pneumonia were present in the database, of which 899 reports were associated with purine antimetabolites. A crude signal strength of ROR 15.76(14.70-16.91) was obtained for purine antimetabolites associated PJP, with the highest signal strength reported with fludarabine and thioguanine [ROR 19.63(17.42-22.13); 19.45(13.21-28.63)]. Stratifying the cases based on autoimmune disorders and the cancer population revealed an ROR of 3.33(2.46-4.50) and 2.93(2.26-3.79) respectively. The highest risk of PJP with use of PAs was observed amongst children with a higher risk of nearly 2 times than the adult population [ROR 11.57(9.16-14.62)]. CONCLUSIONS: Our study provided evidence on the occurrence of PJP with the use of purine antimetabolites among the autoimmune and cancer population. We identified signals for PJP with azathioprine, mercaptopurine, thioguanine, cladribine, fludarabine, and clofarabine. More research with a superior epidemiological study design of a defined population is required to validate these findings.

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations.

In this work, we elucidated some key aspects of the mechanism of action of the cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5'-(2'-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2-3. The affinities of cisplatin metabolites 2-3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2-3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study's insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.

An Organofluorine Isoselenocyanate Analogue of Sulforaphane Affects Antimetabolite 5-Fluorouracil's Anticancer Activity: A Perspective for New Combinatory Therapy in Triple-Negative Breast Cancer.

Antimetabolites, especially 5-fluorouracil, are commonly used clinically to treat breast, colon, and other cancers. However, their side effects and inefficiency in monotherapy have prompted further searches for new combinations. Thus, the anticancer effect of 5-fluorouracil (5-FU) and the sulforaphane analogue, 4-isoselenocyanato-1-butyl 4'-fluorobenzyl sulfoxide (ISC), were tested in in vitro and in vivo models of triple-negative breast cancer (TNBC) as a new option for this treatment-resistant and aggressive type of breast cancer. A synergic interaction between 5-FU and ISC was observed in the TNBC in vitro model MDA-MB-231 cell line, which led to enhanced antiproliferative effects. The results of in vitro studies were confirmed by in vivo tests, which demonstrated stronger tumor growth inhibition and additive interactions between 5-FU and ISC in the murine TNBC model. Moreover, the results of the body mass and blood analysis showed the safety of the tested combination. The mechanistic study revealed that the combined treatment triggered apoptosis and necrosis, as well as inhibited cell migration.

New Steroidal Selenides as Proapoptotic Factors.

Cytostatic and pro-apoptotic effects of selenium steroid derivatives against HeLa cells were determined. The highest cytostatic activity was shown by derivative 4 (GI50 25.0 µM, almost complete growth inhibition after three days of culture, and over 97% of apoptotic and dead cells at 200 µM). The results of our study (cell number measurements, apoptosis profile, relative expression of apoptosis-related APAF1, BID, and mevalonate pathway-involved HMGCR, SQLE, CYP51A1, and PDHB genes, and computational chemistry data) support the hypothesis that tested selenosteroids induce the extrinsic pathway of apoptosis by affecting the cell membrane as cholesterol antimetabolites. An additional mechanism of action is possible through a direct action of derivative 4 to inhibit PDHB expression in a way similar to steroid hormones.

Metabolic vulnerability of cisplatin-resistant cancers.

Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.

A case of palmar hypopigmentation induced by capecitabine in a gastrointestinal cancer patient.

INTRODUCTION: Capecitabine is an antimetabolite antineoplastic agent widely used in the treatment gastrointestinal cancers. The common frequently reported cutaneous adverse drug reaction associated with capecitabin are a palmar-plantar erythrodysesthesia syndrome, rash and hyperpigmentation. This case reports a capecitabine-induced palmar hypopigmentation. CASE REPORT: We report the case of a 74-years old patient with jejunum adenocarcinoma treated by capecitabine. The patient developed a pseudo-vitiligo after 2 cycles capecitabine and without history of cutaneous disorders. The skin lesions were characterized with skin hypopigmentation on both hands.Management and outcome: The hypopigmentation slowly recovered after capecitabine discontinuation. CONCLUSION: This is the first described case of pseudo-vitiligo induced by capecitabine. This impressive but non-severe adverse effect should be known by oncologists and oncology pharmacists to reassure the patients in particular about the possible recovery after discontinuation of capecitabine.

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research.

Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME-administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 µM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

Health- and Vision-Related Quality of Life in a Randomized Controlled Trial Comparing Methotrexate and Mycophenolate Mofetil for Uveitis.

PURPOSE: To evaluate changes in health-related and vision-related quality of life (VRQoL) among patients with noninfectious uveitis who were treated with antimetabolites. DESIGN: Secondary analysis of a randomized controlled trial. PARTICIPANTS: Patients with noninfectious uveitis from India, the United States, Australia, Saudi Arabia, and Mexico. METHODS: From 2013 through 2017, 216 participants were randomized to receive 25 mg weekly oral methotrexate or 1.5 g twice daily oral mycophenolate mofetil. Median changes in quality of life (QoL) were measured using Wilcoxon signed-rank tests, and differences between treatment groups were measured using linear mixed models, adjusting for baseline QoL score, age, gender, and site. Among Indian patients, VRQoL scores from a general scale (the National Eye Institute Visual Function Questionnaire [NEI-VFQ]) and a culturally specific scale (the Indian Visual Function Questionnaire [IND-VFQ]) were compared using Pearson correlation tests. MAIN OUTCOME MEASURES: Vision-related QoL (NEI-VFQ and IND-VFQ) and health-related QoL (HRQoL; physical component score [PCS] and mental component score [MCS] of the Medical Outcomes Study 36-Item Short Form Survey [SF-36v2]) were measured at baseline, the primary end point (6 months or treatment failure before 6 months), and the secondary end point (12 months or treatment failure between 6 and 12 months). RESULTS: Among 193 participants who reached the primary end point, VRQoL increased from baseline by a median of 12.0 points (interquartile range [IQR], 1.0-26.1, NEI-VFQ scale), physical HRQoL increased by a median of 3.6 points (IQR, -1.4 to 14.9, PCS SF-36v2), and mental HRQoL increased by a median of 3.0 points (IQR, -3.7 to 11.9, MCS SF-36v2). These improvements in NEI-VFQ, SF-36v2 PCS, and SF-36v2 MCS scores all were significant (P < 0.01). The linear mixed models showed that QoL did not differ between treatment groups for each QoL assessment (NEI-VFQ, IND-VFQ, PCS SF-36v2, and MCS SF-36v2; P > 0.05 for all). The NEI-VFQ and IND-VFQ scores for Indian participants were correlated highly at baseline and the primary and secondary end points (correlation coefficients, 0.87, 0.80, and 0.90, respectively). CONCLUSIONS: Among patients treated with methotrexate or mycophenolate mofetil for uveitis, VRQoL and HRQoL improved significantly over the course of 1 year and did not differ by treatment allocation. These findings suggest that antimetabolites could improve overall patient well-being and daily functioning.

Tailor-Made Amino Acids in Pharmaceutical Industry: Synthetic Approaches to Aza-Tryptophan Derivatives.

Over the recent years there has been a noticeable upsurge of interest in aza-analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza-tryptophan derivatives are profiled, including aza-substitution in the positions 2, on the five-membered ring, as well as in positions 4, 5, 6, and 7 on the six-membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza-tryptophans is presented and general facets of the biological properties and most promising applications are discussed.

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro.

Oxythiamine (OT) and 3-deazathiamine (DAT) are the antimetabolites of thiamine. The aim of study was to compare the effects of OT and DAT pyrophosphates (-PP) on the kinetics of mammalian pyruvate dehydrogenase complex (PDHC) and the in vitro culture of HeLa cells. The kinetic study showed that 3-deazathiamine pyrophosphate (DATPP) was a much stronger competitive inhibitor (Ki = 0.0026 µM) of PDHC than OTPP (Ki = 0.025 µM). Both Ki values were much lower versus K m for thiamine pyrophosphate (0.06 µM). However, DATPP added to the culture medium for the HeLa cells culture did not hamper the rate of cell growth and showed not significant impact on the viability of the cells, whereas OTPP and OT showed a significant cytostatic effect. The differences between the thiamine antivitamins in their effect on cell growth in vitro may be due to differences in physicochemical properties and difficulty in DAT transport across the cell membrane.

Role of Rutin in 5-Fluorouracil-Induced Intestinal Mucositis: Prevention of Histological Damage and Reduction of Inflammation and Oxidative Stress.

Intestinal mucositis, characterized by inflammatory and/or ulcerative processes in the gastrointestinal tract, occurs due to cellular and tissue damage following treatment with 5-fluorouracil (5-FU). Rutin (RUT), a natural flavonoid extracted from Dimorphandra gardneriana, exhibits antioxidant, anti-inflammatory, cytoprotective, and gastroprotective properties. However, the effect of RUT on inflammatory processes in the intestine, especially on mucositis promoted by antineoplastic agents, has not yet been reported. In this study, we investigated the role of RUT on 5-FU-induced experimental intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, RUT-50, RUT-100, RUT-200, Celecoxib (CLX), and CLX + RUT-200 groups. The mice were weighed daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis); malondialdehyde (MDA), myeloperoxidase (MPO), and glutathione (GSH) concentrations; mast and goblet cell counts; and cyclooxygenase-2 (COX-2) activity, as well as to perform immunohistochemical analyses. RUT treatment (200 mg/kg) prevented 5-FU-induced histopathological changes and reduced oxidative stress by decreasing MDA concentrations and increasing GSH concentrations. RUT attenuated the inflammatory response by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. These results suggest that the COX-2 pathway is one of the underlying protective mechanisms of RUT against 5-FU-induced intestinal mucositis.

Recent advances in the management of non-infectious posterior uveitis.

PURPOSE: To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU). METHODS: We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials. RESULTS: The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects. CONCLUSION: Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic agents.

Needling with 5-fluorouracil for encapsulated blebs after Ahmed glaucoma valve implantation.

Objective: To evaluate the efficacy of 5-fluorouracil (5-FU) needling of encapsulated blebs (EBs) after Ahmed glaucoma valve (AGV) implantation in patients with medically uncontrolled secondary glaucoma. Methods: Thirty-eight eyes of 37 patients who underwent AGV implantation due to secondary glaucoma with EB were recruited in this retrospective non-randomized study. 5-FU needling (0.1 mL of 50 mg/mL) was performed for the restore of the aqueous outflow. Success after needling was defined as last intraocular pressure (IOP) ≤21 mmHg or ≥6 mmHg (with or without the use of antiglaucoma medication) without loss of light perception. Results: The mean follow-up time was 14.5 ± 8.5 (5-36) months after needling. The mean interval between the AGV implantation and the needling was 10.2 ± 7.5 (2-32) weeks. Patients were examined after needling at the 2nd hour, 1st week, 1st month, 3rd month, 6th month, and at the final visit. The success rates were 84.2%, 94.7%, 94.7%, 86.8%, 83.3%, and 71.1%, respectively. The Kaplan-Meier survival analysis revealed 96.4%, 77.4%, and 60.3% cumulative predictive success rates for the 6th, 12th, and 24th months, respectively. The mean IOP before needling was 28 ± 8.4 mmHg. At the final visit, the mean IOP was 18.1 ± 7.5 mmHg (p ≤ 0.001). Complications after needling included Seidel without hypotony (three eyes, 7.9%), hyphema (one eye, 2.6%), and decompression retinopathy (one eye, 2.6%). Neovascular glaucoma was the only factor that affected efficacy of treatment negatively (p = 0.003). Conclusions: Bleb needling with 5-FU seems to be a safe and effective method in patients with EB formation after AGV implantation in secondary glaucoma cases.

Probing the ligand preferences of the three types of bacterial pantothenate kinase.

Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4'-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK.

Generic immunosuppressants.

Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of 'innovator only' policies may be appropriate at this time in order to minimize the risk of under-immunosuppressing patients until the evidence of more stringent bioequivalence has been established.

Drug repositioning for enzyme modulator based on human metabolite-likeness.

BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.