NMR Spectroscopy Study of Enol–Enol Tautomerism of Nitisinone in Solutions

Pharmaceutical Chemistry Journal - The structure of nitisinone (β, β′-triketone reversible inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase) in various protic and aprotic...     

Cost–utility analysis of sofosbuvir for the treatment of genotype 2 chronic hepatitis C in Japan

Objective: Across Japan, around 2 million people are infected with hepatitis C virus (HCV) with long-term complications such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplant (LT). Current treatment options have several limitations due to side effects, interferon intolerability and ineligibility, long treatment durations and low sustained virological responses (SVR) rates, especially for the most severe patients. Sofosbuvir (SOF) is the first nucleotide analog NS5B polymerase inhibitor with pan-genotypic activity. SOF, administered in combination with ribavirin (RBV) with or without pegylated interferon (PEGIFN) resulted in high SVR rates across genotype (GT) 1–6 patients. It is also the first available regimen for patients that are unsuitable for interferon. This analysis assessed the cost–utility ratio of sofosbuvir in GT2 patients in Japan.

Research design and methods: A Markov model followed a cohort of 10,000 GT2 patients until patients reached 100 years of age. Approximately 20% of patients initiated treatment at the cirrhotic stage. Comparators were based on the current recommendations in Japan, including PEGIFN with ribavirin (RBV), telaprevir (TVR) in combination with PEGIFN?+?RBV and no treatment. Costs and outcomes were discounted at 2%.

Results: Sofosbuvir was cost-effective across all the studied indications, especially in patients unsuitable for interferon, with incremental cost–effectiveness ratios (ICERs) lower than JPY 5,000,000. Compared to the other treatments included in the analysis, SOF?+?RBV resulted in improved clinical outcomes. Results were robust to sensitivity analyses.

Conclusion: SOF combined with RBV was shown to be cost-effective in GT2 patients in Japan. Compared to PEGIFN?+?RBV, TVR?+?PEGIFN?+?RBV and no treatment SOF offers a more efficacious, shorter and better tolerated treatment option and extends treatment to reach HCV-infected patients who are ineligible for interferon-based regimens. Although adverse events were not included in the analyses, this would not make any changes to our conclusion.     

An Identifiability Analysis of a Parent–Metabolite Pharmacokinetic Model for Ivabradine

The paper considers the structural identifiability of a parent–metabolite pharmacokinetic model for ivabradine and one of its metabolites. The model, which is linear, is considered initially for intravenous administration of ivabradine, and then for a combined intravenous and oral administration. In both cases, the model is shown to be unidentifiable. Simplification of the model (for both forms of administration) to that proposed by Duffull et al. (1) results in a globally structurally identifiable model. The analysis could be applied to the modeling of any drug undergoing first-pass metabolism, with plasma concentrations available from drug and metabolite.     

In Vitro–In Vivo Correlations of Scalable PLGA-Risperidone Implants for the Treatment of Schizophrenia

Purpose  

Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).     

Development of Orally Applicable,Combinatorial Drug–Loaded Nanoparticles for the Treatment of Fibrosarcoma

Nanoparticulate systems have been receiving a significant attention especially for the treatment of cancer but one of the main hurdles is to produce these developed and high-tech nanosystems in large quantities. Anticancer drug formulations are generally designed for parenteral administrations but oral administration is still the most convenient route. In this study, orally applicable nano-sized chitosan nanoparticles (NPs) were successfully prepared using Nano Spray Dryer. It is possible to produce these NPs in large quantities by simply increasing the processing time using the machine without changing any parameter. A chemotherapeutic agent (imatinib mesylate; IMA) and nonsteroidal anti-inflammatory drug (dexketoprofen trometamol) were loaded together in these NPs. NPs were also functionalized with polyethylene glycol and folic acid to obtain long circulating NPs and tumor targeting. The antitumoral activities of formulations showed that these developed NPs can enhance the effectiveness. Animal experiments were performed on fibrosarcoma-bearing mice model, and the treatment with 0.8 mg/μL/kg IMA-loaded chitosan NPs was found to be successful to slow down the growth of tumors. The tumor tissues were removed from the animals and enzymatic activities were evaluated. The inhibitory effect of tyrosine kinase was found to be enhanced from 36.4% to 68.4% when IMA was used in combination with dexketoprofen trometamol. Furthermore, all dried NPs were found to be stable for more than a year at 25°C. Presented results show that these developed combinatorial drug–loaded NPs can be used for the treatment of fibrosarcoma, and these data can provide an insight, new strategies for productions or alternatives in cancer treatment.     

Cost–utility analysis of ledipasvir/sofosbuvir for the treatment of genotype 1 chronic hepatitis C in Japan

Objective: Hepatitis C is the result of a ribonucleic acid (RNA) virus (hepatitis C virus; HCV). The Japan Society of Hepatology (JSH) estimated that 1.5–2 million people in Japan carry HCV. Six major HCV genotypes (GT) and a large number of subtypes have been described in the literature. In Japan, around 70% to 80% of people are infected with HCV genotype 1b. The progress of the disease primarily affects the liver and may lead to liver cirrhosis, hepatocellular carcinoma (HCC) and death. Sofosbuvir (SOF) is a nucleotide analogue NS5B inhibitor and ledipasvir (LDV) is an inhibitor of the HCV NS5A protein. They are combined in a single tablet regimen for the treatment of GT1 patients and resulted in sustained virological response (SVR) above 94% in large phase III trials. This analysis assesses the cost–utility of LDV/SOF in GT1 patients in Japan.

Research design and methods: A cohort of 10,000 patients was followed through a Markov model until they reached 100 years of age. GT1 treatment-naïve and experienced, non-cirrhotic and cirrhotic patients were studied separately. LDV/SOF was compared to several treatment regimens containing pegylated interferon (PEGIFN), telaprevir (TVR), simeprevir (SMV), daclatasvir (DCV), asunaprevir (ASV) and ribavirin (RBV). Discount rates of 2% were applied to costs and outcomes according to the Japanese guidelines.

Results: LDV/SOF was cost-effective against most comparators with incremental cost-effectiveness ratios (ICERs) below JPY 5,000,000. By applying a societal perspective, LDV/SOF was the dominant treatment strategy in all cases. Moreover, LDV/SOF reduced the number of cases of advanced liver disease. These results were robust to sensitivity analyses.

Conclusions: LDV/SOF was cost-effective compared to most of the currently recommended treatments. Furthermore, LDV/SOF extends treatments to HCV-infected patients who are ineligible for interferon and RBV-based regimens. LDV/SOF thus has the potential to help reduce the burden of HCV in Japan.     

Development of Prodrugs for Treatment of Parkinson‘s Disease: New Inorganic Scaffolds for Blood–Brain Barrier Permeation

The treatment of Parkinson's disease (PD) has not been consistently modified for more than 60 years. L-DOPA, the blood–brain barrier permeable precursor prodrug of dopamine, is to date the only effective therapy on the market. However, it is well known that prolonged treatment with L-DOPA leads to several side effects, which may affect the patient's life expectancy (i.e., the wearing-off phenomenon, on-off fluctuations, and dyskinesia). For this reason, modifications, and supplements to L-DOPA treatment have been and are being studied, which, however, have not yet resulted in a valid alternative to the cornerstone drug. This review aims to summarize the main formulations currently in use for PD treatment, explaining advantages and disadvantages for each class. The attention will be focused on the promising prodrug concept, aimed at finding a suitable L-DOPA substitute with improved pharmacokinetic behavior. In this respect, new potential candidates which show interesting properties for the intended scope, the so-called dicarba-closo-dodecaboranes(12) (carboranes), will be discussed. Carboranes are inorganic molecular icosahedral boron-carbon clusters with 12 vertices and 20 deltahedral faces. They have been extensively studied for applications in medicine as potential pharmacophores, reagents in boron neutron capture therapy (BNCT) and radiotherapy. Here, we discuss them as inorganic scaffolds for dopamine delivery at the central nervous system (CNS) level.     

American Youths' Access to Substance Abuse Treatment: Does Type of Treatment Facility Matter?

Using data from the 2007 National Survey on Drug Use and Health, this study examines whether several social exclusion and psychological factors affect adolescents' receipt of substance abuse treatment. Multinomial logistic regression techniques were used to analyze data. The study asked how the specified factors provide pathways to receipt of specialty and non-specialty substance abuse treatment, as compared to receiving no treatment. The results suggest that, for adolescents, there are racial/ethnic, gender, and socioeconomic differences in receiving substance abuse treatment; there is also a role played by race/ethnicity in income's effect on treatment receipt. Policy implications are briefly discussed.     

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

Purpose  To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA). Methods  A new pH-sensitive Dex-containing monomer (MA–Gly–Gly–NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition–fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer–Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats. Results  P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA–Gly–Gly–NHN=Dex. The P-Dex used for in vitro and in vivo evaluation has a average molecular weight (M _w) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects. Conclusions  A HPMA copolymer–dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis. Xin-Ming Liu and Ling-Dong Quan have contributed equally to this work.     

Cost–effectiveness analysis of sacral neuromodulation (SNM) with Interstim for fecal incontinence patients in Spain

ABSTRACT

Introduction: Fecal incontinence (FI) is a condition with a high impact on the psychological and social life of healthy people. Interstim, the sacral neuromodulation (SNM) therapy, has shown higher effectiveness and safety rates than surgical procedures like dynamic graciloplasty or artificial anal sphincter in patients with intact anal sphincter (IAS) and after sphincteroplasty in patients with structurally deficient anal sphincter (SDAS).

Objective: To assess the cost-effectiveness of FI management in two scenarios – with and without SNM – and to estimate the potential budget impact of its progressive introduction in the Spanish setting.

Methods: Two decision analytical models were developed (IAS and SDAS patients) representing the possible clinical paths for each of the scenarios (with and without SNM), as well as its clinical and economic consequences in the mid-to long term with a Markov model. Clinical and resource use data were retrieved from the literature and validated by a clinician expert panel. Effectiveness was measured with both QALYs and symptom-free years (SFY). A 3% discount rate was used for future costs and benefits (time horizon = 5 years). Prevalence figures were combined with Interstim sales forecasts to estimate the total number of patients to receive therapy over the next 5 years and the associated budget impact.

Results: The introduction of Interstim in the therapeutic management of FI has an associated cost-effectiveness of €16?181 (IAS patients) and €22?195 (SDAS patients) per QALY gained. The progressive introduction of Interstim in 75 to 100 patients/year will have an estimated budget impact of 0.1% of incremental costs in patients with FI.

Conclusions: Introducing Interstim in the management of FI in IAS and SDAS patients in the Spanish setting has shown to be an efficient measure with an incremental cost–effectiveness ratio below the accepted Spanish threshold (around €35?000/QALY), and with a relatively low additional cost for the Spanish NHS.     

Cost–utility comparison of escitalopram and sertraline in the treatment of major depressive disorder

ABSTRACT

Objective: To construct a cost–utility model comparing escitalopram with sertraline in the treatment of major depressive disorders.

Methods: A decision analytic model was created to compare the cost–utility of these two antidepressants from the perspective of a managed-care organization. The model was designed to compare 10–20?mg/day of escitalopram to 50–200?mg/day of sertraline. Benefits (utility) scores were calculated based on clinical and utility data obtained from the literature. Direct medical costs included costs of the antidepressants, titration, treatment failures, and adverse events. Costs and benefits were modeled for a 6-month period and the model was subjected to thorough sensitivity analyses.

Results: The estimated 6-month total cost was $919 for escitalopram and $1351 for sertraline. The estimated QALYs were 0.40296 for escitalopram and 0.39268 for sertraline. These differences were mostly due to differences in drug acquisition costs and adverse events. The robustness of the cost–utility model results were tested in a Monte Carlo simulation of 10?000 patients and it indicated an 88.5% probability that escitalopram was the dominant therapy, suggesting both lower costs and greater QALYs.

Conclusion: This cost–utility model that incorporated the costs of titration and impact of side-effects comparing escitalopram 10–20?mg per day and sertraline 50–200?mg per day shows that escitalopram appeared to be less costly and produced efficacy (utility) at least as good as and maybe slightly better than that of sertraline.     

Targeted Sialic Acid–Doxorubicin Prodrugs for Intracellular Delivery and Cancer Treatment

Purpose To evaluate a novel targeted anticancer prodrug consisting of several copies of sialic acid (SA, targeting moiety), doxorubicin (DOX), citric acid (multifunctional spacer) and poly(ethylene glycol) (PEG, carrier). Methods α, ω bis carboxyl PEG was covalently conjugated with multiple copies of SA and DOX through a citric acid spacer and characterized by proton nuclear magnetic resonance (¹HNMR), matrix-assisted laser desorption/ionization-time of flight (MALDI/TOF), and high-performance liquid chromatography (HPLC). The molecular models of conjugates were established using ChemDraw software. Stability, spontaneous and esterase-stimulated drug release was analyzed by HPLC. Cellular internalization (fluorescence microscopy) and cytotoxicity [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay] of free DOX and prodrugs were evaluated. Results ¹HNMR, MALDI/TOF, and HPLC showed the formation of the PEG prodrug conjugates. More than 40% of the drug was released from its conjugate in the presence of esterase enzyme, whereas the conjugate was stable at pH 7.4 in the absence of enzyme. Molecular modeling studies showed stable conformations of conjugates. The targeted prodrug conjugates with two copies of SA and DOX showed enhanced cytotoxicity when compared with non-targeted prodrugs and free DOX. Conclusions Targeting of the conjugate to cancer cells by SA with increased copies of targeting moiety and anticancer drug enhanced prodrug uptake by cancer cells and cytotoxicity of the prodrug.     

CD44 Receptor–Specific and Redox-Sensitive Nanophotosensitizers of Hyaluronic Acid–Chlorin e6 Tetramer Having Diselenide Linkages for Photodynamic Treatment of Cancer Cells

For reactive oxygen species (ROS)–sensitive and CD44 receptor–mediated delivery of photosensitizers, chlorin e6 (ce6) tetramer was synthesized using tetra acid (TA) via selenocystamine linkages and then conjugated with hyaluronic acid (HA) (abbreviated as HAseseCe6TA). HAseseCe6TA nanophotosensitizers were fabricated by dialysis procedure. HAseseCe6TA nanophotosensitizers showed spherical morphology with small particle sizes less than 100 nm and monomodal pattern. When H₂O₂ was added, size distribution was changed to multimodal pattern and morphological observation showed disintegration of nanophotosensitizers, indicating that HAseseCe6TA nanophotosensitizers have ROS sensitivity. Furthermore, H₂O₂ addition resulted in acceleration of Ce6 release from HAseseCe6TA nanophotosensitizers. In vitro cell culture study, HAseseCe6TA nanophotosensitizers increase Ce6 uptake ratio, ROS production efficiency, and photodynamic therapy efficacy in both B16F10 cells and CT26 cells. Especially, CD44-receptor blocking of cancer cells by pretreatment of HA showed that fluorescence intensity in B16F10 cells was significantly decreased while fluorescence intensity in CT26 cells was not significantly changed, indicating that HAseseCe6TA nanophotosensitizers can be delivered by CD44 receptor–mediated pathway. In vivo animal tumor xenograft study, HAseseCe6TA nanophotosensitizers was selectively delivered to B16F10 tumor rather than CT26 tumor. These results indicated that HAseseCe6TA nanophotosensitizers have ROS sensitivity and have CD44 receptor–recognition properties.     

An Overview of the Treatment of Less Common Non–Lactose-Fermenting Gram-Negative Bacteria

Stenotrophomonas maltophilia, Burkholderia cepacia complex, Elizabethkingia spp., Chryseobacterium spp., Achromobacter spp., and Alcaligenes spp. are less-common non–lactose-fermenting bacteria that have emerged as important opportunistic pathogens. Patients at the highest risk for these infections include the immunocompromised, those with cystic fibrosis, and the critically ill. These opportunistic pathogens are frequently drug resistant through the expression of β-lactamases, multidrug efflux pumps, aminoglycoside-modifying enzymes, and target site alterations discussed in detail throughout this review. As a result, treatment is extremely challenging. For each pathogen, this review will examine the epidemiology, mechanisms of resistance, and in vitro and in vivo data including that for novel β-lactam/β-lactamase inhibitors and cefiderocol. Treatment recommendations are provided based on the available literature.     

An Analysis of Motivation Factors for Students’ Pursuit of Leadership Positions

Objective. To identify factors that influence student involvement and leadership within organizations and to assess the impact of involvement in organizations on professional skill development.Methods. A printed survey was administered to fourth-year pharmacy students at one college of pharmacy (N=202).Results. Most students (82%) indicated they were involved in at least one organization during pharmacy school and 58% reported holding a leadership position at some point. Factors with the largest impact on involvement in organizations were desire to present a well-rounded image to employers, ability to network, and interest in the activities sponsored by the organization. Involvement in professional organizations had a strong influence on their leadership, teamwork, confidence, and time-management skills.Conclusion. That presenting a well-rounded image to employers and having the ability to network with mentors and peers drove student involvement in professional organizations may be reflective of increasing competition for residencies and jobs.     

Can Tramadol be Used for Maintenance Treatment of Opioid Dependence?

Background: Certain limitations of the existing opioid substitution therapies necessitate exploration of other options for maintenance of patients with opioid dependence. This study aimed to present the experience of use of tramadol for long-term treatment of patients with opioid dependence. Methods: This was a cross-sectional interview-based observational study conducted in Uttar Pradesh state in India. Patients with opioid dependence who received oral tramadol treatment for a period of more than 6 months were recruited. Outcome was assessed in terms of self-reported abstinence on tramadol. Results: A total of 102 participants were recruited in the study, with a mean age of 41.3 years. All the participants were males. Abstinence to extraneous opioids was reported by 58.8% of the sample, and the median dose of tramadol at which abstinence was achieved was 350?mg/d. Those who reported to be taking natural opioids (raw opium or poppy husk) at the time of seeking treatment had higher rates of achieving abstinence. Conclusions: Tramadol may be a possible option for the maintenance treatment among some opioid-dependent individuals. Further studies are required to establish its efficacy vis-à-vis other medications used in opioid substitution treatment.     

Trend Analysis of Substance Abuse Treatment Admissions in New Orleans From 2000–2012: A Population-Based Comparison Pre- and Post-Hurricane Katrina

Background: Substance abuse treatment following a natural disaster is often met with challenges. If treatment is available, facilities may be unequipped to service an influx of patients or provide specialized care for unique populations. Objectives: This paper seeks to evaluate trends in substance abuse treatment over time and assess changes pre- and post-Hurricane Katrina. Methods: Substance abuse treatment admission data (N = 42,678) from New Orleans, Louisiana, for years 2000 through 2012 were obtained from the Treatment Episode Data Set. Admissions were examined to evaluate demographic, socioeconomic, psychiatric, and criminality trends in substance abuse treatment and assess changes following Hurricane Katrina. Results: Treatment admissions have decreased from 2000 to 2012. About one in five admissions had a psychiatric illness in addition to a substance abuse problem. A staggering 76% of admissions with a psychiatric illness were referred by the criminal justice system post-Katrina as compared to pre-Katrina. Rates of alcohol and marijuana admissions have remained stable from 2000 to 2012. Cocaine/crack admissions have declined and admissions who abused heroin have increased over time. Conclusions: Treatment admissions stabilized following Hurricane Katrina; however, since 2009, they have begun to decline. Targeted exploration of factors affecting admission to treatment in New Orleans with populations such as the homeless, those with a psychiatric illness in addition to a substance abuse problem, and those referred by the criminal justice system is essential. The results of this study assist in identifying variations in substance abuse treatment characteristics for those admitted to treatment in New Orleans.     

Cost comparison of AUC:MIC– versus trough-based vancomycin monitoring for MRSA bacteremia

ObjectivesIt is anticipated that the updated vancomycin monitoring guidelines will reconsider area under the concentration-time curve to minimum inhibitory concentration ratio (AUC:MIC)–based monitoring instead of trough-based monitoring for methicillin-resistant Staphylococcus aureus (MRSA) infections. The AUC:MIC can be estimated using 2 steady-state serum concentrations and first-order pharmacokinetic equations or Bayesian modeling. The cost of AUC:MIC–based monitoring compared with trough-based monitoring is unknown and has been cited as a potential barrier to implementing this monitoring method. The objective of this study was to compare the total vancomycin drug and monitoring cost for patients with MRSA bacteremia who received AUC:MIC– or trough-based monitoring.DesignThis was a single-center, retrospective cohort study.Setting and participantsThis study included patients who were treated for MRSA bacteremia between May 1, 2013 and December 31, 2018, with an 8-month washout period between trough and AUC:MIC–based monitoring at our institution.Outcome measuresThe primary outcome was the aggregate cost of vancomycin therapy, which included the cost associated with sample collection (i.e., supply cost and nursing time), sample analysis (i.e., assay cost and laboratory technician time), result interpretation (i.e., pharmacist time), and drug cost (i.e., cost of total administered vancomycin dose) during the hospital stay.ResultsA total of 52 patients met inclusion criteria with 26 patients in each group. The median (interquartile range) total vancomycin drug and monitoring cost was $338.14 ($235.07–$601.05) for the AUC:MIC–based group compared with $316.79 ($253.36–$520.96) for the trough-based group (P = 0.687).ConclusionVancomycin monitoring using 2 steady-state serum concentrations and first-order pharmacokinetic equations to calculate AUC:MIC was no more costly than a trough-based approach in patients with MRSA bacteremia at our institution.     

Diosmin Nanocrystal–Loaded Wafers for Treatment of Diabetic Ulcer: In Vitro and In Vivo Evaluation

This work aimed at loading of diosmin nanocrystals into alginate-based wafers for treatment of highly exuding diabetic ulcer in rats using topical route of administration. For this purpose, different formulation variables and preparation techniques to enhance the flexibility and adhesion properties of the prepared sodium alginate (SA) wafers were carried out. The prepared wafers were characterized regarding hydration capacity, bioadhesion, scanning electron microscope, and Fourier-transform infrared spectroscopy. Efficacy of treating diabetic ulcer was studied using diabetic-induced rat model using streptozotocin. Results obtained showed that using SA:gelatin with 1.5%/1.5% w/w gave acceptable wafers with a sustained release of diosmin over 8 h. A complete re-epithelialization, well-organized dermal layers, well-formed granulation tissue, and mature collagen bundles were observed in treated rats. It was concluded that combination of gelatin with SA provided an excellent wafer as a promising medicated wound dressing holding diosmin nanocrystals while maintaining its stability.