The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Bladder Selectivity Based on In Vivo Drug–Receptor Binding Characteristics of Antimuscarinic Agents for Treatment of Overactive Bladder

We have reviewed the binding of antimuscarinic agents, used to treat urinary dysfunction in patients with overactive bladder, to muscarinic receptors in target and non-target tissues in vivo. Transdermal administration of oxybutynin in rats led to significant binding in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin showed significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M₃ subtype. Oral tolterodine bound more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding activity of oral darifenacin in mice was shown to be pronounced and long-lasting in the bladder, submaxillary gland, and lung. In vivo quantitative autoradiography using (+)N-[¹¹C] methyl-3-piperidyl benzilate in rats showed significant occupancy of brain muscarinic receptors on intravenous injection of oxybutynin, propiverine, solifenacin, and tolterodine. The estimated in vivo bladder selectivity compared to brain was significantly greater for solifenacin and tolterodine than oxybutynin. Darifenacin occupied few brain muscarinic receptors. Similar findings were also observed with positron emission tomography in conscious rhesus monkeys. The newer generation of antimuscarinic agents may be advantageous in the bladder selectivity after systemic administration.     

Mechanisms of Chronic Nicotine Treatment–Induced Enhancement of the Sensitivity of Cortical Neurons to the Neuroprotective Effect of Donepezil in Cortical Neurons

We have previously shown that chronic donepezil treatment induces nicotinic acetylcholine receptor up-regulation and enhances the sensitivity of the neurons to the neuroprotective effect of donepezil. Further analyses revealed that the nicotinic receptor is involved in this enhancement. In this study, we examined whether nicotinic receptor stimulation is sufficient to make neurons more sensitive to donepezil. We treated primary cultures of rat cortical neurons with nicotine and confirmed that chronic nicotine treatment induced nicotinic receptor up-regulation and made the neurons more sensitive to the neuroprotective effects of donepezil. Analyses with receptor antagonists and kinase inhibitors revealed that the effects of chronic nicotine treatment are mediated by nicotinic receptors and their downstream effectors including phosphatidylinositol 3-kinase. In contrast to chronic donepezil treatment that enhanced the level of nicotine-induced Ca²⁺ influx, chronic nicotine treatment did not significantly alter the level of Ca²⁺ influx.     

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.     

“It Takes Your Heart”: The Image of Methadone Maintenance in the Addict World and Its Effect on Recruitment into Treatment

Using data gathered on 368 current methadone clients and 142 narcotics users not in treatment in structured interviews and through ethnographic fieldwork, the study examines the image of methadone maintenance treatment in the drug-using community and discusses the effect of that image on recruitment of addicts into methadone treatment. The results indicate that the image of the methadone client as a “loser,” fear of the long-term effects of methadone, and the perception of treatment as an intrusion in the user's daily life make addicts often difficult to recruit and, once in treatment, ambivalent about their participation. The image of methadone is based on both misinformation about treatment and the user's contrasting of a treatment status with the stereotypic ideal of the “righteous dope fiend.” Policy implications and suggestions derived from the data are discussed.     

Effects of Great Lakes Fish Consumption on the Immune System of Sprague–Dawley Rats Investigated during a Two-Generation Reproductive Study: II. Quantitative and Functional Aspects

The effects of Great Lakes fish contaminants on several quantitative and functional aspects of the immune system were investigated in the first (F₁) and second (F₂) generations of Sprague–Dawley rats. The F₀rats were fed either a control diet or diets containing 5 or 20% lyophilized chinook salmon from the Credit River of Lake Ontario (LO) and Owen Sound point of Lake Huron (LH). The F₁and F₂pups were exposed to fishin utero, through the dam's milk to 21 days old, and through the dam's respective diets to 13 weeks of age. The study included an F₁-reversibility (F₁-R) phase in which rats at 13 weeks of exposure to fish or control diets were switched to the control diet for 3 months. The most outstanding finding was a statistically significant increase in absolute spleen leukocytes and absolute and percentage lymphocytes in the F₂male rats fed the LH fish diets compared to the control and to those fed the LO fish diets with the 20% fish diets having higher cell numbers compared to the LO-5% fish diets. A parallel increase in the T-helper/inducer T-lymphocyte subset numbers was observed. Increased but statistically insignificant plaque-forming cell (PFC) numbers were obtained in the F₂male rats fed the LH fish diets compared to those fed the LO fish diets and in the F₁-R female group of rats fed the LH fish diet compared to those fed the LO fish diets. Phagocytosis by resident peritoneal macrophages was significantly increased in the F₁male and F₂female rats fed the fish diets compared to the control. The phagocytic activity was significantly higher in the F₂-generation male and female rats fed the LO diets compared to those fed the LH diets. Other parameters including lymphocyte transformation in response to mitogens, the number ofListeria monocytogenesbacteria surviving in the rat spleens, and the natural killer cell activity were not affected significantly by any of the treatments. Overall, the effects of diets containing chinook salmon from the LO and LH sources on the immune system of rats were minimal and were on quantitative rather than on functional aspects of the system. Further focused research would be required in order to establish conclusively that the immune system of cohorts who ingest Great Lakes fish frequently is at a greater risk for adverse effects.     

The 10th International Conference on Oral Iron Chelators in the Treatment of β-Thalassemia and Other Diseases and Biomed Meeting

Development of oral iron (Fe) chelation therapy remains an important goal for the treatment of Fe-overload disease and perhaps other conditions. For many years, the major problem with Fe chelation therapy has been that the drug in clinical use, desferrioxamine (DFO), requires long sc. infusions (12 - 24 h/day, 5 - 6 days per week). In addition, DFO is not orally effective, is highly expensive and does not easily permeate cell membranes to bind intracellular Fe pools. Obviously, the development of an orally effective and economical drug is vital. The recent 10th International Conference on Oral Iron Chelators (ICOC) discussed the latest findings in this challenging field. The conference was particularly focused to discuss recent investigations with the orally effective chelator, deferiprone (also known as L1, DMHP or 1,2-dimethylhydroxypyridone).     

Congestive Heart Failure/β-Adrenergic Antagonist: Novel Pyridazinones with Combined β-Adrenergic and PDE III Activity for the Treatment of Congestive Heart Failure

Summary

Novelty: Novel pyridazinones, which are both positive inotropes and β-adrenergic blocking agents, are disclosed. As such, they are considered useful in the treatment of congestive heart failure.

Biology: A rat aorta relaxation screen identified PDE inhibitors. The IC₅₀ for the preferred compound is 0.34 μM. Inotropic activity is demonstrated in the anaesthetised dog (ED₅₀ = 0.11 μg/kg), and is not blocked by atenolol. Inotropic activity is also shown in a guinea pig left atrial test (ED₅₀ = 9μM). A pIC₅₀ of 7.57 was reported in a β-adrenoceptor binding assay.

Chemistry: The patent is exemplified by the synthesis of fifty final compounds using standard procedures. The preferred compound is 6-(4-[N-[2-[3-phenoxy-2-hydroxypropylamino]ethyl]-carbamoylmethoxy]-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone.     

Application of the Tissue Composition–Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology

The minipig continues to build a reputation as a viable alternative large animal model to predict humans in dermatology and toxicology studies. Therefore, it is essential to describe and predict the pharmacokinetics in that species to speed up the clinical candidate selection. Essential input parameters in whole-body physiologically based pharmacokinetic models are the tissue-to-plasma partition coefficients and the resulting volume of distribution at steady-state (V_ss). Mechanistic in vitro– and in silico–based models used for predicting these parameters of tissue distribution of drugs refer to the tissue composition–based model (TCM). Robust TCMs were initially developed for some preclinical species (e.g., rat and dog) and human; however, there is currently no model available for the minipig. Therefore, the objective of this present study was to develop a TCM for the minipig and to estimate the corresponding tissue composition data. Drug partitioning into the tissues was predominantly governed by lipid and protein binding effects in addition to drug solubilization and pH gradient effects in the aqueous phase on both sides of the biological membranes; however, some more complex tissue distribution processes such as drug binding to the collagen-laminin material in dermis and a restricted drug partitioning into membranes of tissues for compounds that are amphiphilic and contain sulfur atom(s) were also challenged. The model was validated by predicting V_ss and the dermis-to-plasma partition coefficients (K_p-dermis) of 68 drugs. The prediction of K_p-dermis was extended to humans for comparison with the minipig. The results indicate that the extended TCM provided generally good agreements with observations in the minipig showing that it is also applicable to this preclinical species. In general, up to 86% and 100% of the predicted V_ss values are respectively within 2-fold and 3-fold errors compared to the experimentally determined values, whereas these numbers are 78% and 94% for K_p-dermis when the anticipated outlier compounds are not included. Binding data to dermis are comparable between minipigs and humans. Overall, this study is a first step toward developing a mechanistic TCM for the minipig, with the aim of increasing the use of physiologically based pharmacokinetic models of drugs for that species in addition to rats, dogs, and humans because such models are used in preclinical and clinical transdermal studies.     

New Frontiers in Gut Nutrient Sensor Research: Prophylactic Effect of Glutamine Against Helicobacter pylori–Induced Gastric Diseases in Mongolian Gerbils

Ammonia is one of the important toxins produced by Helicobacter pylori (H. pylori), the major cause of peptic ulcer diseases. We examined whether glutamine or marzulene (a gastroprotective drug containing 1% sodium azulene and 99% glutamine) protects the gastric mucosa against H. pylori in vivo and investigated the mechanism underlying glutamine-induced mucosal protection against ammonia in gastric epithelial cells in vitro. Mongolian gerbils were fed for 3 months with a diet containing glutamine (2% – 20%) or marzulene (20%) starting from 2 weeks or 2 years after H. pylori infection. Then, gastric mucosal changes were evaluated both macro- and microscopically. Cultured gastric epithelial cells were incubated in the presence of ammonia, with or without glutamine; and cell viability, ammonia accumulation, and chemokine production were determined. Gerbils exhibited edema, congestion, and erosion after 3-month infection; and after 2-year infection, they showed cancer-like changes in the gastric mucosa. Glutamine and marzulene significantly suppressed these pathological changes caused in the gastric mucosa by H. pylori infection. Ammonia was accumulated in the cells, resulting in an increase in chemokine production and a decrease in cell viability. These pathological responses were prevented by glutamine. In addition, glutamine decreased chemokine production and cell death through inhibition of cellular accumulation of ammonia, resulting in the prevention of H. pylori–induced gastric diseases in vivo. These results suggest that glutamine/marzulene would be useful for prophylactic treatment of H. pylori–induced gastric diseases in patients.     

Long Acting Ionically Paired Embonate Based Nanocrystals of Donepezil for the Treatment of Alzheimer’s Disease: a Proof of Concept Study

Purpose

The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation.

Methods

D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo.

Results

The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 ± 72.5 nm and PDI 0.152 ± 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model.

Conclusion

Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule.

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Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats

     

Food–drug interactions: effect of capsaicin on the pharmacokinetics of galantamine in rats

1. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is a naturally occurring alkaloid extracted from the fruit of Capsicum plant family. It represents an important ingredient in spicy foods consumed throughout the world. However, little is known about the metabolic interactions between CAP and clinically used drugs.

2. This study attempted to investigate the effect of CAP on the pharmacokinetics of galantamine, a competitive and reversible cholinesterase inhibitor. CAP, dexamethasone or sodium salt of carboxymethyl cellulose (CMC-Na) was given to rats for seven consecutive days and on the seventh day galantamine (10 mg/kg) was administered orally. Dexamethasone was used as a CYP inducer and CMC-Na was used as a vehicle.

3. The results showed that the pretreatment of rats with CAP resulted in a decrease in the AUC_0–∞ of galantamine of about 49.70% (p < 0.01) compared with the control group. After oral administration of galantamine (10 mg/kg), the apparent oral clearance of galantamine was raised by 2.05-fold by pretreatment with CAP (p < 0.05). These results demonstrate that the chronic ingestion of high doses of CAP will decrease the bioavailability of galantamine to a significant extent in rats.

     

Emergency Department Utilization for Substance Use-Related Disorders and Assessment of Treatment Facilities in New York State, 2011–2013

Background: Annually, 1.8 million New York (NY) residents experience substance use disorders (SUDs). Even though emergency departments (EDs) continue to experience high numbers of SUD-related visits, only 15% receive treatment. Objectives: This study estimates hospital-based EDs rates for SUDs in the State of New York. Also, the geographic distribution of substance use treatment centers and EDs are mapped to correlate utilization with access to care. Methods: The 2011–2013 Healthcare Cost and Utilization Project’s NY State Emergency Department Database provided information on utilization of services in EDs, charges, diagnoses, and discharge, as well as patient demographic variables. All patients within NY who had visited the ED for SUDs comprised the study population. Geographic mapping of EDs and substance abuse treatment centers at the county-level is based on data from the National Emergency Department Inventory and National Survey of Substance Abuse Treatment Services, respectively. Results: A total of 492,419 ED visits for SUDs were reported through 2011–2013. Despite NY’s Medicaid expansion in 2012, ED visits increased in 2013. About $856 million was spent in treating SUDs in EDs, with average charge of $1,764 per visit. Conclusions/Importance: Alcohol and drug-induced mental disorders are increasingly prevalent in New York’s EDs. There is a need to develop health policies and programs to improve access to care for SUDs in urban states.     

Effect of Insulin Receptor-Knockdown on the Expression Levels of Blood–Brain Barrier Functional Proteins in Human Brain Microvascular Endothelial Cells

Pharmaceutical Research - The insulin receptor (INSR) mediates insulin signaling to modulate cellular functions. Although INSR is expressed at the blood–brain barrier (BBB), its role in the...     

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.     

Field Test of a Dialectical Behavior Therapy Skills Training–Based Intervention for Smoking Cessation and Opioid Relapse Prevention in Methadone Treatment

Objective: Almost all individuals in methadone treatment for opioid dependence smoke cigarettes, and half of people in methadone treatment have an opioid relapse within six months. Dialectical behavior therapy (DBT) skills training has shown promise for addressing substance use and a variety of health behaviors and conditions; however, it has never been evaluated for smoking cessation in any population. The objective of this study was to field test a DBT skills training–based intervention for tobacco dependence and opioid relapse prevention (DBT-Quit) among people in methadone treatment.

Methods: We recruited seven individuals in methadone treatment to participate in a field test of DBT-Quit. Participants attended 12 weekly 90-minute DBT skills training groups, focusing on mindfulness, emotion regulation, and distress tolerance skills. Participants received nicotine patches for eight?weeks and completed assessments at baseline, 6 weeks (mid-treatment), and 12 weeks (post-treatment).

Results: All but one participant (86%, n?=?6) attended at least 50% of intervention sessions. Participants were “very” or “mostly” satisfied with the intervention. At 12 weeks, all but one (86%, n?=?6) had made a quit attempt, and one (14%) had seven-day point prevalence abstinence. Participants were smoke-free for 24?hours (14%, n?=?1), 7 to 14?days (43%, n?=?3), and 30 to 59?days (29%, n?=?2). Participants smoked significantly fewer cigarettes per day at 6 weeks and 12 weeks as compared to baseline. No participants used illicit drugs. As compared to baseline, at follow-up there were no significant differences in difficulties with emotion regulation, distress tolerance, or mindfulness.

Conclusions: A DBT skills training–based intervention for individuals who smoke and have an opioid use disorder is feasible and acceptable in methadone treatment and may help this population prevent drug relapse, attempt to quit smoking, experience smoke-free days, and cut down on their smoking. More research is needed to determine the optimal structure and components of a DBT skills–based intervention for drug relapse prevention and smoking cessation. Further, a randomized controlled trial of DBT-Quit is needed to determine the efficacy of DBT skills training for smoking cessation and drug relapse prevention in this population.     

Hospital Pharmacists’ Awareness of a New Antibiotic Guideline in the UK: Implications for Practice

Objectives: Pharmacists play an important role in the review of local hospital guidelines. British Thoracic Society (BTS) guidelines for the management of patients with community-acquired pneumonia (CAP) were updated in 2001, and it is important that individual hospital recommendations are based upon this national guidance. The aim of this study was to identify UK Chief Pharmacists’ awareness of these updated guidelines one year after their publication. Secondary aims were to identify whether pharmacists had subsequently initiated revision of institutional CAP guidelines, and what roles different professional staff had performed in this process. Method: A self-completion postal questionnaire was sent to the Chief Pharmacist (or their nominated staff) in 253 UK NHS hospitals in November 2002. This aimed to identify issues relating to their awareness of the 2001 BTS guidelines and subsequent revision of their hospital’s guidelines. Results:188 questionnaires were returned (a response rate of 74%), of which 164 hospitals had local antibiotic prescribing guidelines. Respondents in 29% of these hospitals were unaware of the 2001 BTS publication and institutional guidelines had been revised in only 51% of hospitals where the Chief Pharmacist was purportedly aware of the new BTS guidance. Generally, more staff types were involved in revising guidelines than initiating revision. Conclusions:Variability existed in both Chief Pharmacists’ awareness of new national guidance and subsequent review processes operating in individual hospitals. A lack of proactive reaction to new national guidance was identified in some hospitals, and it is hoped that the establishment of specialist “infectious diseases pharmacists” will facilitate the review of institutional antibiotic prescribing guidelines in the future.