Potential Drug Therapy Research Articles

3.0-T MR Imaging of Intracoronary Local Delivery of Motexafin Gadolinium into Coronary Artery Walls

To develop a technique with clinical 3.0-T magnetic resonance (MR) imaging to delineate local contrast agent distribution in coronary artery walls for potential molecular MR imaging-guided local gene or drug therapy of atherosclerotic coronary artery disease. This animal protocol was approved by the institutional animal care and use committee and was in compliance with the Guide for the Care and Use of Laboratory Animals. For in vitro confirmation, human arterial smooth muscle cells (SMCs) were used to determine capability of SMCs in uptake of motexafin gadolinium (MGd) and its optimal dose. For ex vivo evaluation, a 2-mL mixture of MGd and trypan blue was locally infused into coronary artery walls of six cadaveric pig hearts with MR monitoring and an MR imaging guidewire, surface coils, or both. For in vivo validation, the balloon catheter was placed into coronary arteries of seven living pigs, and the MGd and trypan blue mixture was infused into arterial walls with MR guidance. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of coronary artery walls were recorded by using different coils between pre- and postcontrast infusion, with subsequent histologic confirmation. Paired Student t tests were used to compare average SNRs and CNRs of arterial walls before and after contrast agent infusion with different coils. SMCs could take up MGd with the optimal concentration at 150 µmol/L. Average SNR with the MR imaging guidewire and surface coil combination was significantly higher than that with the MR imaging guidewire only or with surface coils only (P < .05), and average SNR and CNR of postinfusion MR imaging was significantly higher than that of preinfusion MR imaging (P < .05). Histologic analysis was used to confirm successful intracoronary infiltration of MGd and trypan blue within coronary artery walls. MR imaging can be used to delineate locally infused contrast agent distribution in coronary artery walls. This establishes groundwork for development of molecular MR imaging-guided intracoronary therapy.

Heart failure with preserved ejection fraction

Heart failure is a major health problem with significant morbidity and mortality. Although impressive advances in treatment and reduction in mortality have marked heart failure with reduced ejection fraction (HFrEF), the mortality in patients with heart failure with preserved ejection fraction (HFpEF), which accounts for nearly half of heart failure cases, has remained unchanged. This may be because of the lack of consistent diagnostic criteria and limited understanding of the pathophysiology of HFpEF, and thus appropriate treatment options. Recent data suggest that HFpEF consists of multiple abnormalities rather than a distinct entity. Advances in testing have improved diagnosis, but further validation is required. The discoveries of new pathological abnormalities have identified potential new drug therapy targets. Traditional agents with strong evidence in HFrEF have proved unsuccessful in HFpEF. Newer agents such as angiotensin receptor neprilysin inhibitor, sildenafil, and ivabradine have demonstrated benefits without improving mortality. Lastly, as HFpEF patients are older with more comorbidities, alternate endpoints to survival benefit should be considered. Although enormous strides have been made in understanding the pathophysiology and refining the diagnostic criteria of HFpEF, there is currently no pharmacological therapy with mortality benefits. Further characterization and the recruitment of more homogeneous patient populations will be essential to identify effective treatments.

Pharmacists’ responsibilities providing informed consent

Recently, I was asked to be an expert witness for a case involving a patient who experienced an adverse drug reaction and sued the prescriber and pharmacist for not warning them of their risks. This caused me to reflect on my own practice and my responsibilities to counsel and educate patients about their medications so that they can make informed decisions. Recently, I was asked to be an expert witness for a case involving a patient who experienced an adverse drug reaction and sued the prescriber and pharmacist for not warning them of their risks. This caused me to reflect on my own practice and my responsibilities to counsel and educate patients about their medications so that they can make informed decisions. Case 1: A pharmacist received a prescription for sulfamethoxazole/trimethoprim 800 mg/160 mg twice daily for 10 days. Before filling the prescription, the pharmacist reviewed his records and saw that the patient had an allergy to sulfa antibiotics, but he was not sure about the type or severity of the reaction. The pharmacist called the prescrib- er, who told the pharmacist that she was aware of the allergy but believed the antibiotic was the patient’s best option. The pharmacist made a note to talk with the patient about the allergy.■Pharmacists should fully inform patients about their treatment.■Pharmacists should document patient care activities and seek out complete medical histories. ■Pharmacists should fully inform patients about their treatment.■Pharmacists should document patient care activities and seek out complete medical histories. Case 2: A pharmacist was providing medication therapy management services for a new patient, an older man with dementia whose daughter held his power of attorney. The daughter noted that her father’s past medical history was significant for atrial fibrillation, coronary artery disease, hyertension, and hyperlipidemia and that her father had recently moved from another state. The pharmacist saw that the patient and his daughter did not maintain very good medical histories. The patient had not yet established a relationship with a lowith his daughter’s physician next week. The pharmacist noted that the patient took simvastatin 80 mg and extended- release diltiazem 180 mg every day. These cases represent real dilemmas pharmacists face in informed consent and duty to warn. For my recent work as an expert witness, I reviewed the literature regarding informed consent and found an interesting article.1.Wick J.Y. Zanni G.R. Informed consent: what every pharmacist should know.J Am Pharm Assoc. 2001; 41: 523-527Scopus (2) Google Scholar ■From 30% to 50% of patients do not use medication as prescribed because they lack information.■Pharmacists have a professional obligation to counsel patients so that they are informed comanagers of their drug therapy.■Informed consent is an interactive process with patients through which the pharmacist ensures that they fully understand their medications.■Informed consent requires pharmacists to be knowledgeable about treatment risks and benefits and standards of care.■Obstacles to informed consent occur when communication barriers exist between pharmacists and other health care providers and/or between pharmacists and patients.■Uninformed pharmacists result in uninformed patients and failure to meet informed consent guidelines. In the first case, the pharmacist has a responsibility to seek more information about the patient’s previous allergic reaction. After obtaining that information, the pharmacist must communicate with the prescriber to ensure that she has the same information. If the prescriber still wants the patient to receive the antibiotic, then the pharmacist has a responsibility to inform the patient of the risks. As pharmacists, we must both follow prescribers’ orders and fully inform patients about their treatment. Informed patients have the right to refuse treatment even if it is in their best interest. Pharmacists need to routinely document patient care, including recommendations, education, and follow-up. In the second case, a pharmacist with incomplete information was presented with two potential problems—a dosage issue with simvastatin and a drug-drug interaction between simvastatin and diltiazem. This pharmacist was not filling prescriptions, but rather providing a professional service. The patient and caregiver provided incomplete medical histories, so the pharmacist was not able to assess their medications properly. The pharmacist should, if possible, obtain a complete medical history from previous health care providers, including when medications were started, reasons for current doses, and any monitoring data. If that information is not available, then the pharmacist should address the potential problems with the patient and caregiver and send a written work-up to the new physician. Again, the pharmacist should fully document this information in the patient chart. Pharmacists may not always have complete medical histories, but that does not preclude them from informing their patients and other providers of potential drug therapy problems. Not only is this consistent with good patient care—it is the right thing to do.

Current and Potential Therapies for Ocular Neovascular Diseases

therapy approved to treat neovascular AMD. It is a two step procedure involving the intravenous administration of the drug, and subsequent activation by a non-thermal laser beam. This “cool” laser treatment produces a chemical reaction that selectively destroys abnormal blood vessels. However it is only for those patients who have new blood vessel growth under the retina in a well defined, distinctive pattern known as “predominantly classic.” Visudyne was developed by Novartis. Laser photocoagulation is another classic treatment for choroidal NV. The procedure uses laser light to destroy or seal off new blood vessels to prevent leakage. A major drawback of PDT and laser photocoagulation is that recurrent NV post-treatment is extremely common, since that these therapies don’t eliminate the angiogenic stumili. Laser photocoagulation produces many small retinal scars, which cause blind spots in the patient’s visual field. Multiple treatments are always needed. FDA approved the Implantable Miniature Telescope (IMT) in 2010, developed by VisionCare Ophthalmic Technologies. The intraocular implant magnifies images onto the retina to improve central vision damaged by advanced AMD or Stargardt’s maculat dystrophy. This device is only for patients at least 75 years old with severe to profound vision impairment. Among these treatments, VEGF antagonisms have provided major benefits to patients. Recent progress unveiling the molecular pathogenesis of the diseases has lead to potential new drug therapy. Other key angiogenesis mediators, such as Platelet Derived Growth Factor B (PDGF-B) and NF-κB-responsive mediator Vascular Cell Adhesion Molecule-1 (VCAM-1) [9], can provide potential therapy to combat worsening of NV diseases. Nonetheless, monthly injections of VEGF inhibitors into the eyes can cause harmful side effects, and some patients didn’t have an optimal response. A promising potential new treatment is gene-transfer of antiangiogenic factors through viral vectors, which has the potential to provide long-term suppression of NV and excessive vascular leakage [10].

Development of Potential Orphan Drug Therapy of Intravesical Liposomal Tacrolimus for Hemorrhagic Cystitis Due to Increased Local Drug Exposure

The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis. A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II. The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups. Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Group I mGluR antagonist rescues the deficit of D1-induced LTP in a mouse model of fragile X syndrome

BackgroundFragile X syndrome (FXS) is caused by the absence of the mRNA-binding protein Fragile X mental retardation protein (FMRP), encoded by the Fmr1 gene. Overactive signaling by group 1 metabotropic glutamate receptor (Grp1 mGluR) could contribute to slowed synaptic development and other symptoms of FXS. Our previous study has identified that facilitation of synaptic long-term potentiation (LTP) by D1 receptor is impaired in Fmr1 knockout (KO) mice. However, the contribution of Grp1 mGluR to the facilitation of synaptic plasticity by D1 receptor stimulation in the prefrontal cortex has been less extensively studied.ResultsHere we demonstrated that DL-AP3, a Grp1 mGluR antagonist, rescued LTP facilitation by D1 receptor agonist SKF81297 in Fmr1KO mice. Grp1 mGluR inhibition restored the GluR1-subtype AMPA receptors surface insertion by D1 activation in the cultured Fmr1KO neurons. Simultaneous treatment of Grp1 mGluR antagonist with D1 agonist recovered the D1 receptor signaling by reversing the subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in the Fmr1KO neurons. Treatment of SKF81297 alone failed to increase the phosphorylation of NR2B-containing N-methyl D-aspartate receptors (NMDARs) at Tyr-1472 (p-NR2B-Tyr1472) in the cultures from KO mice. However, simultaneous treatment of DL-AP3 could rescue the level of p-NR2B-Tyr1472 by SKF81297 in the cultures from KO mice. Furthermore, behavioral tests indicated that simultaneous treatment of Grp1 mGluR antagonist with D1 agonist inhibited hyperactivity and improved the learning ability in the Fmr1KO mice.ConclusionThe findings demonstrate that mGluR1 inhibition is a useful strategy to recover D1 receptor signaling in the Fmr1KO mice, and combination of Grp1 mGluR antagonist and D1 agonist is a potential drug therapy for the FXS.

The ?7 Nicotinic Acetylcholine Receptor Complex: One, Two or Multiple Drug Targets?

The α7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of diseases ranging from schizophrenia and Alzheimer's disease to chronic pain and inflammatory diseases. Focusing on the central nervous system, we describe how endogenous and experimental compounds and proteins regulate expression and function of the α7 nAChR. Drug development efforts have hitherto focused on direct manipulation of the α7 nAChR, but it is still not clear, whether agonism/antagonism or allosteric modulation is preferable as a potential drug therapy. In addition, the action of such compounds in vivo is highly dependent on α7 nAChR-interacting proteins, such as RIC-3 and lynx1, which modulate expression and function of the receptor. These regulatory proteins are often not expressed in in vitro models used to study α7 nAChR function, and it is not known to what extent they are involved in diseases such as schizophrenia and Alzheimer's disease. Furthermore, α7 nAChR agonists and allosteric modulators differentially alter expression and functionality of the α7 nAChR with repeated administration, which suggests that there may be fundamentally different outcomes of long-term administration with these different types of compounds. Finally, we describe the special case of Aβ1-42 binding to the α7 nAChR, which may pose a unique challenge to drug development of α7 nAChR-specific ligands for Alzheimer's disease. Hopefully, a greater knowledge of the many factors influencing α7 nAChR function as well as an increasing pipeline of specific drug candidates, enabling a more subtle manipulation of α7 nAChR function, may facilitate α7 nAChR drug development efforts.

Toward a Unified Model for Contemporary Institutional Pharmacy Practice

When a patient sees a physician anywhere in Canada or the United States, chances are high that the approach the physician takes to assessing and diagnosing actual or potential medical problems will be virtually the same as that of other physicians, regardless of geographic location or practice setting. Although different physicians may arrive at different diagnoses or different treatment plans for the same diagnosis, the process that they use to reach those decisions is consistent and essentially universal. This congruence reflects the fact that physicians have an established, consistent, widely accepted practice model. The same is true for dentists, as well as for the vast majority of other health care professionals. On the other hand, when a patient is under the care of a hospital pharmacist in Canada or the United States, it is likely that the pharmacist’s approach to assessing and diagnosing drug therapy problems will not be the same as and, in many cases, will not be remotely similar to that of other hospital pharmacists. The approaches of institutional pharmacists to the assessment and diagnosis of drug therapy problems and to the development of treatment plans vary widely from practitioner to practitioner, from institution to institution, and even from patient care unit to patient care unit within the same institution. Furthermore, chances are that the specific role of the pharmacist on the health care team will vary from institution to institution and from unit to unit. More broadly, specific drug distribution models, and the overall process of ensuring that the right patient receives the right drug at the right time, also vary widely from institution to institution, as do the roles assigned to pharmacy technicians. Even the technologies that we use in our drug distribution systems vary substantially from institution to institution. In brief, the profession of pharmacy, including pharmacy as practised in institutional settings, does not have an established, consistent, widely accepted practice model. Why is this so? Why don’t pharmacists have an established, consistent, widely accepted practice model? Part of the reason may be that the role of pharmacists within the health care system has not been precisely defined. I would propose that the role of the pharmacist, as an integral and indispensable member of collaborative multidisciplinary health care teams, is to identify, diagnose, and manage (or prevent) actual and potential drug therapy problems and to be responsible for patients’ outcomes related to drug therapy. With respect to the drug distribution system, I see the role of the pharmacist as primarily that of an overseer, with technicians, using appropriate technology, being primarily responsible for functions within the system. However, my sense is that many pharmacists and other health care professionals would not necessarily agree with me, and they might well propose a different definition of the pharmacist’s role within the health care system. If we cannot define and agree upon our role, how can we delineate the appropriate practice model through which to fulfill that role? Why is it important for medicine, dentistry, and, I would suggest, pharmacy, to have their own established, consistent, widely accepted practice models? Provided that each patient’s drug therapy problems are adequately addressed, does it matter how the pharmacist achieved this? I would suggest that, without an established, consistently effective practice model, it is impos sible to consistently and accurately identify, diagnose, and manage (or prevent) actual and potential drug therapy problems and thereby to improve patients’ outcomes related to drug therapy. In pharmacy, we currently do not know which model of practice is most effective for improving patient outcomes, and this is a fertile area for pharmacy practice and comparative effectiveness research. An effective, consistent practice model would likely also help to establish and affirm the importance of pharmacists to patients and to the other health care professionals with whom we collaborate to deliver care, as it would more consistently demonstrate who we are, what we do, and why our work is important for patient care. Pharmacy practice models, applicable to all pharmacists regardless of practice setting, have been proposed in the past. Most notably, the pharmaceutical care practice model was

A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2

BackgroundMetabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem.ResultsHere, we describe a community-driven effort, in which more than 20 experts in S. Typhimurium biology and systems biology collaborated to reconcile and expand the S. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for S. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches.ConclusionTaken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.

Modeling cholesterol metabolism by gene expression profiling in the hippocampus

An important part of the challenge of building models of biochemical reactions is determining reaction rate constants that transform substrates into products. We present a method to derive enzymatic kinetic values from mRNA expression levels for modeling biological networks without requiring further tuning. The core metabolic reactions of cholesterol in the brain, particularly in the hippocampus, were simulated. To build the model the baseline mRNA expression levels of genes involved in cholesterol metabolism were obtained from the Allen Mouse Brain Atlas. The model is capable of replicating the trends of relative cholesterol levels in Alzheimer's and Huntington's diseases; and reliably simulated SLOS, desmosterolosis, and Dhcr14/Lbr knockout studies. A sensitivity analysis correctly uncovers the Hmgcr, Idi2 and Fdft1 sites that regulate cholesterol homeostasis. Overall, our model and methodology can be used to pinpoint key reactions, which, upon manipulation, may predict altered cholesterol levels and reveal insights into potential drug therapy targets under diseased conditions.

Translating airway biomarker information into practice: From theoretical science to applied medicine

Biomarkers ranging from simple to sophisticated have been used by man for many years of his existence. The main use for biomarkers over that time has been to assess relative states health and well-being, including the presence of functional limitations that presage debilitation and even death. In recent years, there has been intense interest in the development of non-invasive biomarkers to accurately predict disease state and progression, as well as potential drug therapy to assist in early mitigation of morbidity and possibly, forestall premature mortality. The development of biomarkers of airway status has followed a similar pattern, and in recent years, several biomarkers have followed the progression from basic and pre-clinical development, to clinical/translational application, and finally to potential clinical therapeutic application. Inherent in this progression is the refinement of technology that has allowed measurement of these biomarkers in a fast, convenient, and reliable fashion, such that they can be obtainable within a clinical practice setting, to allow the physician to make treatment decisions for diseases such as asthma and COPD. While the clinical therapeutic application of airway biomarkers such as exhaled nitric oxide and β 2-adrenoreceptor Arg-16 polymorphism are still in their infancy, they have followed this common pathway of development, and now will require some years of application to demonstrate their true utility as predictive biomarkers of airway status and treatment response.

Toward the development of podocyte-specific drugs

Most kidney diseases that ultimately lead to end-stage renal failure originate within the glomerulus and are associated with proteinuria. Treatment options are unspecific and offer partial cures at best because available therapies do not primarily treat glomerular cells but rather act systemically and thus cause many side effects. Most glomerulopathies directly stem from injury to podocytes, cells that have a key role in the maintenance of the glomerular filter. Thus, these cells constitute an obvious and promising target for the development of novel kidney-protective drugs. During the last decade, enormous advances have been made in the understanding of podocyte structure and function. A number of pathways that are altered during glomerular diseases may be targeted by novel small- and large-molecule drugs as well as biologicals that have been identified in nephrology and other areas of drug development. Cultured podocytes provide a valuable model for high-throughput drug screening assays. Furthermore, podocytes have been shown to possess many features that make them particularly good target cells for renal protection. This mini-review discusses some of the most recent promising data related to potential drug therapy for proteinuria and kidney disease through direct podocyte targeting.

Genome-Wide Methylation Arrays Reveal Distinct Methylation Profiles in Prognostic Subsets of Chronic Lymphocytic Leukemia.

Abstract 364▪▪This icon denotes an abstract that is clinically relevant. Introduction:Aberrant DNA methylation has been shown to play a strong role in tumorogenesis, where genome-wide hypomethylation and regional hypermethylation of tumor suppressor gene (TGS) promoters are characteristic hallmarks of many cancers. In chronic lymphocytic leukemia (CLL), the epigenetic mechanism of gene regulation has thus far received limited attention, although promoter methylation and transcriptional silencing has been shown for certain individual genes, for example, DAPK1, ZAP70 and PEG10. To date, only the ‘Restriction Landmark Genomic Scanning' technique has been performed to assess the genome-wide methylation status in CLL. However, this technique spans only 3000 CpG islands and does not give a full coverage of the genome. Patients and methods:Here, we analyzed the global methylation profiles in CLL by applying high-resolution genome-wide methylation arrays from Illumina that cover 28,000 CpG sites, spanning 14,000 genes. Specifically, 23 CLL samples belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable prognostic) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets were analysed. The raw data was processed using the BeadStudio software followed by bioinformatic analysis where the arcsin transformed data was used in a moderated t-test to find differentially methylated genes. Only genes with a large absolute difference between the groups were included for further analysis. Methylation-specific PCR (MSP-PCR) and realtime-PCR (RQ-PCR) were performed on a selection of genes to confirm the array data. Additionally, bi-sulfite sequencing was employed on selected genes to confirm the degree of methylation. Moreover, CLL samples were treated with the DNA methyl transferase inhibitor 5-aza-2'-deoxycytidine combined with and without the histone deacetylase inhibitor (HDAC) trichostatin A to induce re-expression of selected methylated genes Results:Overall, we observed significant differences in methylation patterns between the CLL subgroups. Specifically, we identified TSGs that were preferentially methylated in the IGHV unmutated (7 genes, e.g. VHL, ABI3) and IGHV3-21(1 gene, SLC22A18) subgroups. We also identified 10 unmethylated and hence potentially expressed genes shown to be involved in activation of proliferative pathways such as the NFkB pathway (e.g. ADORA3), and the MAP/ERK kinase pathway (e.g. FABP7) in the IGHV unmutated and IGHV3-21 subgroups. In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The methylation status was verified for 4 genes (BCL10, PRF1, ADORA3 and IGSF4) by MSP-PCR and the expression status of 7 genes (BCL10, PRF1, ADORA3, IGSF4, NGFR, ABI3 and VHL) was confirmed using RQ-PCR. Furthermore, bi-sulfite sequencing confirmed the degree of methylation for 2 methylated TSGs (VHL and ABI3) in unmutated CLL samples. Finally, the significance of DNA methylation in regulating gene promoters was shown by re-inducing 3 methylated TSGs ( VHL, ABI3 and IGSF4) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2'-deoxycytidine. Conclusion:Taken together, our data for the first time reveals differences in global methylation profiles between prognostic subsets of CLL, which may unfold important epigenetic silencing mechanisms involved in CLL pathogenesis. Specific inhibition of expression of unmethylated genes involved in facilitating tumorogenesis and re-expression of methylated tumor suppressor genes within the poor-prognostic CLL subgroups may represent potential new drug therapy targets. Disclosures:No relevant conflicts of interest to declare.

Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing

Background: Platelet-derived growth factor (PDGF) has been shown in vivo to increase bone formation and supplement fracture healing, and may have a role as a therapeutic agent in the treatment of bone loss and fracture healing in humans. Objective: A comprehensive review of the recent literature on the effect of PDGF on bone mineral density and fracture healing. Methods: In vitro and in vivo evidence was systematically collected using medical search engines MEDLINE/OVID (1950 to March 2008) and EMBASE (1980 to March 2008) databases. Results/conclusion: Evidence to date suggests that PDGF-BB, and to a lesser extent PDGF-AA, may have potential therapeutic use in the treatment of osteoporosis and bone healing in humans. Additionally, by targeting α-receptors on osteoblasts, a potential anabolic effect on bone metabolism in humans can be anticipated; however, more research needs to be done to assess the role of β-receptors in human bone.

Intravesical Liposome Versus Oral Pentosan Polysulfate for Interstitial Cystitis/Painful Bladder Syndrome

We evaluated the safety and efficacy of intravesical liposomes, a mucosal protective agent, compared to oral pentosan polysulfate sodium for interstitial cystitis/painful bladder syndrome. We performed a prospective longitudinal study of the effect of 2 independent treatments (intravesical liposomes and oral pentosan polysulfate sodium) in patients with interstitial cystitis/painful bladder syndrome. Ten possible responses (or measures) to treatment were monitored at 3 time points, including baseline, and weeks 4 and 8. A total of 24 patients with interstitial cystitis/painful bladder syndrome were evaluated in a 1:1 ratio to intravesical liposomes (80 mg/40 cc distilled water) once weekly or to oral pentosan polysulfate sodium (100 mg) 3 times daily for 4 weeks each. No patient had urinary incontinence, retention or infection due to liposome instillation. There were no unanticipated adverse events and no significant worsening of symptoms during followup. Statistically significant decreases in urinary frequency and nocturia were observed in each treatment group. Statistically significant decreases in pain, urgency and the O'Leary-Sant symptom score were observed in the liposome group. Decreased urgency in the liposome group had the most profound effect of the ordinal measures. Each glycosaminoglycan directed treatment seemed beneficial. Liposome intravesical instillation is safe for interstitial cystitis/painful bladder syndrome with potential improvement after 1 course of therapy for up to 8 weeks. Intravesical liposomes achieved efficacy similar to that of oral pentosan polysulfate sodium. Further large-scale placebo controlled studies are needed. Intravesical liposomes appear to be a promising new treatment for interstitial cystitis/painful bladder syndrome.

Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no current therapy preventing cumulative neuronal loss. There is substantial evidence that mitochondrial dysfunction, oxidative stress, and associated caspase activity underlie the neurodegeneration observed. One potential drug therapy is the potent free radical scavenger and antioxidant cystamine, which has demonstrated significant clinical potential in models of neurodegenerative disorders and human neurological disease. This study examined the oral efficacy of cystamine in the MPTP and 6-hydroxydopamine neurotoxin models of PD. The neuroprotective effects of cystamine treatment significantly ameliorated nigral neuronal loss, preserved striatal dopaminergic projections, and improved striatal dopamine and metabolite levels, as compared to MPTP alone. Cystamine normalized striatal 8-hydroxy-2′-deoxyguanosine levels and ATP concentrations, consistent with reduced oxidative stress and improved mitochondrial function. Cystamine also protected against MPTP-induced mitochondrial loss, as identified by mitochondrial heat shock protein 70 and superoxide dismutase 2, with concomitant reductions in cytochrome c and caspase-3 activities. The neuroprotective value of cystamine was confirmed in the 6-hydroxydopamine model. Together these findings show cystamine's therapeutic benefit to reduce neuronal loss through attenuation of oxidative stress and mitochondrial dysfunction, providing the rationale for human clinical trials in PD patients.

Evaluation of a pilot medication therapy management project within the North Carolina State Health Plan

ObjectiveTo assess the feasibility of a pharmacist-based medication therapy management (MTM) service for North Carolina State Health Plan enrollees. DesignBefore/after design with two control groups. SettingCommunity pharmacies and an ambulatory care clinic in North Carolina serving patients from October 2004 to March 2005. Participants67 patients who used a large number of prescription drugs, 10 community/ambulatory care pharmacists, and more than 600 participants from two control groups. InterventionsPharmacist-conducted MTM reviews for volunteering patients. Main outcome measuresProcess measures (type and frequency of drug therapy problems detected and services performed), economic measures (number and cost of medications dispensed), and humanistic measures (patient satisfaction with services). ResultsPharmacists identified an average of 3.6 potential drug therapy problems (PDTPs) per patient at the first visit. The most common PDTP categories were “potential underuse” and “more cost-effective drug available.” Pharmacist actions were divided nearly equally between activities that would result in increased and decreased drug use. Pharmacists recommended a drug therapy change in about 50% of patients and contacted the prescriber more than 85% of the time. About 50% of patients with PDTPs had a change in drug therapy. Prescription use during the postintervention period decreased in both the study and control groups but was statistically significant only among the control groups. No significant differences were observed in patient co-payment or insurer prescription costs. Pharmacists provided the following educational services: medication use (90%), disease management (88%), adherence, and self-care (60%). Survey results indicated that patients highly valued the service. ConclusionA voluntary MTM program targeted at ambulatory patients using a large number of medications reduced the number of PDTPs but did not necessarily result in reductions in prescription drug use or cost. Nearly all patients received some form of medication adherence or disease education associated with problem detection and resolution. Patient satisfaction levels with the service were very high.

Development of an intelligent decision support system for medication review

The aim was to develop and evaluate a pilot version of a knowledge-based system that can identify existing and potential medication-related problems from patient information. This intelligent system could directly support pharmacists and other health professionals providing medication reviews. Rather than being based on static rules to trigger alerts, this system utilizes a multiple classification ripple-down rules approach, which allows the user to build rules incrementally and improve the accuracy of the knowledge base in identifying medication-related problems while the system is in use, with no outside assistance or training. The system contextualizes the potential drug therapy problems by taking into consideration the patient's demographics, and other medical condition and drugs. The system is capable of both being instructed in the domain of medication review through its routine use by an expert, and acting similarly to the expert when analysing genuine medication review cases. The system was handed over to an experienced clinical pharmacist (expert), with no knowledge or conclusions preloaded into the system. The expert was then able to add the case details and generate the rules required for 126 actual medication review cases. Over 250 rules were generated from the review cases, incorporating demographics, medical history, symptoms, medications and pathology results from these cases. At the completion of the cases, more than 80% of the potential medication-related problems identified by the expert were also detected by the system. The false positive rate, or number of incorrect medication-related problems identified by the system, was <10% overall and was zero for the last 15 cases analysed. The system found significantly more potential medication-related problems than the expert, with the system consistently remaining at least one finding ahead. There was a high incidence of missed potential medication-related problems by the expert, which were automatically repaired by the system. The knowledge-based system has already demonstrated that the technique employed is well suited to a domain of this nature and has furthermore demonstrated that it is capable of improving the quality of service that the medication reviewer can provide. The system will be further enhanced and tested prior to use in the field. It should help pharmacists in the provision of medication reviews, improving their clinical and time management capabilities, and enhancing their ability to contribute to the quality use of medications.

The mastoparanogen from wasp

Mastoparans are a family of small peptides identified from the venom of hymenopteroid insects. Although they have been characterized as early as 1979, and so far are recognized as a leading biomolecule in potential drug therapy, their precursors, mastoparanogen, have still not been determined. In this paper, several mastoparans from the venom of the wasp Vespa magnifica (Smith) are reported. The cDNA of mastoparanogen is 236 base pairs in length, and encodes 40 amino acid residues, including a N-terminal acidic fragment and a C-terminal mature basic mastoparan, which contain multiple acidic amino acid residues and a tetradecapeptide with three lysines, INLKAIAALAKKLL G, respectively. The glycine at the tetradecapeptide end is the donator of –NH 4 for the amidation of the leucine at the C-terminal. As far as we know, this is the first report of the precursor of animal mastoparan.

Effect of exogenous ATP on Momordica charantia Linn. (Cucurbitaceae) induced inhibition of d-glucose, l-tyrosine and fluid transport across rat everted intestinal sacs in vitro

Momordica charantia (MC) is a common oriental vegetable with known antidiabetic, laxative and antimicrobial properties. This study investigates the effects of aqueous fruit extract of MC on the transport of d-glucose, l-tyrosine and fluid across rat-everted intestine in vitro. Everted intestinal sacs from rats were mounted in an organ bath containing Krebs–Henseleit bicarbonate buffer. Graded concentrations (1.5–12 mg/ml) of MC fruit extract were incubated in the mucosal solution with and without exogenous ATP in the mucosal bathing fluid. The serosal appearance and mucosal disappearance of d-glucose, l-tyrosine and the fluid absorptive capacity of the intestine were significantly inhibited ( p < 0.05) with increasing graded concentrations of MC. The concentration of d-glucose accumulated or metabolized by the enterocytes in the intestinal tissues were significantly higher ( p < 0.05) when incubated with MC. Increasing graded concentrations of exogenous ATP (25–200 μM) were incubated with 3.0 mg/ml MC to confirm inhibition of the ATP-dependent active transport of d-glucose, l-tyrosine and fluid across rat enterocytes. It was found that increasing concentrations of mucosal ATP from 25 to 100 μM significantly ( p < 0.05) reverses the MC-depression of the d-glucose, l-tyrosine and fluid uptake across rat everted intestinal sacs. It is hypothesized that bioactive phytochemicals such as saponins in MC fruit extract inhibits the active transport of d-glucose, l-tyrosine and fluid across rat intestine by inhibiting the production of ATP responsible for the active transport of these molecules. It is likely that MC can be a potential alternative drug therapy of postprandial hyperglycaemia via inhibition of glucose uptake across the small intestine.