Results Of Future Clinical Trials Research Articles

Lipopeptide adjuvants for antibiotics and vaccines: the future step in the fight against multidrug-resistant and extensively drug-resistant pathogens

With the surge of antibiotic resistance in bacteria, the need for a larger arsenal of effective antibiotics and vaccines has drastically increased in the past decades. Antibiotics like vaccines can benefit from significant potentiation when used in combination with adjuvants. Antibiotic adjuvants can allow for gram-positive bacteria (GPB) specific treatments to be used against gram-negative bacteria (GNB) infections, with minimal antimicrobial resistance (AMR). In the case of vaccines, they allow for modulation and increase of the immune response. Lipopeptides are molecules of choice because of their ability to activate specific cell surface receptors, penetrate the outer membrane of GNB, safety and ease of synthesis. This review explores the recent developments in lipopeptide adjuvants for antibiotics and vaccines, providing a roadmap on how to develop adjuvants to efficiently combat AMR. After a brief overview of bacterial resistance, lipopeptide adjuvants for antibiotics and vaccines are discussed, providing insights into stability, sources, and delivery methods. Findings discussed in this review could be applied to the development of safer, more effective adjuvants, that could expand the use or repurpose current antibiotics or improve vaccination results in future clinical trials.

Metastasis-directed therapy for oligometastases in breast cancer.

The concept of oligometastases was first proposed to describe a disease state between localized cancer and extensive metastasis. After the emergence of variations in the definition of oligometastasis, in April 2020 the European Society for Radiotherapy and Oncology and the European Organization for Research and Treatment of Cancer defined oligometastases as the presence of one to five metastatic lesions that can be safely treated. However, the pathogenesis of oligometastases remains unknown, and it is uncertain which patients will benefit from metastasis-directed therapy. Breast cancer with oligometastases is generally managed with systemic therapy. Retrospective studies have suggested that the addition of metastasis-directed therapy, such as surgery, radiofrequency ablation and stereotactic body radiation therapy, may increase overall survival in breast cancer patients with oligometastases, but as yet there have been no prospective studies. Phase II trials of stereotactic body radiation therapy or fractionated irradiation for oligometastases of breast cancer have demonstrated impressive rates of local control and overall survival. Although the efficacy of stereotactic body radiation therapy in the SABR-COMET was largely anticipated, it is noteworthy that only 18% of the patient population had breast cancer. For this reason, various trials were planned or are being conducted globally to investigate the efficacy of metastasis-directed therapy for oligometastases of breast cancer. Metastasis-directed therapy for oligometastases has been shown to be effective, and stereotactic body radiation therapy and other therapies are commonly used internationally and are considered to be safe. However, the efficacy of metastasis-directed therapy for oligometastases has not yet been proven. The results of future clinical trials are thus eagerly awaited.

Therapeutic Options Under Development for Nonneovascular Age-Related Macular Degeneration and Geographic Atrophy.

Age-related macular degeneration (AMD) is a chronic, multifactorial disease and a leading cause of irreversible blindness in the elderly population in the Western Hemisphere. Among the two major subtypes of AMD, the prevalence of the nonneovascular (dry) type is approximately 85-90% and the neovascular (wet) type is 10-15%. Healthy lifestyle and nutritional supplements of anti-oxidative micronutrients have been shown to delay the progression of dry AMD and lower the risk of development of wet AMD, and anti-vascular endothelial growth factor (anti-VEGF) injections have been shown to improve visual acuity for wet AMD patients. However, to date, there is no approved treatment for geographic atrophy (GA), a debilitating late stage of dry AMD. Thus, this represents a large unmet need in this patient population. This review focuses on the current management and treatment of nonneovascular AMD, the drugs and devices that have been under investigation for the treatment of GA, and the latest clinical trial results. A few therapeutic options have shown initial promising clinical trial results, but failed to show efficacy in larger trials, while others are awaiting future clinical trial results and long-term follow-up to evaluate safety and efficacy.

Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non–muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guérin

ContextThere is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR. ObjectiveTo elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results. Evidence acquisitionWe performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis. Evidence synthesisMedian CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall–nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities. ConclusionsWe demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space. Patient summaryIn this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non–muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy.

Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.

Learning curve of a trained vitreo-retinal surgeon in sub-retinal injections in a rat model: Implications for future clinical trials.

Purpose:The sub-retinal injections are not very commonly performed procedures in vitreoretina, but form a crucial step in any cell replacement therapy for retinal diseases. The purpose of this study is to describe the learning curve of a trained vitreo-retinal surgeon in sub-retinal injections in a rat model and its implications in future clinical trials.Methods:This is an in-vivo retrospective animal study using Wistar rats. All ARVO guidelines regarding animal handling were followed. After anesthetization, aspectic preparation and dilating the pupils with 1% tropicamide eye drops, subretinal injection of 10 μl saline was done via a limbal entry. Data recorded included time taken for the procedure, success of injection, associated complications, post-operative infections and complications. The rats were followed up for 1 month post procedure. A trend analysis was done for the above factors to look for improvement in ease of procedure, reduction in procedure time and reduction in complications for the clinician using a novel objective scale.Results:About 20 eyes were studied. Mean weight of the rats was 188 ± 12.82 gram. Mean time taken for the procedure was 14.1 ± 5.07 minutes. There was a significant inverse co-relation between the serial number of the eye and time taken for the procedure (r = −0.89, P < 0.0001). Comparative complications noted between the first ten and the last ten eyes were: conjunctival tear 30% versus 10% (P = 0.27), lens touch 50% versus 10% (P = 0.05), subretinal hemorrhage 40% versus 0% (P = 0.13), vitreous loss 30% versus 0% (P = 0.06). The successful subretinal injection without intraocular complications was achieved in 40% versus 90% (P = 0.02). There was a significant co-relation between the serial number of the eye and ease of the procedure (r = 0.87, P < 0.0001). Post operatively none of the eyes had any infection. Six eyes (12%) developed cataract and 3 eyes (6%) had non-resolving retinal detachment at the last examination visit.Conclusion:Subretinal injections in rats have a definite learning curve even for a trained vitreoretinal surgeon. This should be accounted for and resources allocated accordingly to achieve good technical comfort and negate confounding by the surgeon factor in the results of future clinical trials

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model.

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer.

68Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography in advanced prostate cancer: Current state and future trends.

The early and accurate detection of prostate cancer is important to ensure timely management and appropriate individualized treatment. Currently, conventional imaging has limitations particularly in the early detection of metastases and at prostate-specific antigen (PSA) levels < 2.0 ng/mL. Furthermore, disease management such as salvage radiotherapy is best at low PSA levels. Thus, it is critical to capture the disease in the oligometastatic stage as disease progression and commencement of systemic therapies can be delayed by metastasis-directed therapy. Prostate-specific membrane antigen (PSMA) is overexpressed in prostatic cancer cells. Novel imaging modalities using radiolabeled tracers with PSMA such as 68Ga-PSMA-positron emission tomography (PET)/computed tomography (CT) have shown promising results. We review the literature regarding 68Ga-PSMA-PET/CT in the setting of primary prostate cancer and biochemical recurrence. At present, the best utilization of 68Ga-PSMA-PET/CT appears to be in biochemical recurrence. 68Ga-PSMA-PET/CT has high diagnostic accuracy for lymph node metastases and has been shown to have superior detection rates to conventional imaging, especially at low PSA levels.The exact role of 68Ga-PSMA-PET/CT in primary prostate cancer is not yet entirely clear. It has an improved detection rate for smaller lesions and may be able to identify nodal or distant metastatic disease at an earlier stage. While still experimental, there may also be value in combining 68Ga-PSMA-PET to multiparametric magnetic resonance imaging for staging of intraprostatic disease. To date, 68Ga-PSMA-PET/CT has been shown to have considerable clinical value and to impact treatment selection for patients with prostate cancer. Still in its infancy, the results of future clinical trials will be excitedly awaited.

Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes.

To determine the effect of statins and metformin in combination on biochemical recurrence (BCR) among diabetic men undergoing radical prostatectomy (RP). Diabetic men undergoing RP at our institution from January 1995 to March 2012 were retrospectively reviewed. Recipients of adjuvant radiation or hormonal therapy were excluded. Statin and/or metformin use was determined through review of electronic records. BCR-free survival was plotted using Kaplan-Meier analysis, and the effect of statins and metformin on BCR was assessed via a multivariate Cox proportional hazards model. Seven hundred and sixty-seven men met the inclusion criteria. Seventy-six (9.9%) were users of statins only, 56 (7.3%) were users of metformin only and 42 (5.5%) were dual users. Median follow-up time was 27 months. Dual users were less likely than nonusers or users of either medication alone to have a biopsy Gleason sum of 8-10 (P=0.033), and tended towards a lower rate of pathological T stage of pT3 or higher (P=0.064). Dual users had the highest 2-year and 5-year BCR-free survival, although this was not statistically significant (P=0.205). On multivariate regression, neither statin nor metformin use alone was significantly associated with BCR-free survival. However, their interaction led to a significantly lower BCR risk than would be expected from each medication's independent effects (hazard ratio=0.2; P=0.037). The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.

Comparative Analysis of the Immunogenicity and Protective Effects of Inactivated EV71 Vaccines in Mice

BackgroundEnterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China.Methods and FindingsThis comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD50 of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14–21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90–100% survival), while the ED50 of NAb responses and protective effects varied among three FCP-As.ConclusionsThese studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results.

Outcome Measures Used in Pediatric Stroke Studies

Because no gold-standard outcome measure or measures exist to allow comparison of pediatric stroke study outcomes in clinical trials, we designed a systematic review of the literature to survey the current use of pediatric stroke outcome measures. Studies that used at least 1 standardized measure to assess the outcome of children with ischemic or hemorrhagic stroke, from full-term newborn to age 18 years, were included. Although 34 studies were included, an additional 36 studies could not be included because ad hoc, author-generated outcome measures were used. Excluding those measures in neuropsychological batteries, 38 unique outcome measures were used. The Wechsler Intelligence Scales, Pediatric Stroke Outcome Measure, and Bayley Scales of Infant Development were among the most used, but 79% of outcome measures were used by no more than 2 studies. Although many measures used have been validated for use in children with other medical conditions or for adults with stroke, only 1 measure has been specifically validated for use in pediatric ischemic stroke. To maximize comparability of future clinical trial results, agreement regarding a preferred pediatric stroke outcome scale or battery of measures is paramount; these measures should be reliable, responsive to change, and specifically validated for use in children with stroke.

Review of Advanced Heart Failure Device Diagnostics Examined in Clinical Trials and the Potential Benefit from Monitoring Capabilities

Over the past decade, emerging clinical trial data supported the usefulness of implanted therapeutic cardiac devices (pacemakers and defibrillators) for the treatment of heart failure (HF). Interest has now developed in evaluating the potential of device diagnostics to identify HF patients at risk for clinical events and to be used in the management of HF patients. Initial studies have provided inconsistent results. A number of trial design elements have likely played a role in the lack of positive results, including cohort risk determination, intensity of usual care, intensity of the intervention, and selection of end points for the study. These issues will be important to understand when evaluating future clinical trial results and developing new studies, particularly in other HF patient cohorts such as HF with preserved left ventricular function.

Eculizumab for Atypical Hemolytic–Uremic Syndrome

[CI], 0.57 to 0.83) for the first 21 days, 1.00 (95% CI, 0.57 to 1.76) for 22 to 60 days, and 0.38 (95% CI, 0.18 to 0.82) for 61 to 90 days. We also await results of trials such as POINT and TARDIS for confirmation of these results in non-Chinese populations. We agree with Jeong that there may be important differences according to the patients’ eth nicity and environment that limit the generalizability of our results, and we await the results of future clinical trials.

Use of Insulin to Improve Glycemic Control in Diabetes Mellitus

The restoration of normoglycemia ensures the control of diabetic symptoms and reduction in microangiopathic complications in type 1 and type 2 diabetes. However, there is no conclusive evidence that intensive glycemic control alone will prevent macrovascular disease, the commonest cause of morbidity and mortality in type 2 diabetes. As atherosclerosis is an inflammatory condition, it is relevant that the two common insulin resistant states of obesity and type 2 diabetes have significant inflammatory processes, which promote atherosclerosis. It is also relevant that glucose has been shown to have profound effects on the endothelial cell, the leukocyte and the platelet. These effects include the induction of acute oxidative and inflammatory stress and a prothrombotic and pro-apoptotic effect following glucose intake. In contrast insulin has been shown to exert several biological effects at physiologically relevant concentrations, in relation to the endothelial cell, the platelet and leucocyte function, which may be cardioprotective and potentially anti-atherosclerotic. These findings are of great interest as it is possible that the prevention of macrovascular complications in type 2 diabetes may require the use of those glucose lowering drugs which have additional anti-inflammatory effects in addition to the control of comorbid conditions (hypertension and dyslipidemia) associated with this disease. Results of future clinical trials are awaited to confirm the benefits of this approach in the primary and secondary prevention of macrovascular complications in type 2 diabetes.

Delayed gastric emptying (DGE) after pancreatic surgery: A suggested definition by the International Study Group of Pancreatic Surgery (ISGPS)

Delayed gastric emptying (DGE) is one of the most common complications after pancreatic resection. In the literature, the reported incidence of DGE after pancreatic surgery varies considerably between different surgical centers, primarily because an internationally accepted consensus definition of DGE is not available. Several surgical centers use a different definition of DGE. Hence, a valid comparison of different study reports and operative techniques is not possible. After a literature review on DGE after pancreatic resection, the International Study Group of Pancreatic Surgery (ISGPS) developed an objective and generally applicable definition with grades of DGE based primarily on severity and clinical impact. DGE represents the inability to return to a standard diet by the end of the first postoperative week and includes prolonged nasogastric intubation of the patient. Three different grades (A, B, and C) were defined based on the impact on the clinical course and on postoperative management. The proposed definition, which includes a clinical grading of DGE, should allow objective and accurate comparison of the results of future clinical trials and will facilitate the objective evaluation of novel interventions and surgical modalities in the field of pancreatic surgery.

Pharmacological otoprotection strategies against cisplatin-induced ototoxicity

Cisplatin is a platinum-based chemotherapeutic agent, known to be one of the most active platinum compounds in cancer treatment. It is highly effective in the treatment of soft-tissue neoplasms, lung cancer, squamous cell cancer, cancer of the head and neck, testicular, ovarian, cervical, and bladder cancer. Ototoxicity is an important and dose-limited side-effect of cisplatin therapy apart from nephrotoxicity and neurotoxicity. This is mainly due to the generated reactive oxygen species (ROS). In ototoxicity the ROS have a significant effect on the outer hair cells (OHCs) in the organ of Corti. Many agents with chemoprotective action against cisplatin-induced ototoxicity have been tested for a long time. Some show promising results in animal models, but it is important to verify these promising results in future clinical trials. The possible administration modalities of an otoprotector are systemic and transtympanic (local). Considering the technical difficulties and the physical and mental status of a p...

Mejoría clínica y anatomopatológica de la psoriasis en pacientes con artrosis tratados con condroitín sulfato: descripción de 3 casos

After prescribing chrondroitin sulfate for the symptomatic treatment of osteoarthritis, it has been observed that some patients with concomitant psoriasis experience a marked improvement of skin lesions. We describe the clinical and histopathological results of the erythematous and desquamative plaques of three patients with osteoarthritis and psoriasis treated with chondroitin sulfate. Three adult patients with bilateral knee osteoarthritis and long-standing psoriasis characterized by extensive erythematous, desquamative, and hyperkeratotic plaques, which were resistant to different treatment modalities, received 800 mg/day of chondroitin sulfate during two months. Skin biopsies were obtained before and after treatment. All three patients presented a marked clinical improvement in both pathologies. In addition to a decrease in the thickness of the epidermis (total epidermal thickness, maximal thickness from the basal layer to the beginning of the corneal layer, and maximal thickness of the corneal layer), a decrease in the number of keratinocytes in the proliferative phase, a decrease in the degree of psoriatic activity, and a substitution of parakeratotic keratinization by orthokeratotic keratinization were observed. The administration of chrondroitin sulfate resulted in a significant clinical and histological improvement of the psoriatic lesions. The confirmation of these preliminary results in future clinical trials could represent an important advance in the therapeutic armamentarium of patients with psoriasis given the excellent safety profile of this drug.

Glaucoma risk factor assessment and prevention: Lessons from coronary heart disease

Purpose To determine whether multivariable risk factor assessment can be as successful in developing disease prevention strategies in patients with ocular hypertension as it has been in patients at risk for coronary heart disease (CHD). Design From a literature review of the evolution of the global risk assessment model for CHD, parallels are drawn to the evolution of a global risk assessment methodology for glaucoma. Methods This article summarizes the literature on global risk assessment and prevention of CHD in clinical practice, discusses the development of glaucoma risk assessment based on available trial and population data, and reviews the potential for prevention strategies founded on the cardiovascular disease model. Results To improve risk assessment in glaucoma and develop disease management strategies for patients with ocular hypertension, it is first necessary to identify and quantify levels of risk associated with factors that predict disease progression. In addition, the incidence of glaucoma and the average person's life expectancy based on his or her age are needed. Finally, it is necessary to quantify how long it takes to develop a visual defect that affects quality of life once a person develops glaucoma. Conclusion The systematic application of epidemiologic data to CHD risk factor models provides insights into how global risk assessment can be incorporated into treatment recommendations for managing individuals with glaucoma. It is hoped that ophthalmologists can use the results of future clinical trials and long-term studies to develop disease prevention strategies in patients with ocular hypertension based on multivariable risk assessment.

Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting?

Drugs targeting both peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (the thiazolidinediones) and PPAR-alpha (the fibrates) have already been developed for clinical use. However, the thiazolidinediones, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have cardiovascular benefits that have yet to be fully realized. Animal models of atherosclerosis have shown that the thiazolidinediones reduce the extent of atherosclerotic lesions and inhibit macrophage accumulation. Clinical studies have also shown that these drugs improve the lipid profile of patients at risk of developing atherosclerosis and reduce circulating levels of inflammatory markers. This combination of lower lipid concentrations and reduced inflammation may explain the cardiovascular benefits of this class of drugs. Early trials in patients with coronary stents have reported promising findings, with restenosis rates being greatly reduced with thiazolidinedione therapy. It is hoped that the results of future clinical trials will continue to be encouraging, so that the thiazolidinediones' cardiovascular benefits can be fully realized in the clinic.

Sodium-hydrogen exchange inhibition: pre-versus post-ischemic treatment.

Sodium-hydrogen exchange is involved in ischemia-reperfusion injury. Despite the strong research support for the use of sodium-hydrogen exchange blockers to protect the myocardium during ischemia-reperfusion, there is still controversy regarding the most effective time for drug delivery. Studies that initiate drug treatment immediately before or at reperfusion have given conflicting results. The conflict in results may be due to differences in the experimental design. Post-ischemic cardioprotection may be less than optimal due to the vascular permeability barrier or a limited collateral circulation. Increasing the drug dose or allowing more time for the drug to cross the vessel wall may overcome this limitation. Determining the correct dose and delivery protocol, therefore, will be critical for the generation of positive results in future clinical trials and will optimize the beneficial effects of sodium-hydrogen exchange inhibition in the treatment of reperfusion injury.