Clinical Studies In Human Subjects Research Articles

To study anti-hyperglycemic actions of three indigenous drugs namely Momordica charantia, Gymnema sylvestre and Piper betle

Background: Momordica charantia, Gymnema sylvestre, and Piper betle are developing as optional therapy in type 2 diabetes. Animal studies are helping to reveal its anti-diabetic properties. However, clinical studies in human subjects are few. Aims and Objectives: To know the effect of M. charantia on fasting glycemic control in rabbits. Materials and Methods: Blood samples from overnight fasting diabetic rabbits were collected. The drug and vehicle at the indicated dosages were then administered orally to the respective groups using a pediatric nasogastric tube followed by 2 mL of distilled water through the same tube. Subsequent blood samples were taken 2, 4, and 8 h after drug administration, and plasma glucose was estimated for each sample. Results: The standard drug, glyburide, significantly reduces hyperglycemia over a period of 2, 4, and 8 h, with maximum effect achieved after 4 h. Therefore, the choice of a diabetic rabbit animal model is authentic and appropriate. Conclusion: These three herbal extracts were more or less equivalent in reducing fasting blood glucose compared to glyburide in a rabbit model.

Endocannabinoids and Stroke Prevention: Review of Clinical Studies.

The societal burden of ischemic stroke suggests a need for additional therapeutic categories in stroke prevention. Modulation of the endocannabinoid system (ECS) is a rational target for stroke prevention because of its effects on inflammation, vascular tone, and metabolic balance, all well-described stroke risk factors. In this article, we summarize the existing ECS clinical studies in human subjects' research as they relate to conventional vascular risk factors associated with ischemic stroke. To date, 2-arachidonoylglycerol (2-AG) derivative endocannabinoids are consistently reported to be elevated in insulin resistance, whereas the N-arachidonoylethanolamine (AEA) endocannabinoid derivatives are elevated in obesity. The ECS role in metabolic health should examine the effects of 2-AG reduction and AEA augmentation as a means of stroke risk reduction. Cannabinoid receptors are reported on macrophages within atherosclerotic plaques and suggest a role for immunomodulation as a therapeutic for atherosclerosis through both peripheral immune cell CB1 antagonism and/or CB2 agonist. The effects of ECS on hypertension, smoking, physical activity, obstructive sleep apnea, heart failure, and atrial fibrillation are incompletely described and deserve further study. A limitation to ECS research is significant overlap with noncannabinoid molecular targets. Further exploration of the ECS needs to include the larger metabolomics context for a greater understanding of its therapeutic potential. Clinical translational studies in stroke prevention should be directed at ECS in metabolic balance and atherosclerosis.

Organophosphate poisoning and coenzyme Q10: an overview

Organophosphate (OP) poisoning can occur in acute and chronic forms. In developing countries, both forms are common, and represent a major cause of morbidity and mortality. In the UK, organophosphate poisoning is most likely to be encountered in chronic form, with sheep farmers the section of the population at greatest risk. The problem of poisoning in sheep farmers caused by exposure to organophosphate-based sheep dips has become increasingly apparent. Symptoms include fatigue, muscle pain and neurological problems. There is no specific treatment for this condition. OP toxicity is classically associated with inhibition of acetylcholinesterase enzymes involved in the process of neurotransmission. However, there is evidence that OP poisoning can also cause mitochondrial dysfunction, compromised cellular energy supply, oxidative stress and inflammation. Symptoms of sheep dip poisoning correspond with those known to result from depletion of coenzyme Q10 (CoQ10), a vitamin-like substance with a key role in cellular energy generation within mitochondria, as well as antioxidant and anti-inflammatory action. The authors have therefore reviewed evidence that oral supplementation with CoQ10 may provide effective symptomatic relief for farmers suffering from OP sheep dip poisoning. Evidence in support of the above is presented for: (a) OP-induced mitochondrial dysfunction; (b) beneficial effects of CoQ10 administration following OP exposure in relevant animal models; and (c) evidence from clinical studies in human subjects. The dosage of CoQ10 proposed (100 mg three times daily) is based on that required to raise blood levels to at least 3 μg/mL, which has been shown to be a requirement to effectively counter CoQ10 depletion in other disorders, particularly heart disease. It is important to note that a CoQ10 supplement with appropriate documented bioavailability should be used, since poor bioavailability may have been responsible for the failure of some previous studies. The safety of CoQ10 supplementation has been confirmed in more than 200 randomised controlled clinical trial studies on a wide range of disorders. In addition to the above, because of the increased risk of the use of OP compounds in terrorist-type poisoning incidents in the UK, a brief discussion on the management of acute OP poisoning is included.

COMPUTATIONAL MODEL OF RECIRCULATING LYMPHOCYTES

Lymphocyte recirculation plays an important role in controlling the spread of both pathogenic infections and tumor-producing cancer cells in the human body. We present a mathematical and computational framework that allows investigation of recirculating lymphocytes and estimation of model parameters using a genetic algorithm. The framework allows estimating parameters using data obtained from experiments performed in laboratory studies of rats as well as clinical studies of human subjects. Our computational model allows improved understanding of these data. Mathematical models enable investigators to obtain a quantitative picture of immune system kinetics and diversity in human health and disease outcomes. Our data-driven systems biology and immunological modeling approach contributes to a growing understanding of the dynamics of lymphocyte recirculation.

African American Females: A Potential Link Between Vitamin D Insufficiency and Type-2 Diabetes

African American females are a high-risk population for both vitamin D insufficiency and type-2 diabetes. Numerous comparison studies have been conducted between African Americans and other racial groups, regarding vitamin D insufficiency and type 2-diabetes. African Americans, especially African American females, are at a higher risk for becoming insufficient in vitamin D when compared to other ethnic groups. The prevalence of hypovitaminosis D among African American women is ten times higher than white women. In addition, African Americans, especially African American females, have a higher prevalence of type-2 diabetes. African American females surpass white females with 100% prevalence. Although many factors may contribute to the onset of type-2 diabetes, serum 25-hydroxyvitamin D concentrations have been found to have a positive association with insulin sensitivity. In this article, we review the effects of diet and subcutaneous vitamin D synthesis on vitamin D status as well as type-2 diabetes prevalence in the most vulnerable population of both conditions, African American females. We further focus on the mechanistic studies in cell cultures and animal models, as well as cohort, intervention, and clinical studies in human subjects. In conclusion, development of vitamin D assessment in the prevention of type-2 diabetes for African American females may provide further insight for intervention and education. Adequate vitamin D intake should be promoted and recommended to decrease disparities within this population.

Quench the Thirst

Thirst, as a symptom, has long been considered the most prevalent clinical complaint patients voice in healthcare settings. Yet, rarely have researchers examined thirst by its correlation with physiologic factors. This review was undertaken to examine the relationships between thirst ratings and factors mediating its primary physiologic correlates: plasma osmolality (pOsm) and arginine vasopressin peptide (AVP). A literature search was undertaken to identify clinical studies in human subjects that investigated the relationship of thirst to specific physiologic thirst-related correlates and associated thirst mediators. Thirst was induced in 17 selected clinical studies by hyperosmolar infusion, through water deprivation or exercise weight-loss regimens. Positive linear relationships between the subjects' thirst ratings and rising serum pOsm levels confirmed the presence of intact osmotic thirst drives. However, there were significant variations in normal compensatory rises in AVP levels that followed the rises in plasma osmolality after the subjects were exposed to cold, physical pre-conditioning and water immersion tests. Notably, older adults in the studies reported diminished thirst ratings. Weak correlations suggest that angiotensin II may play only a minor role in thirst mediation. Atrial natriuretic hormone's inhibitory effect on thirst was inconsistent. Findings indicated that older adults are at higher risk for profound dehydration due to sensory deficits along with failure to correct volume losses. The thirst trials results support the close correlation between serum pOsm values and patients' thirst ratings, with the exception of the older adult.

Lessons on Aggressive Intravenous Hydration in Acute Pancreatitis: A Meta-Analysis of Clinical Trials

Purpose: Largely based on animal studies and indirect evidence in humans, experts have put forth the notion that aggressive intravenous hydration (AIH), early in the course, would attenuate the severity of the disease in patients with acute pancreatitis (AP). Recent clinical studies in human subjects evaluating the efficacy of AIH have demonstrated conflicting results. The purpose of our study was to systematically review, analyze and combine the different studies in a meta-analysis to determine patterns of efficacy that may exist in order to promote appropriate fluid management in patients with AP. Methods: In order to be included in the analysis, the published study needed to include patients with AP were enrolled in a consecutive, prospective or retrospective fashion. The study needed to provide information regarding the amount of fluid for each group, and outcome, such as organ failure, necrosis and mortality. The amount of fluid over the first 24-48 hours needed to be provided. When combining the various studies, the weighted mean of power (sample size) was used to determine the relative value of significance. Sensitivity analysis evaluated sample sizes, timing, type of fluids and severity of patients included. Results: Ten published studies fulfilled the criteria to be included in the analysis, which included 1,495 patients. There were six retrospective, four prospective studies. While three studies concluded that AIH was beneficial, seven studies showed no benefit and/or harm. Using a weighted mean analysis, when evaluating the effectiveness of AIH beyond 24 hours, there was no significant difference in the development of organ failure, pancreatic necrosis or mortality (OR 1.2, CI 0.4 -1.9). However, in a subgroup analysis excluding patients presenting with severe disease, there was a significant benefit to AIH in preventing organ failure and/or pancreatic necrosis (OR 1.8, CI 1.5 -2.8, p = 0.02). Additionally, there was a significant decrease in organ failure and/or pancreatic necrosis if the AIH was given early, within the first 24 hours (OR 2.1, CI 1.6 - 2.9, p= 0.03) and 6-12 hours (p = 0.02). Conclusion: Based on this meta-analysis, AIH appears to be most beneficial when applied to patients with AP early in the course of the disease, within the first 6-24 hours, before severe disease develops. In general, there does not appear to be a benefit to AIH in patients with AP beyond the first 24 hours. Clinicians should recognize the importance of applying the principles of AIH as early as possible, especially to patients who have mild disease. The benefit of early aggressive hydration appears to be preventing severe disease, organ failure and/or pancreatic necrosis.

Comparison of standard forward-viewing mode versus ultrawide-viewing mode of a novel colonoscopy platform: a prospective, multicenter study in the detection of simulated polyps in an in vitro colon model (with video)

Although colonoscopy is the criterion standard for detecting colorectal adenomas and cancers, a significant percentage of adenomas are missed. To compare forward-viewing with ultrawide-viewing colonoscopy in the detection of simulated colon polyps in an in vitro colon model. Prospective, multicenter. Six endoscopy units (3 in the United States and 3 in Israel). In vitro colon model with simulated colon polyps (n = 21 metallic beads). Detection of simulated colon polyps on colonoscope withdrawal. Incremental detection of simulated colon polyps and endoscopist evaluation of the usability, visibility, and maneuverability of ultrawide-viewing colonoscopy. On forward-viewing colonoscopy, the number of simulated polyps (mean ± standard deviation) detected per endoscopist was 11.1 ± 2.3 polyps, a 52.9% detection rate. Simulated polyp detection rates per colon segment were 3.0 ± 0.93 (60.0%) right colon, 2.4 ± 0.87 (48.0%) transverse colon, and 5.7 ± 1.5 (51.8%) left colon. On ultrawide-viewing colonoscopy, the simulated polyp detection rate per endoscopist significantly increased to 18.0 ± 1.98 polyps, an overall 85.7% polyp detection rate (P < .001). Simulated polyp detection rates were also significantly higher by using the ultrawide-viewing mode in each colon segment, 4.5 ± 0.65 polyps (90.0%) right colon, 4.0 ± 0.87 (80.0%) polyps transverse colon, and 9.6 ± 1.28 polyps (87.3%) left colon (all comparisons, P < .001). Importantly, the ultrawide-viewing mode detected significantly more "hidden" simulated polyps (81.9% vs 31.9%, P < .0001). Nonrandomized design, use of a colon model, and "simulated" colon polyps. Ultrawide-view colonoscopy significantly improved simulated polyp detection in a colon model. Clinical studies in human subjects should be pursued to further evaluate this new endoscopic technology.

PI3K Pathway Inhibitors: Better Not Left Alone

The PI3K/Akt/mTOR signaling pathway plays a key role in diverse physiologic processes. It is also central to many aspects of the malignant process. Genetic phenomena that lead to constitutive pathway activation are common in human cancer; the most relevant are mutations affecting the catalytic subunit of PI3K and loss of function of the PTEN tumor suppressor. These factors have made this important cascade attractive as a potential target for cancer therapeutics. A host of inhibitors are now in various stages of development that target key nodes within the PI3K pathway. To date, however, the efficacy of these agents has fallen short of expectation, with at least one possible explanation being the presence of feedback loops and cross-talk that exists within and between PI3K and other signaling pathways. Accordingly, enthusiasm is again high as strategies employing therapeutic combinations are gaining pace, with encouraging results documented in both preclinical studies and emerging clinical trials. Here, we review the agents that have reached evaluation in early phase clinical studies of human subjects with cancer, and discuss the rationale for and use of novel drug combinations. Keywords: PI3K, PIK3CA, PTEN, mTOR, Akt, PI3K inhibitor, therapeutic combination, clinical trial, signaling pathway, tumor suppressor

Has the Time Come for Predictive Computer Modeling in CNS Drug Discovery and Development?

We discuss whether a new paradigm, quantitative systems pharmacology (QSP), based on computational neuroscience modeling combined with proper drug target engagement and pharmacology, human pathology, imaging studies, and calibration and validation using clinical studies in human subjects might improve the success rate of central nervous systems research and development (CNS R&D) projects. We suggest that an improved understanding of neuronal circuit interactions using a humanized computer-based integration of physiology and pharmacology knowledge can substantially de-risk new CNS projects.

RATIONAL INTRAABDOMINAL PRESSURE MONITORING: HOW TO DO IT?

Introduction: Intraabdominal hypertension (IAH) is increasingly appreciated by intensivists as an important cause of organ dysfunction, even at pressure levels which were previously thought to be harmless. Therefore, the goal of this review is to describe the different methods commonly used in clinical practice for intraabdominal pressure (IAP) measurement, the advised methodology for each measurement method, and finally to give a rational approach for IAP monitoring in daily clinical practice.Methods: A Medline search of the English literature was performed using the term “intra abdominal pressure” and “measurement”. This resulted in 194 studies, which were then analysed based on the title and abstract. Only clinical studies in human subjects with IAP measurement or related issues as the subject of the study, were considered for inclusion in the study. Reviews, animal experiments and case reports were excluded, while one specific review on IAP measurement and 3 large animal studies (domestic swine > 40 kg) were included in the analysis. This left us with 19 studies, published between 1984 and 2006: 1 specific review, 2 studies in children, 13 in adults and 3 in domestic swine. The references from these studies were searched for relevant articles that may have been missed in the primary search. These articles served as the basis for the recommendations below.Results: Clinical data regarding the validation of new IAP measurement methods or the reliability of established measurement techniques are scarce. The transvesical route, which has been studied most extensively, can be used as reliable route for intermittent IAP measurement, as long as instillation volumes below 25mL are used. Continuous IAP and APP monitoring can be done via a balloon-tipped catheter placed in the stomach or directly intraperitoneal.Conclusions: Rational IAP monitoring should be based on a site specific protocol, based on known risk factors, the monitoring equipment available and nursing staff experience, and should be linked directly to a local treatment protocol.

The FDA's role in medical device clinical studies of human subjects

This paper provides an overview of the United States Food and Drug Administration's (FDA) role as a regulatory agency in medical device clinical studies involving human subjects. The FDA's regulations and responsibilities are explained and the device application process discussed. The specific medical device regulatory authorities are described as they apply to the development and clinical study of retinal visual prosthetic devices. The FDA medical device regulations regarding clinical studies of human subjects are intended to safeguard the rights and safety of subjects. The data gathered in pre-approval clinical studies provide a basis of valid scientific evidence in order to demonstrate the safety and effectiveness of a medical device. The importance of a working understanding of applicable medical device regulations from the beginning of the device development project is emphasized particularly for novel, complex products such as implantable visual prosthetic devices.

SQUIDs in Neuro- and Cardiomagnetism

In this paper, an adequate account of the theory and practice of SQUIDs and of magnetoencephalography (MEG) and magnetocardiography (MCG) is given. MEG and MCG are two completely non-invasive imaging techniques, suitable for basic and clinical studies of human subjects. Large SQUID arrays, operating at liquid helium temperatures, are employed for detecting and localizing the magnetically active regions, modelled by current dipoles, in the working brain or heart. The measurements are usually performed in magnetically shielded rooms. Time resolution of both methods is better than 1 ms and spatial uncertainty 5. . . 6 mm. The evoked brain signals are as small as 40 fT, one billionth of the earths geomagnetic field. The dc SQUID is discussed with a detailed description of the ideas behind and construction of the modern VTT superconducting sensor. A shorted account is given on the PTB SQUID. Commercial multi-SQUID instruments, briefly described, are now available from three manufacturers. Seven examples of brain studies, including two clinical applications, are discussed. Cardiomagnetic instrumentation is described and the use of MCG in detecting heart abnormalities is presented with three examples. The advantages and drawbacks of modern imaging techniques, including MEG, MCG, MRI, fMRI, and PET, are compared and the future of MEG and MCG is discussed. Eventually, when it becomes feasible to use high-Tc SQUIDs in MEG and MCG, the high cost of magnetic measurements can be reduced.

Macular pigment Raman detector for clinical applications.

Clinical studies of carotenoid macular pigments (MP) have been limited by the lack of noninvasive, objective instruments. We introduce a novel noninvasive optical instrument, an MP Raman detector, for assessment of the carotenoid status of the human retina in vivo. The instrument uses resonant excitation of carotenoid molecules in the visible wavelength range, and quantitatively measures the highly specific Raman signals that originate from the single- and double-bond stretch vibrations of the pi-conjugated carotenoid molecule's carbon backbone. The instrument is a robust, compact device and suitable for routine measurements of MP concentrations in a clinical setting. We characterized and tested the instrument in clinical studies of human subjects to validate its function and to begin to establish its role as a possible screening test for macular pathologies. We also show that the MP Raman spectroscopy technology has potential as a novel, highly specific method for rapid screening of carotenoid antioxidant levels in large populations at risk for vision loss from age-related macular degeneration, the leading cause of blindness of the elderly in the developed world.

Biologic agents in the treatment of rheumatoid arthritis.

Advances in the understanding of the pathogenesis of rheumatoid arthritis (RA) as well as improved biotechnology has enabled selective targeting of the pathogenic elements of disease. Targeting cell recruitment through adhesion molecules has been shown to be successful in pre-clinical murine models. Results of studies of an anti-ICAM-1 monoclonal antibody and anti-sense oligonucleotides have been encouraging. An alternate approach to inhibiting recruitment has been the targeting of chemoattractant molecules ie. chemokines. Important advances have been made in cytokine directed therapy targeting TNFalpha and IL-1. TNF antagonists (anti-TNF monoclonal antibody/soluble TNF receptor Fc fusion protein) have resulted in rapid and substantial improvement in signs and symptoms of disease as well as disease modification, shown by slowing of radiological progression. IL-1 receptor antagonist protein appears to have a significant effect on radiological progression despite a modest effect on symptoms and signs. Studies using anti-inflammatory cytokines such as IL-10 are in progress. A more recent therapeutic approach has been to target T-cell activation by interfering with co-stimulatory complexes such as CD40L/CD40 and CD28/CD80 and CD86. Both pre-clinical and preliminary clinical studies in human subjects support the concept. Another approach involving T-cell receptor peptide vaccination with VB peptides over-utilized in RA synovium has shown to be beneficial. Targeting the cytokines driving T-cells in the RA synovium ie. IL-12 & IL-15 has also proven beneficial in animal studies. Recent attention has also been directed toward the invading synovial fibroblast using Fas-FasL mediated apoptosis. Pre-clinical studies in which angiogenesis and osteoclast activation are targeted have been encouraging. In conclusion, the proof of principle has been established that selective targeting of pathogenic elements of disease results in substantial improvement in signs and symptoms as well as disease progression. Improved efficacy is expected with more aggressive targeting of the pathogenic elements.

The Potential for Monocyte-Mediated Immunotherapy During Infection and Malignancy - Part II: In Vivo Activation by Exogenous Cytokines and Clinical Applications

The monocyte system exhibits a range of immunological mechanisms that may be harnessed for therapeutic effect against infection and malignancy. The advent of novel therapies aimed at treating infection and malignancy is complemented by a resurgence of clinical interest in immunotherapeutic programmes to treat diseases by modification or direct augmentation of host immunity. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ modulate the function of monocytes and have been used to experimentally probe the immunotherapeutic potential of monocytes against micro-organisms and malignancy. However, monocytes rarely act alone but communicate with other leukocytes involved in cell-mediated immunity. In particular monocytes cooperate with the T-helper (Th1 and Th2) sub-populations of peripheral lymphocytes. Moreover, sub-populations of monocytes, as identified by the co-expression of membrane-associated CD14 and CD16, have been shown to exist. At the preclinical level, this provides a unique opportunity to explore the effect of immunotherapeutic strategies on the function of monocyte sub-populations against infectious or malignant challenge and may allow immunotherapeutic strategies to be targeted towards specific monocyte sub-populations. Preclinical and clinical studies in human subjects suggest that GM-CSF and other cytokines such as IFN-γ are the most promising biological response modifiers for augmenting monocyte-mediated immunity. In this review, the immunotherapeutic potential of the monocyte system will be discussed in the context of combating microbial and malignant disease.Monocytes and their communication with other cells of the immune system play a key role in the regulation of host immunity. Selective modulation of monocyte function by the exogenous therapeutic use of GM-CSF or other cytokines, may improve current treatment of severe infections in immunosuppressed patients. Moreover, monocyte-directed immunotherapy may have applications in those patients undergoing cancer chemotherapy, especially in the context of MRD. The availability of recombinant cytokines has led to renewed optimism in the immunotherapeutic treatment of a whole spectrum of diseases. This is complemented with a resurgence of clinical programs involving monocyte/macrophage activation. Refinements in these protocols and a better understanding of the biological processes involved in the cellular and molecular regulation of host immunity may ultimately produce genuine and sustained benefits.

Medical applications of SQUIDs in neuro- and cardiomagnetism

Magnetoencephalography (MEG) and magnetocardiography (MCG) are two completely non-invasive imaging techniques, suitable for basic and clinical studies of human subjects. Large SQUID arrays, operating at liquid helium temperatures, are employed for detecting and localizing magnetically the active regions, modelled by current dipoles, in the working brain or heart. The measurements must be performed in magnetically shielded rooms. Time resolution of both methods is 0.5 ms and spatial accuracy 5-6mm. Commercial multi-SQUID instruments are now available from several manufacturers. An adequate account of the theory and practice of both techniques is given. Three examples of brain studies and two investigations of the heart are described. The advantages and drawbacks of modern imaging techniques, including MRI and PET, are compared and the future of MEG and MCG is discussed.

Isotopic Method for Measurement of Calcium Absorption from the Gastro-intestinal Tract

The study of calcium metabolism is made difficult by the fact that in the normal adult some 80% of the calcium excretion takes place via the faecal route. This means that in order to get calcium-balance data by traditional techniques it has been necessary to subject the faeces to manipulations which are not only time-consuming and liable to considerable error but disagreeable as well. With the increasing availability of iso topes of calcium suitable for clinical studies in human subjects it seems reasonable to consider their use to measure absorption of calcium from the gastro-intestinal tract. We here describe a test in which 47Ca is given by mouth and the faecal radio activity measured without further manipulation of the faeces. From these figures and the calcium intake the calcium absorbed is calculated, and this is compared with data obtained simul taneously by the usual balance techniques. This appears to be the first report in which such a comparison has been made in a reasonably large series of patients.