Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients

TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (E_max) and 50% inhibitory concentrations (IC₅₀). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an E_max of −1.43 log₁₀ copies/ml and IC₅₀ of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.     

Does FVIII-activity increase with age in patients with haemophilia A and carriers of haemophilia A?

The retrospective cohort study surveys the influence of age, co-morbidity and laboratory values on FVIII-activity (FVIII:C) in patients with haemophilia A with (mild n = 48, moderate n = 10, severe n = 7 and carriers n = 23). Median observation was 19 years for patients with haemophilia A and 9,5 years for carriers. Results: FVIII:C levels collected from patients with mild haemophilia A displayed a significant median increase of 6.5% with proceeding age (p = 0.0013). Patients with moderate haemophilia A (and carriers of haemophilia A) showed a non significant median increase of 1.05% (carriers 8%). Eight patients showed FVIII:C levels at last blood withdrawal that indicated a change of severity from moderate to mild haemophilia A. A significant correlation was found between FVIII:C and VWF:RCo (p = 0.0203) and AFP (p < 0.0005). The correlation between FVIII:C and triglycerides and LDH was significant negative (p < 0.0005). No significant correlation could be found for FVIII:C and co-morbidity, fibrinogen, cholesterol and VWF:Ag.     

How individual can personalized antiretroviral treatment be? Deep salvage in an HIV-1-infected patient

We present an HIV-1-infected male (who is now 52 years old) with a multi-drug-resistant virus and discuss the considerations finally leading to an antiretroviral regimen resulting in long-term viral suppression and excellent immunological response in a deep salvage situation. Even in a desperate situation with high-level multi-class resistance, highly individual, personalized antiretroviral regimes can be tailor-made to achieve unexpected improvements in the health status of a patient.     

Does biofeedback affect incontinence and quality of life in Turkish women?

Although urinary incontinence (UI) is not a life‐threatening disease, it is a common health problem that affects quality of life. This study was conducted to investigate the effect of pelvic floor muscle exercise (PFE) with biofeedback on incontinence and quality of life in women with UI. This clinical study was a randomized, controlled and experimental research conducted on 60 patients in total (30 control and 30 intervention patients) at a university hospital. Data were collected by using a questionnaire, Incontinence Quality of Life (I‐QOL) instrument, and International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF). The intervention group received biofeedback treatment for 16 sessions in total, each of which lasted 20 min, for 8 weeks, twice weekly, in a urodynamic unit. The obtained data were evaluated using χ², Student's t, one‐way analysis of variance (anova) , Mann–Whitney U and Kruskal–Wallis tests. It was observed that the incontinence inquiry form mean score of 16·1 ± 2·2 in the intervention group before biofeedback application decreased to 11·6 ± 4·6 after the application, whereas it increased from 14·0 ± 4·7 to 14·7 ± 4·7 in the control group (p < 0·05). It was also determined that the quality of life total mean score of 52·1 ± 10·5 in the intervention group before biofeedback application increased to 58·7 ± 14·7 after the application, whereas it decreased from 58·1 ± 16·1 to 53·5 ± 16·1 in the control group (p < 0·05). At the end of this study it was observed that PFE with biofeedback reduced incontinence and increased quality of life in women.     

CXCR3+CCR5+ T cells and autoimmune diseases: guilty as charged?

Prior to the 1990s, genetic analyses indicated that many autoimmune diseases are driven by T cell responses; however, the identity of the pathogenic T cell populations responsible for dysfunctional autoimmune responses remained unclear. Some 20 years ago, the discovery of numerous chemokines and their receptors along with the development of specific mAbs to these provided a distinct advance. These new tools revealed a remarkable dichotomy and disclosed that some chemokine receptors guided the constitutive migration of T cells through lymphoid tissues, whereas others, such as CCR5 and CXCR3, guided effector and memory T cell migration to inflammatory lesions. These T cell markers enabled a new understanding of immune responses and the types of T cells involved in different inflammatory reactions.     

Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea?

OBJECTIVE: To investigate the effects of modafinil, a central nonamphetamine awakening substance, on blood pressure and heart rate in hypersomnolent patients with obstructive sleep apnea. DESIGN: This double-blind, randomized, placebo-controlled crossover trial was performed over 2 days and 3 nights in a single-center study of hospitalized patients from a referred care center. Twenty-six otherwise healthy men (age range, 30 to 60 years) with mild to moderate obstructive sleep apnea were recruited by the outpatient department of the Marburg University Sleep Laboratory. Patients were given 200 mg oral modafinil in the morning and 100 mg at midday. Placebo was given in the same manner in a crossover design. Mean arterial (radial) blood pressure was monitored continuously during nocturnal sleep and during a series of standardized daytime physical and psychologic performance tests. RESULTS: The difference in the main end point between the treatment with modafinil and placebo was 1.17+/-0.83 (mean +/- SE) mm Hg (95% confidence interval: -0.56 to 2.91 mm Hg). The maximal differences in blood pressure values occurred under loaded conditions (systolic blood pressure, ergometry: 5.62+/-1.13 mm Hg; mental stress test: 6.19+/-1.33 mm Hg). CONCLUSION: Short-term administration of modafinil did not elicit a significant response with regard to the main end point. However, cardiovascular effects during mental and physical load were observed. Longterm studies that include subjects with hypertension are necessary to investigate the clinical relevance of the cardiovascular effects of modafinil.     

Does computed tomographic scan affect diagnosis and management of patients with suspected renal colic?

Background

Patients with renal colic commonly present to the emergency department (ED) and are usually treated with analgesics, antiemetics and hydration. Computed tomographic (CT) scan is commonly utilized in evaluating patients with suspected renal colic.

Objectives

We compared diagnosis and treatment plans before and after CT in patients with suspected renal colic with the aim to evaluate how often changes in diagnosis, treatment and disposition are made.

Methods

In this prospective observational study, we enrolled a convenience sample of clinically Stable ED patients older than 17 with suspected renal colic for whom CT was planned. Exclusion criteria were: chronic kidney disease, urinary tract infection, recent CT and history of previous kidney stone. Pre-CT and Post-CT surveys were completed by the treating provider.

Results

The discharge diagnosis was renal colic in 62 of 93 enrolled patients (67%). Urinalysis showed blood in 52 of these patients (84%). CT confirmed obstructing kidney or bladder stone in 50 patients. There were five cases of alternative diagnoses noted on CT scan. After CT scan, 7 patients had changes in disposition. Sixteen providers felt that CT would not change management. In these cases, CT offered no alternative diagnosis and didn't change disposition.

Conclusion

CT scan didn't change management when providers did not expect it would. This indicates that providers who are confident with the diagnosis of renal colic should consider forgoing a CT scan. CT scan did occasionally find important alternative diagnoses and should be utilized when providers are considering other concerning pathology.     

Does methylene blue administration to septic shock patients affect vascular permeability and blood volume?

OBJECTIVE: To assess the effects of the inhibition of guanylate cyclase, an enzyme involved in sepsis-related vascular and myocardial dysfunctions, on hemodynamic variables including blood volume and pulmonary vascular permeability during septic shock. DESIGN: Prospective, open study with repeated measurements. SETTING: A medicosurgical intensive care unit of a university hospital. PATIENTS: Fifteen patients with septic shock associated with persisting hypotension despite conventional treatment including fluid loading, vasopressors, and inotropes. INTERVENTIONS: A fiberoptic catheter was inserted for the determination of blood and extravascular volumes by the thermal-dye double indicator technique, using indocyanine green (COLD system). A bolus dose of methylene blue (3 mg/kg) was infused intravenously over 10 mins. COLD-derived variables were recorded before methylene blue and 20 mins, 1 hr, and 2 hrs after the end of methylene blue infusion. MEASUREMENTS AND MAIN RESULTS: Standard hemodynamic and oxygen-derived variables; total, intrathoracic, systolic, and diastolic cardiac blood volumes; extravascular lung water; plasma osmolarity; and lactate and protein concentrations were recorded. Mean arterial and pulmonary artery pressures, systemic and pulmonary vascular resistances, and left ventricular stroke work index increased, and blood lactate transiently decreased after methylene blue (p <.05). The other variables recorded were unchanged during the 2-hr period following methylene blue infusion. CONCLUSIONS: This study confirmed the acute vasoconstrictive and positive inotropic effects of methylene blue during septic shock. These effects were not associated with changes in blood volume, myocardial diastolic function, or pulmonary vascular permeability assessed by extravascular lung water.     

Does the organization of care processes affect outcomes in patients undergoing total joint replacement?

Background Surgeons realize that safe and efficient care processes for total joint replacement requires more than just well‐performed operations. Orthopaedic teams are reorganizing care process to improve efficacy and shorten length of stay. Little is known on the impact of organizational changes on patient outcome. This paper studies the relation between the organization of care processes and patient outcomes in hip and knee. Clinical pathways are used as one of the methods to structure the care process. Although evidence is available on the effect of pathways in total joint replacement, their impact with the organization of the care process has not been studied previously. Methods A cross‐sectional multicentre study was performed on 39 care processes and 737 consecutive patients. Regression models were used to analyse the relation between the organization of the care process and risk‐adjusted patient outcomes. The use of pathways and the organization of the care process, measured by the Care Process Self Evaluation Tool (CPSET), were measured at organizational level. Length of stay, pain, mobility and elapsed time to discharge were measured at patient level. Results The use of pathways had a positive effect on four out of five subscales and the overall CPSET score. Using pathways decreased length of stay (P = 0.014), pain (P = 0.052) and elapsed time to discharge (P = 0.003). The CPSET subscale communication was related with three risk adjusted outcomes. Multivariate analysis demonstrated a significant effect by three different variables on the length of stay; (1) use of pathways; (2) coordination of care processes; and (3) communication with patients and family. Both the use of pathways and coordination of the care process were determinants for the elapsed time to discharge. A significant interaction effect was found between use of pathways and coordination of the care process. Conclusion This large multicentre study revealed the relation between the use of pathways, organization of the care process and patient outcomes. This information is important for both clinicians and managers to understand and further improve the organization of orthopaedic care. Level of evidence Level I prognostic study.     

Does manual therapy improve pain and function in patients with plantar fasciitis? A systematic review

Objective: To assess if manual therapy (MT) in the treatment of plantar fasciitis (PF) patients improves pain and function more effectively than other interventions.

Methods: A systematic review of all randomized control trials (RCTs) investigating the effects of MT in the treatment of human patients with PF, plantar fasciosis, and heel pain published in English on PubMed, CINAHL, Cochrane, and Web of Science databases was conducted. Research quality was appraised utilizing the PEDro scale. Cohen’s d effect sizes (ES) and associated 95% confidence intervals (CI) were calculated between treatment groups.

Results: Seven RCTs were selected that employed MT as a primary independent variable and pain and function as dependent variables. Inclusion of MT in treatment yielded greater improvement in function (6 of 7 studies, CI that did not cross zero in 14 of 25 variables, ES = 0.5–21.5) and algometry (3 of 3 studies, CI that did not cross zero in 9 of 10 variables, ES = 0.7–3.0) from 4 weeks to 6 months when compared to interventions such as stretching, strengthening, or modalities. Though pain improved with the inclusion of MT, ES calculations favored MT in only 2 of 6 studies (3 of 13 variables) and was otherwise equivalent in effectiveness to comparison interventions.

Discussion: MT is clearly associated with improved function and may be associated with pain reduction in PF patients. It is recommended that clinicians consider use of both joint and soft tissue mobilization techniques in conjunction with stretching and strengthening when treating patients with PF.

Level of Evidence: Treatment, level 1a.     

Does aerobic exercise affect the hypothalamic-pituitary-adrenal hormonal response in patients with fibromyalgia syndrome?

[Purpose] The hypothalamic-pituitary-adrenal (HPA) axis in the etiopathogenesis of fibromyalgia is not clear. This study aimed to analyze the effects of a 6-week aerobic exercise program on the HPA axis in patients with fibromyalgia and to investigate the effects of this program on the disease symptoms, patients’ fitness, disability, and quality of life. [Subjects and Methods] Fifty fibromyalgia patients were randomized to Group 1 (stretching and flexibility exercises at home for 6 weeks) and Group 2 (aerobic exercise three times a week and the same at-home exercises as Group 1 for 6 weeks). Serum levels of cortisol, adrenocorticotropic hormone, insulin-like growth factor-1, and growth hormone were analyzed at baseline and at the end of, and 1 hr after an exercise stress test. [Results] Group 2 showed better improvement in morning stiffness duration and pain. Growth hormone levels significantly increased after intervention and cortisol levels significantly decreased at time-time interaction in both groups. No significant differences in adrenocorticotropic hormone and insulin-like growth factor-1 were found. [Conclusion] The results of this study seem to support the hypothesis that there is a dysregulation of the HPA axis in patients with FM, and that a six-week exercise program can influence symptoms and affect the HPA axis hormones.Key words: Fibromyalgia, Aerobic exercise, Hypothalamic-pituitary-adrenal axis     

Does pulse pressure variation predict fluid responsiveness in critically ill patients? A systematic review and meta-analysis

Introduction

Fluid resuscitation is crucial in managing hemodynamically unstable patients. The last decade witnessed the use of pulse pressure variation (PPV) to predict fluid responsiveness. However, as far as we know, no systematic review and meta-analysis has been carried out to evaluate the value of PPV in predicting fluid responsiveness specifically upon patients admitted into intensive care units.

Methods

We searched MEDLINE and EMBASE and included clinical trials that evaluated the association between PPV and fluid responsiveness after fluid challenge in mechanically ventilated patients in intensive care units. Data were synthesized using an exact binomial rendition of the bivariate mixed-effects regression model modified for synthesis of diagnostic test data.

Result

Twenty-two studies with 807 mechanically ventilated patients with tidal volume more than 8 ml/kg and without spontaneous breathing and cardiac arrhythmia were included, and 465 were responders (58%). The pooled sensitivity was 0.88 (95% confidence interval (CI) 0.81 to 0.92) and pooled specificity was 0.89 (95% CI 0.84 to 0.92). A summary receiver operating characteristic curve yielded an area under the curve of 0.94 (95% CI 0.91 to 0.95). A significant threshold effect was identified.

Conclusions

PPV predicts fluid responsiveness accurately in mechanically ventilated patients with relative large tidal volume and without spontaneous breathing and cardiac arrhythmia.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0650-6) contains supplementary material, which is available to authorized users.     

Does interferon and ribavirin combination therapy ameliorate growth hormone deficiency in HCV genotype-4 infected patients?

ObjectivesTo explore the impact of response to interferon and ribavirin antiviral therapy on human growth hormone (hGH) levels in Egyptian chronic hepatitis C genotype-4 infected patients.Design and methodsWe studied eighty Egyptian HCV infected patients visiting outpatient clinics of Tropical Medicine and Hepatology Department, El-Kasr El-Aini Hospital, Cairo University, Egypt. HCV patients received treatment of interferon and ribavirin combination therapy for 24 weeks. Clinical, virological, histological characteristics, and biochemical tests including; liver function tests (ALT and AST), prothrombin time (PT), alpha fetoprotein (AFP), complete blood picture (CBC), and hGH were monitored in hepatitis C genotype-4 infected patients before and after interferon therapy, and healthy controls.ResultsChronic HCV genotype-4 infected patients have high significant decrease of hGH as compared to healthy control individuals. In addition to, there was high significant increase of hGH in responders as compared to non-responders after treatment.ConclusionWe concluded that Egyptian HCV genotype-4 infected patients have growth hormone insufficiency. Besides, we found that response to interferon/ribavirin treatment has an impact on growth hormone levels.     

Does therapeutic touch help reduce pain and anxiety in patients with cancer?

With more than 10 million patients with cancer in the United States, pain and symptom management is an important topic for oncology nurses. Complementary therapies, such as therapeutic touch, may offer nurses a nonpharmacologic method to ease patients' pain. Using 12 research studies, the authors examined the evidence concerning the effectiveness of this type of treatment in reducing pain and anxiety.