Evaluating the Effects of Acupuncture Using a Dental Pain Model in Healthy Subjects – A Randomized,Cross-Over Trial

Acupuncture is a complementary and nonpharmacological intervention that can be effective for the management of chronic pain in addition to or instead of medication. Various animal models for neuropathic pain, inflammatory pain, cancer-related pain, and visceral pain already exist in acupuncture research. We used a newly validated human pain model and examined whether acupuncture can influence experimentally induced dental pain. For this study, we compared the impact of manual acupuncture (real acupuncture), manual stimulation of a needle inserted at nonacupuncture points (sham acupuncture) and no acupuncture on experimentally induced dental pain in 35 healthy men who were randomized to different sequences of all 3 interventions in a within-subject design. BORG CR10 pain ratings and autonomic responses (electrodermal activity and heart rate variability) were investigated. An initial mixed model with repeated measures included preintervention pain ratings and the trial sequence as covariates. The results showed that acupuncture was effective in reducing pain intensity when compared to no acupuncture (β = −.708, P = .002), corresponding to a medium Cohen's d effect size of .56. The comparison to the sham acupuncture revealed no statistically significant difference. No differences in autonomic responses between real and sham acupuncture were found during the intervention procedures.PerspectiveThis study established a dental pain model for acupuncture research and provided evidence that experimentally induced dental pain can be influenced by either real acupuncture or manual stimulation of needles at nonacupuncture points. The data do not support that acupoint specificity is a significant factor in reducing experimental pain.     

Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of Recombinant Human Parathyroid Hormone (1–34) in Healthy Chinese Subjects

Background

The recombinant human parathyroid hormone (1–34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China.

Objective

The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1–34) after single and multiple subcutaneous doses in healthy Chinese subjects.

Methods

Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1–34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1–34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1–34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1–34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters.

Results

Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1–34) was well tolerated during the investigated single (10–60 μg) and multiple (10–20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1–34), the drug was rapidly absorbed, with a T_max of 20 to 30 minutes, and rapidly cleared from the plasma, with a t_½ of 47.2 to 60.6 minutes. The mean C_max, AUC_0–t, and AUC_0–∞ increased in proportion to the doses, whereas the t_½, total clearance, and T_max values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for T_max in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels.

Conclusions

All rhPTH(1–34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.     

Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study

Objective

To determine whether the early trials in chronic medical conditions demonstrate an effect size that is larger than that in subsequent trials.

The Diagnosis of Concussion in Pediatric Emergency Departments: A Prospective Multicenter Study

Background

The accurate identification of children with a concussion by emergency physicians is important to initiate appropriate anticipatory guidance and management.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Recombinant Parathyroid Hormone (1–84) in Patients With Hypoparathyroidism: An Open-Label,Single-Dose,Phase I Study

Background

Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1–84 (rhPTH[1–84]) is being developed for the treatment of hypoparathyroidism.

Objective

The goal of this study was to investigate the pharmacokinetics and pharmacodynamics of a single subcutaneous injection of rhPTH(1–84) in patients with hypoparathyroidism.

Methods

This was an open-label, dose-escalating study of single subcutaneous administration of 50 µg and then 100 µg of rhPTH(1–84). Enrolled patients (age range, 25–85 years) had ≥12 months of diagnosed hypoparathyroidism defined according to biochemical evidence of hypocalcemia with concomitant low-serum intact PTH and were taking doses ≥1000 mg/d of oral calcium and ≥0.25 µg/d of active vitamin D (oral calcitriol). The patient’s prescribed dose of calcitriol was taken the day preceding but not on the day of or during the 24 hours after rhPTH(1–84) administration. Each patient received a single 50-µg rhPTH(1–84) dose, had at least a 7-day washout interval, and then received a single 100-µg rhPTH(1–84) dose. The following parameters were assessed: plasma PTH; serum and urine total calcium, magnesium, phosphate, and creatinine; and urine cyclic adenosine monophosphate.

Results

After administration of rhPTH(1–84) 50 µg (n = 6) and 100 µg (n = 7), the approximate t_½ was 2.5 to 3 hours. Plasma PTH levels increased rapidly, then declined gradually back to predose levels at ~12 hours. The median AUC was similar with calcitriol and rhPTH(1–84) for serum 1,25-dihydroxyvitamin D (calcitriol, 123–227 pg · h/mL; rhPTH[1–84], 101–276 pg · h/mL), calcium (calcitriol, 3.3–3.7 mg · h/dL; rhPTH[1–84], 3.3–7.6 mg · h/dL), and magnesium (calcitriol, 0.7–0.9 mg · h/dL; rhPTH[1–84], 1.3–2.8 mg · h/dL). In contrast, the median AUC for phosphate was strongly negative with rhPTH(1–84) (calcitriol, −1.0 to 0.8 mg · h/dL; rhPTH[1–84], −21.3 to −26.5 mg · h/dL). Compared with calcitriol, rhPTH(1–84) 50 µg reduced 24-hour calcium excretion and calcium-to-creatinine ratios by 12% and 23%, respectively, and rhPTH(1–84) 100 µg reduced them by 26% and 27%. There was little overall impact on urine magnesium levels. Compared with calcitriol, rhPTH(1–84) 50 µg increased urinary phosphate excretion and phosphate-to-creatinine ratios by 53% and 54%, respectively, and rhPTH(1–84) 100 µg increased them by 45% and 42%. Urine cyclic adenosine monophosphate–to–creatinine ratio increased with rhPTH(1–84) by 2.3-fold (50 µg) and 4.4-fold (100 µg) compared with calcitriol.

Conclusions

PTH replacement therapy with rhPTH(1–84) regulated mineral homeostasis of calcium, magnesium, phosphate, and vitamin D metabolism toward normal in these study patients with hypoparathyroidism.     

P1A Recombinant β-Lactamase Prevents Emergence of Antimicrobial Resistance in Gut Microflora of Healthy Subjects during Intravenous Administration of Ampicillin

Ipsat P1A is a recombinant β-lactamase which degrades antibiotic residue in the gastrointestinal tract. In an open-label, single-center controlled trial, 36 healthy subjects were randomized to receive (i) ampicillin (1 g intravenously [i.v.] every 6 h [q6h]), (ii) oral P1A recombinant β-lactamase (8.2 mg q6h), or (iii) ampicillin (1 g i.v. q6h) in combination with oral P1A recombinant β-lactamase (8.2 mg q6h) for 5 days. Fecal samples were collected before treatment, during treatment (days 3 to 5), and at follow-up (day 12). The primary end points were (i) changes in gastrointestinal microflora (determined by temperature gradient gel electrophoresis [TGGE]) and (ii) emergence of bacterial resistance (determined by conventional microbiology and PCR of TEM β-lactamase genes). Thirty-five subjects completed the study. The mean similarity percentages of TGGE profiles between baseline and each treatment day sample were significantly lower for the ampicillin group than for the group receiving ampicillin plus P1A recombinant β-lactamase on days 3, 4, and 5 (P < 0.001). Compared with the ampicillin group, subjects receiving ampicillin plus P1A recombinant β-lactamase had significantly fewer ampicillin-resistant coliforms on days 3, 4, and 5 and at follow-up (P ≤ 0.001) and fewer TEM β-lactamase genes on days 3, 4, and 5 (P < 0.02). P1A recombinant β-lactamase was safe and well tolerated. In healthy subjects, P1A recombinant β-lactamase prevents ampicillin-induced alterations in intestinal microflora, emergence of resistance, and the number of TEM genes.The health care system has been impacted greatly by the increasing rates of infection with antibiotic-resistant pathogens (14, 20). Many patients in whom infections occur have previously been exposed to antibiotics, either for prophylaxis or as treatment. While antibiotic treatment can reduce the incidence of infections with certain organisms (prophylactic effect), it may not modify others and can even increase the incidence of infections with some organisms. These effects are attributable to direct antimicrobial activity against the causative organism and/or to effects on competing microflora. The effect on intestinal microflora is of particular interest, as it may lead to selection for bacterial strains resistant to antimicrobial agents, a process that may have particularly severe consequences, resulting in increased mortality, morbidity, and costs (5, 8). Antibiotics that are excreted in high concentrations in bile into the intestinal tract can cause profound disruption of the indigenous microflora (9, 29, 30), resulting in an increased incidence of secondary infections due to acquisition and overgrowth of antimicrobial-resistant pathogens, including vancomycin-resistant enterococci, Candida species, and multiresistant gram-negative bacilli, and also in a number of adverse effects observed in Clostridium difficile infections (1, 2, 6, 8).β-Lactam antibiotics are among the most widely used classes of antimicrobials, and many of these agents are excreted into the intestinal tract in high concentrations. Previous studies have demonstrated that the normal intestinal microflora contains various degrees of antibiotic resistance genes (19, 32, 34) and that healthy individuals may harbor intestinal bacteria that can produce TEM β-lactamases (31, 34). It has further been shown that the resistance patterns of enteric bacteria change in response to increased levels of exposure to antibiotics and that selective pressure from ampicillin treatment can result in increased levels of ampicillin-resistant bacteria (12, 13).The active ingredient of Ipsat P1A capsule is P1A protein. P1A protein is a recombinant class A β-lactamase with a molecular mass of 29 kDa which is capable of hydrolyzing penicillin, aminopenicillins (e.g., ampicillin), and ureidopenicillins (e.g., piperacillin). P1A protein has structural and functional similarities to naturally occurring β-lactamases in the gastrointestinal (GI) microflora. P1A protein is intended for oral use and is presented in a gastroresistant formulation in P1A pellets designed to protect P1A protein from the influence of the acidic gastric medium in the stomach and to start the release of P1A protein in the intestine when the pH exceeds 5.5. This is achieved by using the pH-dependent polymer Eudragit L 30 D-55.In dogs, orally administered P1A recombinant β-lactamase was shown to effectively degrade the GI residue of intravenously administered ampicillin, ampicillin-sulbactam, amoxicillin-clavulanate, and piperacillin-tazobactam (10, 11, 24, 33). Studies using mouse models demonstrated that oral administration of P1A recombinant β-lactamase given in conjunction with ampicillin or piperacillin preserved colonization resistance, reduced antibiotic-associated alteration in the indigenous microflora, and prevented overgrowth of vancomycin-resistant enterococci and Clostridium difficile (35, 36, 37).The aims of this trial with healthy subjects were to evaluate the preventive effect of P1A recombinant β-lactamase on ampicillin-induced changes in GI microflora and the emergence of antimicrobial resistance in intestinal coliforms. The changes in the composition and numbers of selected groups of GI microflora were assessed by culture-based and molecular approaches (temperature gradient gel electrophoresis [TGGE]). Resistance to 10 antimicrobials other than ampicillin was evaluated by determining the susceptibility of coliforms in fecal samples by using the disc diffusion method (CLSI) and quantifying the bla_TEM genes in fecal samples by quantitative PCR. In addition, the safety and tolerability of P1A recombinant β-lactamase were studied.(The results of this study were presented in part at the 15th ECCMID, 2 to 5 April 2005, Copenhagen, Denmark, and at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, 16 to 19 December 2005, Washington, DC.)     

Clinical Characteristics of Biopsy-Proven IgA Vasculitis in Children and Adults: A Retrospective Cohort Study

ObjectiveTo describe the differences in clinical characteristics and outcome between adult- and childhood-onset biopsy-proven IgA vasculitis (IgAV) in North America.Patients and MethodsPatients with IgAV diagnosed from January 1, 1997, through December 31, 2016, were retrospectively identified. Data were abstracted from direct medical record review. Kaplan-Meier methods were used to estimate survival rates.ResultsA total of 243 patients with IgAV were included (227 [93.4%] white, 141 [58.0%] male); 174 patients were adults (≥21 years), and 69 were younger than 21 years. Compared with patients younger than 21 years, adults at baseline more frequently had ulcerative skin lesions (19 [10.9%] vs 1 [1.4%]; P=.02) and nephrotic-range proteinuria (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P=.007) but less commonly had abdominal pain (59 [33.9%] vs 42 [60.9%]; P<.001), ischemic gastrointestinal tract involvement (18 [10.3%] vs 14 [20.3%]; P=.04), and arthralgias (66 [37.9%] vs 42 [60.8%]; P<.001). During 389 person-years of follow-up, 29 deaths were observed. Five-year survival rates for patients aged younger than 21, 21 to 50, and 51 years or older were 100%, 94%, and 40%, respectively. In comparison to data from the United States life tables for whites, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality (standardized mortality, 7.60 [95% CI, 5.01-11.06]; P<.001).ConclusionIgA vasculitis in adults is associated with more severe skin/kidney involvement and poorer renal outcome. Among adults with IgAV, patients aged 51 years or older at diagnosis have significantly higher mortality (P<.001).     

A Randomized Phase I Study Comparing the Pharmacokinetics of HD201, a Trastuzumab Biosimilar,With European Union–sourced Herceptin

Purpose

This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*.

Home-Based Exercise Enhances Health-Related Quality of Life in Persons With Spinal Cord Injury: A Randomized Controlled Trial

Objective

To assess the influence of a home-based exercise intervention on indices of health-related quality of life (HRQOL) in persons with spinal cord injury (SCI).

Cardiorespiratory Fitness and the Risk of Serious Ventricular Arrhythmias: A Prospective Cohort Study

Cardiorespiratory fitness (CRF) is an established risk factor for cardiovascular disease outcomes. However, the relationship of CRF with risk of ventricular arrhythmias (VAs) is unknown. We aimed to assess the prospective association of CRF with the risk of serious VAs. Cardiorespiratory fitness, as measured by maximal oxygen uptake, was assessed using a respiratory gas exchange analyzer in 2299 middle-aged men in the Kuopio Ischemic Heart Disease prospective cohort. We corrected for within-person variability in CRF levels using data from repeated measurements 11 years apart. During median follow-up of 25.3 years (interquartile range, 18.7-27.2 years), 73 serious VAs were recorded. The age-adjusted regression dilution ratio of CRF was 0.58 (95% CI, 0.53-0.64). In analysis adjusted for age, the hazard ratio (HR) for serious VAs per 1-SD increase in CRF was 0.64 (95% CI, 0.49-0.84). The association persisted on additional adjustment for body mass index, systolic blood pressure, history of hypertension, prevalent coronary heart disease, smoking, history of diabetes, cholesterol level, alcohol consumption, and physical activity (HR, 0.67; 95% CI, 0.51-0.88). The corresponding adjusted HRs (95% CIs) were 0.29 (0.14-0.59) and 0.32 (0.15-0.65), respectively, comparing the top vs bottom tertiles. The associations were stronger on correction for regression dilution bias, remained consistent on exclusion of men with a history of coronary heart disease, and did not vary importantly in several relevant clinical subgroups. Cardiorespiratory fitness is inversely associated with future risk of serious VAs, independently of several cardiovascular disease risk factors. Further research is needed to assess the causal relevance of these findings.     

Effects of Whole Body Vibration on Tibia Strength and Structure of Competitive Adolescent Swimmers: A Randomized Controlled Trial

Background

Swimming has no effect on bone mass or structure. Therefore, adolescent swimmers present similar bone strength values when compared to normo-active controls, and lower values when compared to weight-bearing athletes. It thus seems necessary to try to improve bone structure and strength of adolescent swimmers through a weight-bearing intervention in order to reduce the risk of suffering osteoporosis later in life.

Understanding the Outcome in the Chinese Changjiang Disaster in 2015: A Retrospective Study

Background

Rescue after a maritime disaster remains a great challenge in emergency medicine.

“Life on Hold”: A Qualitative Study of Patient Experiences with Outpatient Commitment in Two Norwegian Counties

In recent decades, outpatient commitment orders have been increasingly used in the follow-up of persons with serious mental disorders. Most studies on outpatient commitment orders have focused on compliance and consumption of health care services; there is little research on the content of outpatient commitment orders from a patient perspective. The aim of this study is to examine patients’ experiences of living with outpatient commitment orders, and is based on qualitative interviews with 16 persons in two Norwegian counties. The data were analysed using a constructivist, interpretive approach to the grounded theory method. The main finding was that patients with outpatient commitment orders felt that their lives were on hold. The feeling of being seen only as patients prevented them from taking responsibility for their own lives. The medical context was perceived as an obstacle to recovery and transition to a more normal life. Patients’ daily lives were dominated by the agenda set by health care providers and many said they were subjected to control measures that resulted in a reduced quality of life. However, informants also spoke of positive experiences as outpatient commitment order patients, such as feeling safe and secure and having easy access to health care staff and services.