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1.
Tian-tian Zhang Sen Wang Ning Wan Li Zhang Zugui Zhang Jie Jiang 《Clinical therapeutics》2018,40(7):1122-1139
Purpose
The prominent efficacy of the addition of daratumumab to lenalidomide and dexamethasone (DRd) or the addition to bortezomib and dexamethasone (DVd) was proven previously for patients with relapsed or refractory multiple myeloma (RRMM). However, the cost-effectiveness of adding daratumumab to traditional doublet regimens versus doublet regimens alone (DRd vs Rd; DVd vs Vd) was unknown.Methods
We developed a semi-Markov model by using a US payer perspective and 10-year time horizon to estimate the cost and quality-adjusted life years (QALYs) for treatments. Clinical data were obtained from the POLLUX (Phase 3 Study Comparing DRd Versus Rd in Subjects with Relapsed or Refractory Multiple Myeloma [RRMM]) and CASTOR (Phase 3 Study Comparing DVd Versus Vd in Subjects with RRMM) trials. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty.Findings
The incremental cost-effectiveness ratio (ICER) for DVd compared with Vd was $284,180 per QALY; the ICER for DRd compared with Rd was $1,369,062 per QALY. Only when the price of daratumumab was reduced to 37% (US $702/vial) of the current price could the addition of daratumumab to Vd be cost-effective under the US willingness-to-pay (WTP) of $50,000/QALY. However, under no discount level of the daratumumab price is the addition of daratumumab to Rd acceptable. When the WTP increased to $300,000/QALY, the addition of DVd had a 56.7% probability of being cost-effective compared with the Vd regimen.Implications
Due to the high price of daratumumab, neither the addition of daratumumab to Rd nor Vd proved to be cost-effective under US WTP. However, if the daratumumab price fell to a certain discount level, the DVd regimen might be cost-effective. 相似文献2.
3.
Rajeev Ayyagari Derek Tang Oscar Patterson-Lomba Zhou Zhou Jipan Xie David Chandiwana Anand A. Dalal Polly Ann Niravath 《Clinical therapeutics》2018,40(4):628-639.e3
Purpose
The comparative efficacy of endocrine-based therapies (ETs) for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (mBC) is not well characterized. This network meta-analysis (NMA) synthesized available evidence on progression-free survival (PFS) with first-line ETs for postmenopausal HR+/HER2– mBC.Methods
A systematic literature review identified randomized controlled trials of first-line ETs. Pairwise hazard ratios and 95% credible intervals (CrIs) were obtained via a Bayesian NMA model. Subgroup NMAs were conducted among late progressors (disease-free interval ≥12 months from completion of [neo] adjuvant therapy with letrozole or anastrozole at the time of randomization) and de novo patients, defined as patients whose initial BC diagnosis is mBC.Findings
Five trials and 5 regimens (ribociclib + an aromatase inhibitor [AI] [LEE + AI], palbociclib + AI [Pal + AI], fulvestrant 250 mg + AI [Ful250 + AI], fulvestrant 500 mg [Ful500], and AI) were selected. LEE + AI, Pal + AI, Ful250 + AI, and Ful500 had significantly longer PFS versus AI (95% CrI upper-bound ≤1). LEE + AI had a 30% and 29%, and Pal + AI had a 31% and 30%, reduced hazard of progression or death versus Ful250 + AI and Ful500 (95% CrI upper-bound ≤1), respectively. The probability of being the most efficacious was 46% for LEE + AI and 54% for Pal + AI. In subgroup analyses among late progressors, LEE + AI had a 4% reduced hazard of progression or death versus Pal + AI but was not statistically significant. In the de novo analysis, Pal + AI and LEE + AI had a 29% and 40% reduced hazard of progression or death versus Ful500, respectively, but were not statistically significant. In both subgroup analyses, all therapies had significantly longer PFS compared with AI.Implications
Pal + AI, LEE + AI, Ful250 + AI, or Ful500 as first-line treatment for HR+/HER2– mBC had longer PFS than AI alone. Given the lack of head-to-head clinical trials comparing the efficacy of recently approved first-line ETs for HR+/HER2– mBC, these results have important clinical implications for the treatment of HR+/HER2– mBC in the first-line setting. 相似文献4.
Sonja Sorensen Mark Wildgust Nishan Sengupta Cristina Trambitas Joris Diels Suzy van Sanden Yingxin Xu Emily Dorman 《Clinical therapeutics》2017,39(1):178-189.e5
Purpose
Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months’ follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.Methods
A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician’s choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS.Findings
A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician’s choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04–0.11; and OS HR = 0.25; 95% CI, 0.12–0.54), physician’s choice (PFS HR = 0.41; 95% CI, 0.25–0.66; and OS HR = 0.50; 95% CI, 0.23–1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings.Implications
In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician’s choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy. 相似文献5.
Maria Angeles Quijada-Manuitt Yolanda Escamilla Antonio Vallano Alda Cardesín Manuel Bernal-Sprekelsen Caridad Pontes 《Clinical therapeutics》2018,40(1):136-149.e19
Purpose
We assessed the evidence for the use of α2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery.Methods
We systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles were fully reviewed. Data on study design, population, A2AA drug and control groups, bleeding and surgical field quality outcomes, and adverse effects were extracted and synthesized.Findings
A total of 13 RCTs that included 896 individuals (7 double-blind trials, 5 single-blind trials, and 1 open-label trial) were selected that assessed the efficacy of clonidine (6 RCTs, 407 patients), dexmedetomidine (6 RCT, 423 patients), or both (1 RCT, 66 patients). Clonidine was compared with placebo (3 RCTs), midazolam (1 RCT), and remifentanil (2 RCTs). Dexmedetomidine was compared with esmolol (2 RCTs), remifentanil (2 RCTs), nitroglycerin and esmolol (1 RCT), and magnesium sulfate (1 RCT). Clonidine and dexmedetomidine were compared in 1 RCT. Clonidine reduced the proportion of individuals with an impaired surgical field by 23% vs placebo (number needed to treat = 4). Clonidine was better than midazolam and remifentanil in 2 trials, and dexmedetomidine was better than magnesium sulfate and esmolol in 2 trials but was not superior to esmolol, remifentanil, or nitroglycerin in 4 trials. Dexmedetomidine produced significantly better differences in bleeding outcomes versus clonidine. Adverse events were infrequent and mainly caused by hypotension or bradycardia.Implications
RCTs consistently report that A2AAs reduce bleeding and improve surgical field quality during endoscopic sinus surgery. Adverse event reporting was often omitted in RCTs. Well-designed RCTs with appropriate sample sizes are desirable to identify the best A2AAs and confirm their potential effects on clinical outcomes. 相似文献6.
Gráinne Kelly Aoife Reilly Hannah Moloney Jonathan Moran Caitriona Cunningham Julie Broderick 《Physiotherapy》2018,104(4):359-366
Background
Randomised controlled trials (RCTs) are described as the gold standard of investigative clinical research. Evidence based practice is critical to the physiotherapy profession, and it is therefore important to explore the research underpinning practice by examining published RCTs.Objectives
The main aims of this review were to profile the quantity and quality of RCTs published in the journal Physiotherapy over the past 50 years.Data sources
Physiotherapy journal, hand searched (1967 to 1987) and electronically (1988 to 2017).Study selection or eligibility criteria
Studies identified as RCTs.Study appraisal and synthesis methods
Quality assessed via PEDRO criteria.Results
120 RCTs were identified from January 1967 to January 2017. The frequency of RCTs published has increased steadily and the UK was the most common source of RCTs, but the prevalence of non-UK based trials is increasing. The quality of RCTs improved steadily over the decades, with a mean PEDro score of 6.9 in the most recent decade (2017 to 2008), indicative of ‘high quality’. The mean number of trial participants was 60 and the most commonly evaluated area was musculoskeletal physiotherapy.Limitations
RCTs were not evaluated against CONSORT criteria.Conclusion and implications of key findings
Frequency of publication of RCTs in the journal Physiotherapy has increased over this time, mirroring trends in the wider medical literature. This highlights the predominance of some areas of research such as musculoskeletal and exercise-based research while other prominent areas such as neurology appear to be less researched. 相似文献7.
Purpose
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions.Methods
A literature search of Medline and PubMed was conducted (January 2000–October 2017) to identify recent reports of targeted drugs in EOC.Findings
A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection.Implications
The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. 相似文献8.
Xu Steven Xu Meletios A. Dimopoulos Pieter Sonneveld P. Joy Ho Andrew Belch Merav Leiba Marcelo Capra David Gomez Eva Medvedova Shinsuke Iida Chang-Ki Min Jordan Schecter Richard Jansson Liping Zhang Yu-Nien Sun Pamela L. Clemens 《Advances in therapy》2018,35(11):1859-1872
Introduction
Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.Methods
Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n?=?3), 4 mg/kg (n?=?3), 8 mg/kg (n?=?4), and 16 mg/kg (n?=?34). A total of 650 patients in EQUULEUS (n?=?128), POLLUX (n?=?282), and CASTOR (n?=?240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.Results
Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.Conclusion
These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.Funding
Janssen Research & Development.9.
Introduction
Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in ‘unfit’ (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.Methods
For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.Results
In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).Conclusion
G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.Funding
F. Hoffmann-La Roche Ltd.10.
Junlong Li Medha Sasane Jing Zhao Viviana Garcia Horton Pingkuan Zhang Marie Louise Ricculli Zheng-Yi Zhou James Signorovitch 《Advances in therapy》2018,35(7):1035-1048
Introduction
Due to the rarity of BRAF V600E mutation, no randomized study has compared the combination targeted therapy dabrafenib?+?trametinib with other second-line treatments for advanced or metastatic non-small-cell lung cancer (NSCLC). A network meta-analysis (NMA) was conducted to assess the comparative efficacy of treatments among patients with previously treated advanced or metastatic NSCLC.Methods
Randomized trials of dabrafenib?+?trametinib, docetaxel, erlotinib, nintedanib?+?docetaxel, nivolumab, pemetrexed, pembrolizumab, and best supportive care as second-line or above treatments for advanced or metastatic NSCLC identified in a systematic literature review were included in the NMA. Overall response rates (ORRs) and disease control rates (DCRs) were compared using logit models; progression-free survival (PFS) and overall survival (OS) were compared using fractional polynomial hazards models. Dabrafenib?+?trametinib was linked into the evidence network through a matching-adjusted indirect comparison versus nivolumab.Results
Ten trials met the inclusion criteria and were included in the NMA. Dabrafenib?+?trametinib, pembrolizumab, and nivolumab were associated with the highest odds of achieving overall response (12.2, 1.2, and 0.7 times higher, respectively, compared with docetaxel). Estimated DCR was higher for dabrafenib?+?trametinib, nintedanib?+?docetaxel, and pemetrexed compared with other treatments. Patients treated with dabrafenib?+?trametinib, nivolumab, and pembrolizumab had the lowest hazards of disease progression or death during follow-up (72, 61, and 29% lower hazard of progression at 6 months; 61, 48, and 46% lower hazard of death at 1 year, respectively, compared with docetaxel).Conclusion
Dabrafenib?+?trametinib, pembrolizumab, and nivolumab were associated with higher ORR and prolonged PFS and OS compared with chemotherapy in previously treated advanced or metastatic NSCLC.Funding
Novartis Pharmaceuticals Corporation.11.
Rahul P. Patel Jilson Jacob Mohammed Sedeeq Long Chiau Ming Troy Wanandy Syed Tabish R. Zaidi Gregory M. Peterson 《Clinical therapeutics》2018,40(4):664-667
Purpose
The aim was to investigate the stability of cefazolin in elastomeric infusion devices.Methods
Elastomeric devices (Infusor LV) that contain cefazolin (3 g/240 mL and 6 g/240 mL) were prepared and stored at 4°C for 72 hours and then at 35°C for 12 hours, followed by 25°C for 12 hours. An aliquot was withdrawn at predefined time points and analyzed for the concentration of cefazolin. Samples were also assessed for changes in pH, solution color, and particle content.Findings
Cefazolin retained acceptable chemical and physical stability over the studied storage period and conditions.Implications
These findings will allow the administration of cefazolin by the Infusor LV elastomeric device in the outpatient and remote settings. 相似文献12.
Purpose
The ability of sophisticated sensors and medical devices to monitor critical biomarkers has the potential to greatly advance precision medicine initiatives. A stakeholder event was organized to develop working models for the evolution of the field.Methods
A workshop devoted to the subject matter was held at the Tufts Clinical and Translational Science Institute involving clinicians, device developers, regulators, engineers, and scientists.Findings
Several areas for collaborative development were identified and interested teams offered resources for development of research programs.Implications
The diversity of relevant stakeholders presents a major opportunity and challenge in translational research. It is evident that the CTSI national network can take a leadership role in the rapidly advancing and potentially transformative field of digital biomarkers. 相似文献13.
Purpose
The decline of central nervous system (CNS) function is a hallmark characteristic of multiple sclerosis (MS) that can manifest as cognitive impairment. We believe that exercise represents a potential behavioral approach for counteracting the declines in CNS structure and associated function among persons with MS (ie, exercise as a countermeasure of CNS decline). This theory is important because disease-modifying drugs represent a first-line approach for modifying the immune system and its effects on the CNS, but these drugs do not generally demonstrate robust improvements in cognitive performance.Methods
To the best of our knowledge, this article presents the first argument positioning exercise as a countermeasure for CNS decline in MS.Finding
The reviewed research indicates a proliferating body of evidence describing physical fitness, physical activity, and exercise effects on cognitive performance and neuroimaging outcomes (ie, CNS functioning) in MS, with the consistent and strong association between cognitive performance and neuroimaging outcomes in this population as a backdrop.Implications
We further present a framework and future research directions for better positioning exercise as a possible neuroprotective behavior against declining CNS function in MS. 相似文献14.
Purpose
The American College of Physicians (ACP) published a set of guidelines on how to prevent fractures in men and women with low bone density or osteoporosis. As the population ages, the overall risk of fractures increases, thus burdening the health care system. These guidelines review current evidence for osteoporosis management, providing an update to the previous 2008 ACP’s guidelines.Methods
The ACP put forth 6 recommendations addressing the complexities in osteoporosis management based on evidence available through October 2016 with a focus on bisphosphonates, calcium, vitamin D, and estrogen. Evidence was graded according to recommended strength by using the ACP standard methods.Findings
The ACP recommends anti-osteoporosis therapy with 1 of 3 bisphosphonates (alendronate, risedronate, or zoledronic acid) or denosumab in patients with osteoporosis, while excluding anabolic therapies, and recommends against raloxifene. Although bisphosphonates are the mainstay of treatment, anabolic therapy and raloxifene may be used in specific situations. Pharmacologic therapy is recommended for 5 years, oversimplifying length of therapy and failing to promote an individualized patient-centered care approach. Moreover, abrupt discontinuation of denosumab is associated with a decline in bone mineral density (BMD), which must be addressed. Routine monitoring of BMD by dual x-ray absorptiometry is not endorsed during treatment, which leads to underrecognition of management issues. Pharmacologic treatment with bisphosphonates for male osteoporosis is recommended, although therapies such as denosumab and teriparatide are excluded. Finally, the ACP recommends treatment for women aged ≥65 years at high risk for fracture with osteopenia after a discussion of patient preferences, fracture risk profile, and medications.Implications
Osteoporosis management is complex. The 2017 ACP guidelines address challenges faced by clinicians but oversimplify more complex issues. These are among a number of guidelines that are available for osteoporosis management, which may be used in combination with other sources to assist clinicians with diagnostic and management strategies. 相似文献15.
Mohit Kumar Adam Chapman Saad Javed Uazman Alam Rayaz A Malik Shazli Azmi 《Clinical therapeutics》2018,40(6):850-861
Purpose
This review provides an update on the investigations and treatment options for gastroparesis.Methods
A comprehensive literature search of Medline, PubMed, Embase and OVID was conducted which included all systematic reviews and research articles that focused on the diagnosis, investigations and management diabetic gastroparesis.Findings
Dietary modifications and pharmacologic treatment with prokinetics to increase gastric motility form the mainstay of treatment. However, the use of prokinetics is limited by adverse effects and serious adverse effects, leaving metoclopramide as the only drug approved by the US Food and Drug Administration for the treatment of gastroparesis. Newer therapies, including motilin receptor agonists, ghrelin receptor agonists, and neurokinin receptor antagonists, are currently being investigated. Transpyloric stenting, gastric electrical stimulation, and gastric per-oral endoscopic myotomy provide mechanical options for intervention, and surgical interventions in severe intractable gastroparesis include laparoscopic pyloroplasty or gastrectomy.Implications
Advances to better understand the pathophysiology and management of diabetic gastroparesis have been limited, especially with discordance between symptoms and severity of delay in gastric emptying. Established treatment options are limited; however, recent pharmacologic and surgical interventions show promise. 相似文献16.
Xiawei Hu Jinlei Li Riyong Zhou Quanguang Wang Fangfang Xia Thomas Halaszynski Xuzhong Xu 《Clinical therapeutics》2017,39(1):89-97.e1
Purpose
A literature review of multiple clinical studies on mixing additives to improve pharmacologic limitation of local anesthetics during peripheral nerve blockade revealed inconsistency in success rates and various adverse effects. Animal research on dexmedetomidine as an adjuvant on the other hand has promising results, with evidence of minimum unwanted results. This randomized, double-blinded, contrastable observational study examined the efficacy of adding dexmedetomidine to a mixture of lidocaine plus ropivacaine during popliteal sciatic nerve blockade (PSNB).Methods
Sixty patients undergoing varicose saphenous vein resection using ultrasonography-guided PSNB along with femoral and obturator nerve blocks as surgical anesthesia were enrolled. All received standardized femoral and obturator nerve blocks, and the PSNB group was randomized to receive either 0.5 mL (50 µg) of dexmedetomidine (DL group) or 0.5 mL of saline (SL group) together with 2% lidocaine (9.5 mL) plus 0.75% ropovacaine (10 mL). Sensory onset and duration of lateral sural cutaneous nerve, sural nerve, superficial peroneal nerve, deep peroneal nerve, lateral plantar nerve, and medial plantar nerve were recorded. Motor onset and duration of tibial nerve and common peroneal nerve were also examined.Findings
Sensory onset of sural nerve, superficial peroneal nerve, lateral plantar nerve, and medial plantar nerve was significantly quicker in the DL group than in the SL group (P < 0.05). Sensory onset of lateral sural cutaneous nerve and deep peroneal nerve was not statistically different between the groups (P > 0.05). Motor onset of tibial nerve and common peroneal nerve was faster in the DL group than in in the SL group (P < 0.05). Duration of both sensory and motor blockade was significantly longer in the DL group than in the SL group (P < 0.05).Implications
Perineural dexmedetomidine added to lidocaine and ropivacaine enhanced efficacy of popliteal approach to sciatic nerve blockade with faster onset and longer duration. 相似文献17.
Yunona Khomitskaya Nadezhda Tikhonova Konstantin Gudkov Svetlana Erofeeva Victoria Holmes Brian Dayton Nigel Davies David W. Boulton Weifeng Tang 《Clinical therapeutics》2018,40(4):550-561.e3
Purpose
Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation.Methods
Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center. Pharmacokinetic parameters (AUC0–t, Cmax, and Cmax/AUC0–t) were used to assess bioequivalence of dapagliflozin/metformin XR (10/1000 mg) FCDP to the individual component tablets (dapagliflozin [10 mg] plus metformin XR [2 × 500 mg]) under standard fed conditions. Safety and tolerability were also assessed.Findings
Forty healthy subjects were included (47.5% male; mean age, 30 years; and mean body mass index, 24.2 kg/m2). Dapagliflozin and metformin XR in the FCDP were bioequivalent to the individual component tablets marketed in the Russian Federation, with the 90% CIs of the geometric least-squares mean ratios for all key pharmacokinetic parameters being contained within the 80% to 125% bioequivalence limits. Both FCDP and the individual component formulations were well tolerated, with no serious adverse events.Implications
Bioequivalence of dapagliflozin/metformin XR FCDP and the individual components was established without any new safety concerns, presenting a safe alternative for patients currently receiving regimens including each component individually. ClinicalTrials.gov identifier: NCT02722239. 相似文献18.
Purpose
The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns.Methods
Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case.Findings
The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million).Implications
For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees. 相似文献19.
Naomi C. Sacks Philip L. Cyr Arthur C. Louie Yanmei Liu Michael T. Chiarella Abhishek Sharma Karen C. Chung 《Clinical therapeutics》2018,40(5):692-703.e2
Purpose
Acute myeloid leukemia (AML) disproportionately affects older adults; the prognosis in this subpopulation is generally poor, with variable use of inpatient chemotherapy. This study characterizes treatment patterns, hospitalizations, and outcomes among older patients with AML.Methods
Using the Centers for Medicare & Medicaid Services' 2010–2012 100% Limited Data Set (LDS), data from all hospital claims from fee-for-service Medicare beneficiaries between 60 and 75 years of age with newly diagnosed AML and ≥1 hospitalization were analyzed.Findings
Among 3700 identified patients with AML, 1979 (53.5%) received chemotherapy. Hospitalization rates were highest initially and then declined over time, irrespective of chemotherapy use. The mean length of initial hospital stay was longer in patients receiving chemotherapy. Intensive care unit admissions occurred in 33% of initial hospitalizations. Factors associated with receiving chemotherapy included younger age, fewer comorbidities, and the absence of prior hematologic disorders. Chemotherapy was associated with significantly increased survival compared with no chemotherapy (P < 0.0001).Implications
AML in older patients is associated with frequent hospitalizations and intensive care unit admissions. New treatment options with more favorable risk-to-benefit profiles are needed in this population. 相似文献20.
Caridad Pontes Josep Ramon Marsal Josep Maria Elorza Maria Aragón Daniel Prieto-Alhambra Rosa Morros 《Clinical therapeutics》2018,40(2):270-283