Standard of care for lipedema in the United States.

BACKGROUND: Lipedema is a loose connective tissue disease predominantly in women identified by increased nodular and fibrotic adipose tissue on the buttocks, hips and limbs that develops at times of hormone, weight and shape change including puberty, pregnancy, and menopause. Lipedema tissue may be very painful and can severely impair mobility. Non-lipedema obesity, lymphedema, venous disease, and hypermobile joints are comorbidities. Lipedema tissue is difficult to reduce by diet, exercise, or bariatric surgery. METHODS: This paper is a consensus guideline on lipedema written by a US committee following the Delphi Method. Consensus statements are rated for strength using the GRADE system. RESULTS: Eighty-five consensus statements outline lipedema pathophysiology, and medical, surgical, vascular, and other therapeutic recommendations. Future research topics are suggested. CONCLUSION: These guidelines improve the understanding of the loose connective tissue disease, lipedema, to advance our understanding towards early diagnosis, treatments, and ultimately a cure for affected individuals.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a ß-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants.

Relebactam is a novel class A and C ß-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals. Following single- or multiple-dose intravenous administration over 30 min, plasma relebactam concentrations declined biexponentially, with a terminal half-life (t1/2) ranging from 1.35 to 1.85 h independently of the dose. Exposures increased in a dose-proportional manner across the dose range. No clinically significant differences in pharmacokinetics between men and women, or between adult and elderly participants, were observed. Urine pharmacokinetics demonstrated that urinary excretion is the major route of relebactam elimination. No drug-drug interaction between relebactam and imipenem-cilastatin was observed, and the observed t1/2 values for relebactam, imipenem, and cilastatin were comparable, thus supporting coadministration. Relebactam administered alone or in combination with imipenem-cilastatin was well tolerated across the dose ranges studied. No serious adverse events or deaths were reported. The pharmacokinetic profile and favorable safety results supported q6h dosing of relebactam with imipenem-cilastatin in clinical treatment trials.

Use of a Small-Bore Needle Arthroscope to Diagnose Intra-Articular Knee Pathology: Comparison With Magnetic Resonance Imaging.

The use of arthroscopy for purely diagnostic purposes has been largely supplanted by noninvasive technologies, such as magnetic resonance imaging (MRI). The mi-eye+TM (Trice Medical) technology is a small-bore needle unit for in-office arthroscopy. We conducted a pilot study comparing the mi-eye⁺™ unit with MRI, using surgical arthroscopy as a gold-standard reference. We hypothesized that the mi-eye⁺™ needle arthroscope, which can be used in an office setting, would be equivalent to MRI for the diagnosis of intra-articular pathology of the knee. This prospective, multicenter, observational study was approved by the Institutional Review Board. There were 106 patients (53 males, 53 females) in the study. MRIs were interpreted by musculoskeletally trained radiologists. The study was conducted in the operating room using the mi-eye⁺™ device. The mi-eye⁺™ device findings were compared with the MRI findings within individual pathologies, and a "per-patient" analysis was performed to compare the arthroscopic findings with those of the mi-eye⁺™ and the MRI. Additionally, we identified all mi-eye⁺™ findings and MRI findings that exactly matched the surgical arthroscopy findings. The mi-eye⁺™ demonstrated complete accuracy of all pathologies for 97 (91.5%) of the 106 patients included in the study, whereas MRI demonstrated complete accuracy for 65 patients (61.3%) (P < .0001). All discrepancies between mi-eye⁺TM and arthroscopy were false-negative mi-eye⁺™ results, as the mi-eye⁺TM did not reveal some aspect of the knee's pathology for 9 patients. The mi-eye⁺™ was more sensitive than MRI in identifying meniscal tears (92.6% vs 77.8%; P = .0035) and more specific in diagnosing these tears (100% vs 41.7%; P < .0001). The mi-eye⁺™ device proved to be more sensitive and specific than MRI for intra-articular findings at time of knee arthroscopy. Certainly there are contraindications to using the mi-eye⁺™, and our results do not obviate the need for MRI, but our study did demonstrate that the mi-eye⁺™ needle arthroscope can safely provide excellent visualization of intra-articular knee pathology.

In vitro activity of MK-7655, a novel ß-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria.

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel ß-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

Quantitative determination of odanacatib in human plasma using liquid-liquid extraction followed by liquid chromatography-tandem mass spectrometry analysis.

Odanacatib (ODN, MK-0822) is an investigational drug under development for the treatment of osteoporosis. A quantitative LC/MS-MS methodology was developed and validated to determine ODN concentrations in human plasma, with a linear calibration range from 0.500 to 500ng/mL. Stable isotope (13)C(6)-labeled ODN was employed as the internal standard (IS). Sample preparation was based on liquid-liquid extraction of basified plasma with methyl t-butyl ether in a 96-well plate format. The extracted samples were analyzed on a liquid chromatography-tandem mass spectrometry system equipped with a turbo ion spray source. Chromatographic separation of the analyte and IS was achieved on a Phenomenex Luna C18 (50mm×2.0mm, 5µm) column. Ion pairs m/z 526→313 for the analyte and m/z 532→319 for the IS were monitored in positive ionization mode for MS detection. This methodology has been fully validated and proved to be rugged and reproducible. Intra- and inter-run variability was within 5.88%, with accuracy between 95.6 and 106% of the nominal concentrations. Analyte stability was evaluated under various sample preparation, analysis and storage conditions. This assay has been utilized to analyze human plasma samples obtained from phase I to III clinical trials.

Muscle contributions to support and progression during single-limb stance in crouch gait.

Pathological movement patterns like crouch gait are characterized by abnormal kinematics and muscle activations that alter how muscles support the body weight during walking. Individual muscles are often the target of interventions to improve crouch gait, yet the roles of individual muscles during crouch gait remain unknown. The goal of this study was to examine how muscles contribute to mass center accelerations and joint angular accelerations during single-limb stance in crouch gait, and compare these contributions to unimpaired gait. Subject-specific dynamic simulations were created for ten children who walked in a mild crouch gait and had no previous surgeries. The simulations were analyzed to determine the acceleration of the mass center and angular accelerations of the hip, knee, and ankle generated by individual muscles. The results of this analysis indicate that children walking in crouch gait have less passive skeletal support of body weight and utilize substantially higher muscle forces to walk than unimpaired individuals. Crouch gait relies on the same muscles as unimpaired gait to accelerate the mass center upward, including the soleus, vasti, gastrocnemius, gluteus medius, rectus femoris, and gluteus maximus. However, during crouch gait, these muscles are active throughout single-limb stance, in contrast to the modulation of muscle forces seen during single-limb stance in an unimpaired gait. Subjects walking in crouch gait rely more on proximal muscles, including the gluteus medius and hamstrings, to accelerate the mass center forward during single-limb stance than subjects with an unimpaired gait.

Cortical processing of respiratory occlusion stimuli in children with central hypoventilation syndrome.

RATIONALE: The ability of patients with central hypoventilation syndrome (CHS) to produce and process mechanoreceptor signals is unknown. OBJECTIVES: Children with CHS hypoventilate during sleep, although they generally breathe adequately during wakefulness. Previous studies suggest that they have compromised central integration of afferent stimuli, rather than abnormal sensors or receptors. Cortical integration of afferent mechanical stimuli caused by respiratory loading or upper airway occlusion can be tested by measuring respiratory-related evoked potentials (RREPs). We hypothesized that patients with CHS would have blunted RREP during both wakefulness and sleep. METHODS: RREPs were produced with multiple upper airway occlusions and were obtained during wakefulness, stage 2, slow-wave, and REM sleep. Ten patients with CHS and 20 control subjects participated in the study, which took place at the Children's Hospital of Philadelphia. Each patient was age- and sex-matched to two control subjects. Wakefulness data were collected from 9 patients and 18 control subjects. MEASUREMENTS AND MAIN RESULTS: During wakefulness, patients demonstrated reduced Nf and P300 responses compared with control subjects. During non-REM sleep, patients demonstrated a reduced N350 response. In REM sleep, patients had a later P2 response. CONCLUSIONS: CHS patients are able to produce cortical responses to mechanical load stimulation during both wakefulness and sleep; however, central integration of the afferent signal is disrupted during wakefulness, and responses during non-REM are damped relative to control subjects. The finding of differences between patients and control subjects during REM may be due to increased intrinsic excitatory inputs to the respiratory system in this state.

Effect of sleep stage on breathing in children with central hypoventilation.

The early literature suggests that hypoventilation in infants with congenital central hypoventilation syndrome (CHS) is less severe during rapid eye movement (REM) than during non-REM (NREM) sleep. However, this supposition has not been rigorously tested, and subjects older than infancy have not been studied. Given the differences in anatomy, physiology, and REM sleep distribution between infants and older children, and the reduced number of limb movements during REM sleep, we hypothesized that older subjects with CHS would have more severe hypoventilation during REM than NREM sleep. Nine subjects with CHS, aged (mean +/- SD) 13 +/- 7 yr, were studied. Spontaneous ventilation was evaluated by briefly disconnecting the ventilator under controlled circumstances. Arousal was common, occurring in 46% of REM vs. 38% of NREM trials [not significant (NS)]. Central apnea occurred during 31% of REM and 54% of NREM trials (NS). Although minute ventilation declined precipitously during both REM and NREM trials, hypoventilation was less severe during REM (drop in minute ventilation of 65 +/- 23%) than NREM (drop of 87 +/- 16%, P = 0.036). Despite large changes in gas exchange during trials, there was no significant change in heart rate during either REM or NREM sleep. We conclude that older patients with CHS frequently have arousal and central apnea, in addition to hypoventilation, when breathing spontaneously during sleep. The hypoventilation in CHS is more severe during NREM than REM sleep. We speculate that this may be due to increased excitatory inputs to the respiratory system during REM sleep.

Determination of sitagliptin in human urine and hemodialysate using turbulent flow online extraction and tandem mass spectrometry.

High turbulence liquid chromatography (HTLC, or turbulent flow online extraction) and tandem mass spectrometry (MS/MS) methods for the determination of sitagliptin in human urine and hemodialysate were developed and validated to support clinical studies. A narrow bore large particle size reversed-phase column (Cyclone, 50 mm x 1.0 mm, 60 microm) and a BDS Hypersil C18 column (30 mm x 2.1 mm, 3 microm) were used as extraction and analytical columns, respectively. For the urine assay, the LLOQ was 0.1 microg/ml, the linear calibration range was 0.1 to 50 microg/ml, the interday precision (R.S.D.%, n=5) was 2.3-6.5%, and the accuracy was 96.9-106% of the nominal value. For the urine quality control samples (QCs), the intraday precision (R.S.D.%, n=5) and accuracy were 1.8-2.6% and 96.2-106% of the nominal value, respectively. The interday precision (R.S.D.%) for 56 sets of urine QCs over a 6-month period varied from 3.8% to 5.5% and the accuracy from 102% to 105% of the nominal value. For the hemodialysate assay, the LLOQ was 0.01 ng/ml, the linear dynamic range was 0.01-5.0 ng/ml, the interday precision was 1.6-4.1%, and the accuracy was 89.8-104% of the nominal value. For hemodialysate QCs, the intraday precision and accuracy varied from 2.3% to 8.9% and from 99.8% to 111% of the nominal value, respectively. These results demonstrated that both methods are selective, accurate, precise, reproducible, and suitable for quantifying sitagliptin in hemodialysate and human urine samples.

Determination of a prostaglandin D2 antagonist and its acyl glucuronide metabolite in human plasma by high performance liquid chromatography with tandem mass spectrometric detection--a lack of MS/MS selectivity between a glucuronide conjugate and a phase I metabolite.

A method for the determination of a prostaglandin D(2) receptor antagonist (I, a compound being evaluated for the prevention of niacin induced flushing) and its acyl glucuronide metabolite (II) in human plasma is presented. The method utilized high performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection using an atmospheric pressure chemical ionization (APCI) interface operated in the positive ionization mode. The product ion was a radical cation generated via a homolytic bond cleavage. A chemical analog of the drug was used as internal standard (III). The acyl glucuronide metabolite (II) was detected using the same precursor-to-product ion transition used for the parent compound after chromatographic separation of I and II. Drug and metabolite were extracted using semi-automated, 96-well format solid phase extraction (SPE), and chromatography was performed using a reverse phase analytical column with an isocratic mobile phase. The chromatographic retention factor (k') of II was found to be highly sensitive to mobile phase formic acid concentration. An adjustment in mobile phase formic acid concentration improved the chromatographic separation between II and a mono-hydroxylated metabolite after an unexpected lack of MS/MS selectivity between the two molecules was observed. The dependence of retention factor on formic acid concentration (k' increased as formic acid concentration decreased) was thought to indicate polar interactions between II and the stationary phase. The stability of II in spiked human plasma was determined. The rate of hydrolysis back to parent compound was relatively low (approximately 0.1 and 0.5% per hour at room temperature and 4 degrees C, respectively) indicating that significant changes in analyte concentrations did not occur during sample processing. The concentration range of the assay was 10-2500 ng/mL for both drug and glucuronide metabolite.

Determination of a peptide-doxorubicin, prostate-specific antigen activated prodrug, and its active metabolites in human plasma using high-performance liquid chromatography with fluorescence detection. Stabilization of the peptide prodrug with EDTA.

A method for the determination of I, a peptide-doxorubicin conjugate that was evaluated for the treatment of prostate cancer, and two of its active metabolites, doxorubicin and leucine-doxorubicin is described. Blood samples were chilled immediately after being drawn in order to prevent ex vivo entry of the metabolites into red blood cells. EDTA (10 mg/ml final concentration) was used to prevent plasma-mediated degradation of the peptide portion of the prodrug. After the addition of internal standard, plasma was prepared for analysis using a C-8 solid-phase extraction column. In order to overcome secondary ionic interactions with the silica-based extraction column, the analytes were eluted with ammonium hydroxide in methanol. The extracts were evaporated to dryness, reconstituted, and assayed by step change, gradient, reverse phase HPLC with fluorescence detection. Two interfering metabolites found in post dose plasma were chromatographically separated by an adjustment of the mobile phase pH. The within-day reproducibility of the doxorubicin and leucine-doxorubicin chromatographic retention times was improved by a brief washing of the analytical column with 90% acetonitrile after each injection. The range of the standard curve was 12.5-1250 ng/ml for doxorubicin and 25-2500 ng/ml for I and leucine-doxorubicin.