Prevention of Dislocation After Total Hip Arthroplasty.

BACKGROUND: Prevention of dislocation after primary total hip arthroplasty (THA) begins with patient preoperative assessment and planning. METHODS: We performed a literature search to assess historical perspectives and current strategies to prevent dislocation after primary THA. The search yielded 3458 articles, and 154 articles are presented. RESULTS: Extremes of age, body mass index >30 kg/m2, lumbosacral pathology, surgeon experience, and femoral head size influence dislocation rates after THA. There is mixed evidence regarding the effect of neuromuscular disease, sequelae of pediatric hip conditions, and surgical approach on THA instability. Sex, simultaneous bilateral THA, and restrictive postoperative precautions do not influence the dislocation rates of THA. Navigation, robotics, lipped liners, and dual-mobility acetabular components may improve dislocation rates. CONCLUSIONS: Risks for dislocation should be identified, and measures should be taken to mitigate the risk. Reliance on safe zones of acetabular component positioning is historical. We are in an era of bespoke THA surgery.

Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome.

Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.

Role of the Whole Body Vibration Machine in the Prevention and Management of Osteoporosis in Old Age: A Systematic Review.

A literature search of related articles was carried out in electronic data sources. Initially, 276 randomised controlled trials related to the title were collected, after which 44 were selected using the keywords. Overlapping articles, articles with a study duration of less than six months, and studies involving young participants were removed from the list. The remaining 20 articles were checked for entitlement using the PEDro scale. A total of nine eligible articles with 1486 participants were analysed. Seven trials used dual-energy x-ray absorptiometry (DXA) to measure bone mineral density (BMD). The six trials published from 2005 to 2013 found a significant increase in BMD. In the remaining one trial, there was no significant increase in BMD. One study published in 2013 reported a significant increase in BMD measured with peripheral qualitative computed tomography, whereas another trial published in 2014 stated that there was a reduction in calcaneal bone density measured by peripheral qualitative ultrasound. From these findings it can be concluded that the whole body vibration machine is a good adjunctive therapy for the prevention and management of osteoporosis in postmenopausal women. However, further investigations are necessary before the same can be recommended for elderly men.

Highly sensitive method for the determination of JI-101, a multi-kinase inhibitor in human plasma and urine by LC-MS/MS-ESI: method validation and application to a clinical pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of JI-101 in human plasma and urine using LC-MS/MS-ESI in the positive-ion mode. The assay procedure involves extraction of JI-101 and alfuzosin (internal standard, IS) from human plasma/urine with a solid-phase extraction process. Chromatographic resolution was achieved on two Zorbax SB-C(18) columns connected in series with a PEEK coupler using an isocratic mobile phase comprising acetonitrile-0.1% formic acid in water (70:30, v/v). The total run time was 2.0 min. The MS/MS ion transitions monitored were 466.20 → 265.10 for JI-101 and 390.40 → 156.10 for IS. The method was subjected to rigorous validation procedures to cover the following: selectivity, sensitivity, matrix effect, recovery, precision, accuracy, stability and dilution effect. In both matrices the lower limit of quantitation was 10.0 ng/mL and the linearity range extended from ~10.0 to 1508 ng/mL in plasma or urine. The intra- and inter-day precisions were in the ranges 1.57-14.5 and 6.02-12.4% in plasma and 0.97-15.7 and 8.66-10.2% in urine. This method has been successfully applied for the characterization of JI-101 pharmacokinetics in cancer patients.

A CT-based classification of prior ACL femoral tunnel location for planning revision ACL surgery.

PURPOSE: The purposes of this study are to describe an ACL femoral tunnel classification system for use in planning revision ACL reconstruction based on 3-D computed tomography (CT) reconstructions and to evaluate its inter- and intra-rater reliability. METHODS: A femoral tunnel classification system was developed based on the location of the femoral tunnel relative to the lateral intercondylar ridge. The femoral tunnel was classified as Type I if it was located entirely below and posterior to the ridge as viewed from distally, Type II if it was slightly malpositioned (either vertically, anteriorly, or both), and Type III if it was significantly malpositioned. To evaluate the reproducibility of the classification system, CT scans of 27 knees were obtained from patients scheduled for revision ACL reconstruction, and 3-D reconstructions were created. Four views of the 3-D reconstruction of each femur were then obtained, and inter- and intra-observer reliability was determined following classification of the tunnels by eight observers. RESULTS: Twenty-five tunnels were classified as Type I (5 tunnels), Type II (9 tunnels), or type III (11 tunnels) by at least 5 of 8 observers, while insufficient agreement was noted to classify two tunnels. The interobserver reliability of tunnel classification as type I, II, or III yielded a κ coefficient of 0.57, while intra-observer reliability yielded a κ coefficient of 0.67. Subclassification of type II femoral tunnels into the subgroups anterior, vertical, and both was possible in four of the nine type II patients. The interobserver reliability of the complete classification system yielded a κ coefficient of 0.50, while the intra-observer reliability yielded a κ coefficient of 0.54. CONCLUSION: Classification of the location of ACL femoral tunnels utilizing 3-D reconstructions of CT data yields moderate to substantial inter- and intra-observer reliability. LEVEL OF EVIDENCE: Diagnostic Level III.

Development of lipid-based nanoparticles for enhancing the oral bioavailability of paclitaxel.

The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution, surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability studies were conducted in male Swiss albino mice after oral administration of PTX-SLNs. SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The mean particle size of SLNs was 96 ± 4.4 nm with a low polydispersity index of 0.162 ± 0.04 and zeta potential of 39.1 ± 0.8 mV. The drug entrapment efficiency was found to be 75.42 ± 1.5% with a loading capacity of 31.5 ± 2.1% (w/w). Paclitaxel showed a slow and sustained in vitro release profile and followed Higuchi kinetic equations. After oral administration of the PTX-SLNs, drug exposure in plasma and tissues was ten- and twofold higher, respectively, when compared with free paclitaxel solution. PTX-SLNs produced a high mean C (max) (10,274 ng/ml) compared with that of free paclitaxel solution (3,087 ng/ml). The absorbed drug was found to be distributed in liver, lungs, kidneys, spleen, and brain. The results suggested that PTX-SLNs dispersed in an aqueous environment are promising novel formulations that enhanced the oral bioavailability of hydrophobic drugs, like paclitaxel and were quite safe for oral delivery of paclitaxel as observed by in vivo toxicity studies.

Intraosseous device for arthrodesis in foot and ankle surgery: Review of the literature and biomechanical properties.

BACKGROUND: Arthrodesis is the surgical fusion of a diseased joint for the purposes of obtaining pain relief and stability. There have been numerous fixation devices described in literature for foot and ankle arthrodesis, each with their own benefits and drawbacks. AIM: To review the use of intraosseous devices in foot and ankle surgery. METHODS: There were 9 papers included in the review (6 clinical and 3 experimental studies) all evaluating arthrodesis in the foot and ankle using the IOFIX device (Extremity Medical™, Parsippany, NJ, United States). Outcome scores, union rates, as well as complications were analysed. RESULTS: IOFIX appears to be safe and effective in achieving arthrodesis of the 1st metatarsophalangeal, and talonavicular joints with early rehabilitation. In comparison to plate/screw constructs there were fewer soft tissue complications and issues of metalwork prominence. Cadaveric and biomechanical studies on the use of intramedullary fixation for fusion of the tarsometatarsal and ankle joint showed decreased load to failure, cycles to failure and stiffness in comparison to traditional fusion methods using plates and screws, however IOFIX devices produced higher compressive forces at the joint. CONCLUSION: We describe the reasons for which this biomechanical behavior of the intraosseous fixation may be favorable, until prospective and comparative studies with larger sample size and longer follow-up confirm the effectiveness and limitations of the method.

Management of limb length problems during total hip arthroplasty for patients with developmental dysplasia of the hip.

The anatomy of the acetabulum and femur is usually significantly altered in people with developmental dysplasia of the hip and this leads to secondary osteoarthritis of the hip joint. Ideal positioning of implants and reduction of the joint is technically demanding during arthroplasty. Lengthening may result in nerve palsies and therefore procedures may have to be undertaken to shorten the femur. Other complications include dislocation and non-union at the shortening osteotomy site. Thorough preoperative planning and templating is required before surgery to assess the need for shortening. Shortening osteotomies can be performed at the proximal femur, diaphysis or distal femoral levels, with subtrochanteric being the most common level. The procedure should be customised for each patient after extensive planning and detailed counselling.

Does Platelet-rich Plasma Augmentation Following Hip Arthroscopy Improve Outcomes: A Systematic Review.

Platelet-rich plasma (PRP) has gathered widespread acceptance among orthopaedic surgeons because of its multimodal effects on tissue healing. Varying results have been reported when PRP injections are combined with hip arthroscopic surgery. To evaluate the influence of PRP on clinical outcomes following hip arthroscopy. We hypothesized that patients treated with PRP would have improved postoperative outcome scores. A search of the National Institute for Health and Care Excellence (NICE) healthcare database advanced search (HDAS) via Athens (PubMed, MEDLINE, CINAHL, EMBASE, and AMED databases) was conducted from their years of inception to May 2018 with the keywords: "Hip Arthroscopy" and "Platelet-Rich Plasma". A quality assessment was performed based on the Cochrane risk of bias tool. Three studies were included for analysis; two of which had low risk of bias. The studies included 363 hips, of which 141 were randomised for PRP treatment. The mean age of all patients was 35 years and the follow-up ranged from 18.5 to 36 months. Authors used different PRP systems and preparations. Modified Harris hip score was reported in all three studies with two studies favouring the use of PRP. The use of PRP following hip arthroscopy did not lead to significantly improved postoperative pain or functional outcomes when compared to control groups in the studies included in this review.

Hematological Effects of Non-Homogenous Ionizing Radiation Exposure in a Non-Human Primate Model.

Detonation of a radiological or nuclear device in a major urban area will result in heterogenous radiation exposure, given to the significant shielding of the exposed population due to surrounding structures. Development of biodosimetry assays for triage and treatment requires knowledge of the radiation dose-volume effect for the bone marrow (BM). This proof-of-concept study was designed to quantify BM damage in the non-human primate (NHP) after exposure to one of four radiation patterns likely to occur in a radiological/nuclear attack with varying levels of BM sparing. Rhesus macaques (11 males, 12 females; 5.30-8.50 kg) were randomized by weight to one of four arms: 1. bilateral total-body irradiation (TBI); 2. unilateral TBI; 3. bilateral upper half-body irradiation (UHBI); and 4. bilateral lower half-body irradiation (LHBI). The match-point for UHBI vs. LHBI was set at 1 cm above the iliac crest. Animals were exposed to 4 Gy of 6 MV X rays. Peripheral blood samples were drawn 14 days preirradiation and at days 1, 3, 5, 7 and 14 postirradiation. Dosimetric measurements after irradiation indicated that dose to the mid-depth xiphoid was within 6% of the prescribed dose. No high-grade fever, weight loss >10%, dehydration or respiratory distress was observed. Animals in the bilateral- and unilateral TBI arms presented with hematologic changes [e.g., absolute neutrophil count (ANC) <500/ll; platelets <50,000/ll] and clinical signs/symptoms (e.g., petechiae, ecchymosis) characteristic of the acute radiation syndrome. Animals in the bilateral UHBI arm presented with myelosuppression; however, none of the animals developed severe neutropenia or thrombocytopenia (ANC remained >500/µl; platelets >50,000/µl during 14-day follow-up). In contrast, animals in the LHBI arm (1 cm above the ilieac crest to the toes) were protected against BM toxicity with no marked changes in hematological parameters and only minor gross pathology [petechiae (1/5), splenomegaly (1/5) and mild pulmonary hemorrhage (1/5)]. The model performed as expected with respect to the dose-volume effect of total versus partial-BM irradiation, e.g., increased shielding resulted in reduced BM toxicity. Shielding of the major blood-forming organs (e.g., skull, ribs, sternum, thoracic and lumbar spine) spared animals from bone marrow toxicity. These data suggest that the biological consequences of the absorbed dose are dependent on the total volume and pattern of radiation exposure.

Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis.

OBJECTIVES: Osteoporosis is a rapidly rising cause of concern for elderly patients. Various classes of drugs are available in the market. Bisphosphonates are considered as a first-line therapy for the prevention and treatment. Denosumab is an antiresorptive agent which is a RANK ligand inhibitor. There is a scarcity of comparison between these two classes of drugs. The aim of this study is to compare efficacy of Bisphosphonates and Denosumab in various parameters. METHODS: Literature search was done for randomized controlled trials (RCTs) comparing bisphosphonates with denosumab. RCTs with a treatment period of at least one year with a baseline bone mineral density (BMD) and bone turnover markers (BTM) and follow up values at one year were included in the study. All included studies were also analysed for complications. The study has also been registered in PROSPERO International prospective register of systematic reviews. RESULTS: A total of five RCTs were identified providing data on 3751 participants. In all five studies, the BMD changes at both hip and spine were statistically significant in favour of denosumab. Result was similar in three studies that studied BMD changes at the wrist. Denosumab also produced significant reduction in BTM as early as one month, but at one year there was no difference compared to the bisphosphonates. There was no statistically significant differences in the complication rates. CONCLUSIONS: Though both bisphosphonates and denosumab were effective with similar side effects, the latter was statistically superior in increasing the BMD and reducing the BTM.

Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model.

AIM: Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent. MATERIAL AND METHODS: DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats. RESULTS: RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900-9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P<0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats. CONCLUSIONS: The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.

RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes.

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC(50) values of 32, 31 and 39nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150-300 fold) and other proline-specific proteases (>200-2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/kg) in Wistar rats with the oral bioavailability (F(oral)) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.

Integration of physicochemical and pharmacokinetic parameters in lead optimization: a physiological pharmacokinetic model based approach.

There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug-like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization.

Enhanced expression of recombinant proteins utilizing a modified baculovirus expression vector.

The baculovirus expression vector system (BEVS) has been widely used for over-expressing eukaryotic proteins due to a close resemblance in post-translational modification, processing, and transportation properties of the expressed protein, to that of the mammalian cells. In comparison to the bacterial expression system, protein yield from BEVS is relatively low, resulting in higher cost of production. To improve the existing recombinant protein expression levels, baculovirus homologous region1 (hr1) was strategically integrated into the bacmid-based transfer vectors. Luciferase reporter, human Protein Kinase B-alpha (PKB-A), and N-terminal-modified CYP-1A2 genes were independently cloned in non-hr1 and hr1 constructs for generating respective bacmids and baculoviruses. These recombinant baculoviruses were utilized for comparing the expression levels at varying multiplicity of infections (MOI) and time intervals in Spodoptera frugiperda (Sf21) or Trichoplusia ni (Tni) insect cell lines. Targeted insertion of hr1 upstream to CYP-1A2, PKB-A, and Luciferase genes, compared to the non-hr1 sets, led to 3-, 3.5-, and 4.5-fold increase in the resultant protein levels, respectively. Moreover, at equal protein concentration, the corresponding activity and inhibition characteristics of these high expression hr1 sets were comparable to that of the respective non-hr1 sets. Utilization of this modified baculovirus expression construct offers significant advantage of producing recombinant proteins in a cost-effective manner for various biotechnological and therapeutic applications.

Simple method for the determination of rosiglitazone in human plasma using a commercially available internal standard.

To the best of our knowledge, bioanalytical methods to determine rosiglitazone in human plasma reported in literature use internal standards that are not commercially available. Our purpose was to develop a simple method for the determination of rosiglitazone in plasma employing a commercially available internal standard (IS). After the addition of celecoxib (IS), plasma (0.25 mL) samples were extracted into ethyl acetate. The residue after evaporation of the organic layer was dissolved in 750 microL of mobile phase and 50 microL was injected on to HPLC. The separation was achieved using a Hichrom KR 100, 250 x 4.6 mm C(18) with a mobile phase composition potassium dihydrogen phosphate buffer (0.01 m, pH 6.5):acetonitrile:methanol (40:50:10, v/v/v). The flow-rate of the mobile phase was set at 1 mL/min. The column eluate was monitored by fluorescence detector set at an excitation wavelength of 247 nm and emission wavelength of 367 nm. Linear relationships (r(2) > 0.99) were observed between the peak area ratio rosiglitazone to IS vs rosiglitazone concentrations across the concentration range 5-1000 ng/mL. The intra-run precision (%RSD) and accuracy (%Dev) in the measurement of rosiglitazone were <+/-10.69 and <-12.35%, respectively across the QC levels (50-1000 ng/mL). The extraction efficiency was >80% for both rosiglitazone and IS from human plasma. The lower limit of quantitation of the assay was 5 ng/mL. In summary, the methodology for rosiglitazone measurement in plasma was simple, sensitive and employed a commercially available IS.

HPLC method for the determination of rosiglitazone in human plasma and its application in a clinical pharmacokinetic study.

Rosiglitazone (CAS 155141-29-0, Avandia) is a novel insulin sensitizer used in the treatment of type 2 diabetes. A sensitive high performance liquid chromatography (HPLC) method for its determination in human plasma using fluorescence detection (excitation: 247 nm, emission: 367 nm) with a suitable internal standard (I. S.) is described. Ethyl acetate was used as extraction solvent. A mobile phase consisting of phosphate buffer, acetonitrile and methanol was used at a flow rate of 1.0 ml/min on a C18 column. The absolute recovery was > 90% and the lower limit of quantitation was 5 ng/ml. The intra- and inter-day relative standard deviations ranged from 0.58-6.69% and 0.82-6.63%, respectively. The method described is simple, economical, precise and accurate and has been successfully applied in a pharmacokinetic study conducted in healthy human volunteers.