Heart Transplantation for Adults With Congenital Heart Disease Can Be Performed at Adult or Pediatric Hospitals With Comparable Outcomes.

INTRODUCTION: The goal of this study was to evaluate the relationship between hospital-related factors and hospital type on outcomes of heart transplantation for patients with adult congenital heart disease (ACHD). METHODS: Patients with ACHD who underwent heart transplant between 2010 and 2021 were identified using the United Network for Organ Sharing data registry. The primary outcome was post-transplant mortality. Kaplan-Meier unadjusted survival curves were compared using the log-rank test. Multivariable Cox proportional hazard models were used for risk-adjustment in evaluating the independent effect of hospital type on post-transplant mortality. RESULTS: Of 70 centers, 54 (77.1%) adult centers performed 415 (87.0%) heart transplants and 16 (22.9%) pediatric centers performed 62 (13.0%) heart transplants. Patients transplanted at pediatric centers were younger, had lower creatinine levels, and had lower body mass index. The unadjusted 1-y and 5-y survival was comparable in pediatric versus adult centers, respectively: 93.4% versus 86.6% (log-rank P = 0.16) and 87.4% versus 73.9% (log-rank P = 0.06). These findings persisted after risk-adjustment. One-year mortality hazard ratio for pediatric hospitals: 0.64 (0.22-1.89, P = 0.416) and 5-y mortality hazard ratio for pediatric hospitals: 0.53 (0.21-1.33, P = 0.175). Rates of acute rejection, postoperative stroke, and new-onset postoperative dialysis were also comparable. CONCLUSIONS: Heart transplantation for patients with ACHD can be performed safely in adult centers. The majority of heart transplant for ACHD in the United States are performed at adult hospitals. However, further research is needed to delineate the impact of individual surgeon characteristics and hospital-related factors on outcomes.

Risk Factors for 1-Year Mortality After Heart Transplant in Obese Patients Bridged With an LVAD.

BACKGROUND: Heart transplantation is relatively contraindicated in morbidly obese patients because of increased morbidity and mortality. This study identified risk factors for post-heart transplantation mortality in obese patients with a left ventricular assist device (LVAD). METHODS: The United Network for Organ Sharing database was used to identify patients with a body mass index ≥35 kg/m2 who had a durable LVAD at the time of isolated heart transplantation between 2010 and 2021. The primary outcome was post-heart transplantation 1-year mortality. Multivariable Cox regression modeling was used to identify significant risk factors for 1-year mortality. Receiver-operating characteristic analyses were performed to identify optimal thresholds for continuous variables associated with the primary outcome. Patients were stratified by the number of risk factors, and Kaplan-Meier analysis was used to compare survival. RESULTS: A total of 1222 obese patients were bridged to heart transplantation with a durable LVAD. Six risk factors were identified as significantly associated with 1-year post-heart transplantation mortality: recipient age >62.5 years, body mass index >36.6 kg/m2, bilirubin level >0.95 mg/dL, cold ischemic time >3.7 hours, recipient-donor sex mismatch, and pretransplantation mechanical ventilation. The distribution of cumulative risk factors was as follows: 8.6% with 0, 30.6% with 1, 37.0% with 2, and 23.8% patients with ≥3 risk factors. The 1-year survival rate decreased significantly from 96.0% in those patients with 0 risk factors to 77.6% in those with 3 or more risk factors. CONCLUSIONS: These data provide a useful guide for risk stratification and patient selection in obese LVAD candidates being considered for heart transplantation.

Donor utilization in heart transplant with donation after circulatory death in the United States.

Heart transplantation using donation after circulatory death (DCD) was recently adopted in the United States. This study aimed to characterize organ yield from adult (≥18 years) DCD heart donors in the United States using the United Network for Organ Sharing registry. The registry does not identify potential donors who do not progress to circulatory death, and only those who progressed to death were included for analysis. Outcomes included organ recovery from the donor operating room and organ utilization for transplant. Multiple logistic regression was used to identify predictors of heart recovery and utilization. Among 558 DCD procurements, recovery occurred in 89.6%, and 92.5% of recovered hearts were utilized for transplant. Of 506 DCD procurements with available data, 65.0% were classified as direct procurement and perfusion and 35.0% were classified as normothermic regional perfusion (NRP). Logistic regression identified that NRP, shorter agonal time, younger donor age, and highest volume of organ procurement organizations were independently associated with increased odds for heart recovery. NRP independently predicted heart utilization after recovery. DCD heart utilization in the United States is satisfactory and consistent with international experience. NRP procurements have a higher yield for DCD heart transplantation compared with direct procurement and perfusion, which may reflect differences in donor assessment and acceptance criteria.

Waitlist and transplant outcomes in heart transplant candidates bridged with temporary endovascular right ventricular assist devices.

BACKGROUND: Advances in mechanical circulatory support and changes in allocation policy have shifted waitlisting practices for heart transplantation (HT) in the United States. This analysis reports waitlist and transplant outcomes among HT candidates bridged with temporary endovascular right ventricular assist devices (tRVADs). METHODS: Patients awaiting HT from 2008 to 2022 in the United Network of Organ Sharing registry were grouped by the presence of tRVAD while waitlisted and propensity matched. Waitlist outcomes were HT and a competing outcome of death/deterioration requiring waitlist inactivation. Competing-risks regression was used to model waitlist outcomes. Subanalyses were performed to compare waitlist outcomes among patients with durable and temporary left ventricular assist devices (LVADs) with and without concomitant tRVADs. One-year posttransplant mortality was estimated using Kaplan-Meier analysis. RESULTS: Of 41,507 HT candidates, 133 (0.3%) had tRVADs. After propensity matching, patients with tRVAD had a similar likelihood of HT and an elevated hazard for death/deterioration (hazard ratio 2.2, 95% confidence interval 1.4-3.2, p < 0.001) compared to those without tRVAD. Most patients with tRVAD (84%) had concomitant LVADs. tRVAD was associated with an elevated risk for deterioration/death among those with temporary LVADs but not durable LVADs. For patients undergoing HT, tRVAD was associated with an increased risk for 1-year mortality compared to propensity-matched recipients. CONCLUSIONS: Bridging with tRVAD is uncommon and primarily used in patients requiring biventricular support. tRVADs are associated with waitlist inactivation or death, particularly with concomitant temporary LVAD support. As temporary devices are increasingly used as a bridge to HT, outcomes of patients with tRVADs should inform future allocation policy, particularly for candidates with biventricular failure.

Reverse Offset Printed, Biocompatible Temperature Sensor Based on Dark Muscovado.

A reverse-offset printed temperature sensor based on interdigitated electrodes (IDTs) has been investigated in this study. Silver nanoparticles (AgNPs) were printed on a glass slide in an IDT pattern by reverse-offset printer. The sensing layer consisted of a sucrose film obtained by spin coating the sucrose solution on the IDTs. The temperature sensor demonstrated a negative temperature coefficient (NTC) with an exponential decrease in resistance as the temperature increased. This trend is the characteristic of a NTC thermistor. There is an overall change of ~2800 kΩ for the temperature change of 0 °C to 100 °C. The thermistor is based on a unique temperature sensor using a naturally occurring biocompatible material, i.e., sucrose. The active sensing material of the thermistor, i.e., sucrose used in the experiments was obtained from extract of Muscovado. Our temperature sensor has potential in the biomedical and food industries where environmentally friendly and biocompatible materials are more suitable for sensing accurately and reliably.

Flow Behavior of AA5005 Alloy at High Temperature and Low Strain Rate Based on Arrhenius-Type Equation and Back Propagation Artificial Neural Network (BP-ANN) Model.

To realize the purpose of energy saving, materials with high weight are replaced by low-weight materials with eligible mechanical properties in all kinds of fields. Therefore, conducting research works on lightweight materials under specified work conditions is extremely important and profound. To understand the relationship of aluminum alloy AA5005 among flow stress, true strain, strain rate, and deformation temperature, hot isothermal tensile tests were conducted within the strain rate range 0.0003-0.03 s-1 and temperature range 633-773 K. Based on the true stress-true strain curves obtained from the experiment, a traditional constitutive regression Arrhenius-type equation was utilized to regress flow behaviors. Meanwhile, the Arrhenius-type equation was optimized by a sixth-order polynomial function for compensating strain. Thereafter, a back propagation artificial neural network (BP-ANN) model based on supervised machine learning was also employed to regress and predict flow stress in diverse deform conditions. Ultimately, by introducing statistical analyses correlation coefficient (R2), average absolute relative error (AARE), and relative error (δ) to the comparative study, it was found that the Arrhenius-type equation will lose accuracy in cases of high stress. Additionally, owning higher R2, lower AARE, and more concentrative δ value distribution, the BP-ANN model is superior in regressing and predicting than the Arrhenius-type constitutive equation.

Optimization of Forming Parameters in Incremental Sheet Forming of AA3003-H18 Sheets Using Taguchi Method.

The surface finish is an important characteristic in the incremental sheet forming (ISF) process and is often influenced by numerous factors within the forming process. Therefore, this research was aimed at identifying the optimal forming parameters through the Taguchi method to produce high-quality formed products. The forming tool radius, spindle speed, vertical step increment, and feed rate were chosen as forming parameters in the experimental design, with surface roughness as the response variable. Taguchi L16 orthogonal array design and analysis of variance (ANOVA) test were used to identify the parameter's optimal settings and examine the statistically significant parameters on the response, respectively. Results confirmed that a significant reduction in surface roughness occurred with a drop in vertical step size and an increase in feed rate. In detail, the vertical step size has the most significant influence on the surface roughness, followed by the feed rate and the forming tool radius. In conclusion, the optimum level settings were obtained: forming tool radius at level 3, spindle speed at level 1, vertical step size at level 1, and feed rate at level 4. Additionally, confirmation experiment results based on the optimal settings indicated a good agreement against the experimental observation. Further, the response surface methodology (RSM) was also exploited to devise a mathematical model for predicting the surface roughness. The results comparison confirmed that both techniques could effectively improvise the surface finish.

Patent Ductus Arteriosus Stenting for All Ductal-Dependent Cyanotic Infants: Waning Use of Blalock-Taussig Shunts.

[Figure: see text].

Bronchus compression relieved by patent ductus arteriosus stenting.

BACKGROUND: Patent ductus arteriosus (PDA) stenting is evolving as an alternative to surgical aorto-pulmonary shunts for infants with ductal-dependent pulmonary blood flow. Given anatomical proximity, the PDA can compress the ipsilateral bronchus. We report a case series of four patients with bronchial compression by a tortuous PDA who underwent PDA stenting. METHODS: Our four patients received PDA stents for ductal-dependent pulmonary blood flow despite preprocedure imaging evidence of bronchial compression. We reviewed the cross-sectional chest imaging to assess the degree of bronchial compression and the variables that affect it, namely PDA size, PDA tortuosity, and the anatomical relationship between the compressed bronchus and the PDA. RESULTS: Three out of the four patients had postprocedure imaging, and all showed relief of the previously seen bronchial compression. Post-PDA stenting patients had a smaller and straight PDA with significant lateralization away from the compressed bronchus. None of the four patients developed symptoms of bronchial compression poststenting. CONCLUSIONS: Our study suggests that pre-existing bronchial compression does not preclude PDA stenting. Stent placement in an engorged and tortuous PDA led to significant improvement in pre-existing bronchial compression. Improvement may be attributed to PDA shrinkage, straightening, and lateralization. Further studies are needed to confirm our findings.

Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats.

Synthetic parathyroid hormone (PTH) is clinically indicated for the treatment of osteoporosis, through its anabolic effects on parathyroid hormone receptors (PTHRs), located on osteoblast cells. However, the bioavailability of PTH for bone cells is restricted by the short half-life of PTH and the widespread distribution of PTHRs in non-skeletal tissues. To impart affinity for mineralized bone surfaces, bisphosphonate (BP)-mediated PTH analogues were synthesized, characterized, and evaluated in vitro and in vivo. The successful synthesis of PTH-PEG-BP was identified on MALDI-ToF mass spectra; bone-targeting potential was evaluated by hydroxyapatite binding test; and receptor bioactivity was assessed in UMR-106 (rat osteosarcoma) cells that constitutively express PTHRs. Therapeutic efficacy was evaluated using ovariectomized rats that remained untreated for 8 weeks to allow development of osteopenia. Those rats then received daily subcutaneous injections of PTH-PEG-BP, thiol-BP vehicle, or unmodified PTH, and compared to sham-operated healthy rats at 0, 4, 8, 12, and 16 weeks. In vivo micro-CT was conducted on the proximal tibial metaphysis to measure microstructural bone parameters, and new bone formation was detected using dynamic labeling. Bone strength was assessed using three-point bending mechanical testing. Our study determined that PTH-PEG-BP conjugates significantly enhanced PTH targeting to the bone matrix while retaining full PTH bioactivity. Moreover, PTH-PEG-BP conjugates significantly increased trabecular bone quality, anabolic bone formation, and improved bone strength over systemically administered PTH alone. We highlight the promise of a novel class of bone-targeting anabolic compound for the treatment of osteoporosis and related bone disorders.

Evaluation of bone targeting salmon calcitonin analogues in rats developing osteoporosis and adjuvant arthritis.

Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant (P<0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with 20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase (P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21 days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis, and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.

Expression, characterization, and evaluation of a RANK-binding single chain fraction variable: an osteoclast targeting drug delivery strategy.

A single chain Fraction variable (scFv) employs antibody-like target recognition specificity. Osteoclasts, responsible for bone resorption, express Receptor Activator of Nuclear factor Kappa B (RANK) receptors. This study aimed to express, characterize, and evaluate scFv against RANK receptors that may serve as a platform to target osteoclasts. Using phage display technology, scFv against RANK receptor was expressed and characterized by DNA sequencing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption-ionization time-of-flight (MALDI TOF), enzyme-linked immunosorbent assay (ELISA), Western blot, and immunocytochemistry. The potential for cytotoxicity was evaluated using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, and its cross reactivity was evaluated using ELISA. Osteoclast-like cells were generated from RAW 264.7 cells, and the osteoclast targeting ability of scFv was evaluated using immunocytochemistry. ScFv's antiresorptive efficacy was studied using a tartrate-resistant acid phosphatase (TRAP) assay and resorption assay. Anti-RANK scFv was successfully expressed and characterized. No cross reactivity with other tumor necrosis factor receptor (TNFR) members and no cytotoxic effect on a non-RANK bearing cell line were observed. It showed specificity toward a RANK receptor and an inhibitory effect on osteoclast activity. With the increase in development trends for biologics as therapeutics and growing knowledge on the importance of osteoclast targeted therapy, this study may provide a drug delivery strategy to target osteoclasts, thereby leading to a promising therapy for resorptive bone diseases.

Synthesis, characterization and biodistribution studies of (125)I-radioiodinated di-PEGylated bone targeting salmon calcitonin analogue in healthy rats.

PURPOSE: The objective of this study was to prepare a bisphosphonate (BP) mediated bone targeting di-PEGylated salmon calcitonin analogue sCT-2(PEG-BP) as a novel bone targeting pharmaceutical. METHODS: HPLC was used for isolation of sCT-2(PEG-BP) from the reaction mixture, followed by determination of possible PEGylation sites by trypsin digestion. Stability of the compound over time, bone mineral affinity using hydroxyapatite, and biodistribution in normal rats after radiolabeling of sCT-2(PEG-BP) or control sCT with (125)I was evaluated. RESULTS: PEGylated sCT analogues were synthesized, and sCT-2(PEG-BP) was isolated by HPLC and confirmed by MALDI-TOF and ICP-MS. MALDI-TOF analysis of trypsinized fragments suggested Cys(1) (or Lys(11)) and Lys(18) to be the two PEGylation sites. Bone mineral affinity test showed sCT-2(PEG-BP) or (125)I-sCT-2(PEG-BP) exhibited significantly increased bone mineral affinity over sCT or (125)I-sCT, respectively. sCT-2(PEG-BP) remained stable for at least 1 month. In vivo biodistribution study showed significantly increased bone retention and prolonged plasma circulation time for sCT-2(PEG-BP) compared to the control sCT. CONCLUSION: Those results support sCT-2(PEG-BP) as a promising new drug candidate for the treatment of resorptive and/or maladaptive bone conditions, such as Osteoporosis, Osteoarthritis, Rheumatoid Arthritis, Paget's disease and bone cancers.

Synthesis, characterization and evaluation of bone targeting salmon calcitonin analogs in normal and osteoporotic rats.

In order to assess the therapeutic efficacy of an antiresorptive drug with imparted bone targeting potential using bisphosphonate (BP) conjugation and an improved pharmacokinetic profile using PEGylation, we synthesized, characterized and evaluated in vivo efficacy of bone-targeting PEGylated salmon calcitonin (sCT) analog (sCT-PEG-BP). sCT-PEG-BP was compared with non-PEGylated bone targeting sCT analog (sCT-BP) and unmodified, commercially available sCT. sCT-PEG-BP conjugates were characterized by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) analysis. The effect of PEG-BP or BP upon sCT secondary structure was examined by Circular Dichroism and sCT-PEG-BP was evaluated for in vitro bone mineral Hydroxyapatite (HA) binding ability and calcium salts specificity using a binding assay for bone HA and several calcium salts. Anti-calcitonin antibody binding ability of these analogs was determined using enzyme-linked immunosorbent assay (ELISA), by reacting bone targeting sCT analogs with calcium phosphate coated Osteologic® plates and detecting the bound sCT using anti-sCT antibody. Potential cytotoxicity of these compounds was evaluated in monocytic RAW 264.7 cells, and sCT bioactivity was evaluated using an in vitro intracellular cAMP stimulation assay in human T47D breast cancer cells. Finally, in vivo efficacy of each compound was evaluated by determining the plasma levels of calcium after s.c. administration in normal rats, and in a rat model of Osteoporosis, secondary to ovariectomy (OVX). In vivo micro-computed tomography (micro-CT) was used to temporally map and quantify alterations in bone volume and bone mineral density (BMD) in the same animals at 1, 4, 8 and 12 weeks after OVX surgery. Sixteen 6 week old virgin female rats underwent OVX surgery followed by the daily s.c. injection of 2.5IU/kg/day sCT or equivalent analogs, and compared to four sham-operated, placebo treated control rats. Our results showed the chemical coupling of PEG-BP or BP to sCT altered its secondary structure without altering its antibody binding ability. sCT analogs retained strong sCT bioactivity, were non-toxic to RAW 264.7 cells in culture and elicited a comparable hypocalcemic effect to that of unmodified sCT in normal rats. Compared to marketed unmodified sCT, sCT-PEG-BP showed significantly improved efficacy in terms of preserving bone volume, BMD and trabecular micro-architecture in osteoporotic rats at the initial dose tested. Bisphosphonate-mediated targeting of PEGylated sCT to bone represents a new class of targeted antiresorptive compounds that has not previously been attempted.

Antibody-mediated "universal" osteoclast targeting platform using calcitonin as a model drug.

PURPOSE: To generate and characterize a specific monoclonal antibody (mAb) against recombinant human RANK receptor and to develop an antiresorptive strategy using this mAb as an osteoclast-targeting platform that selectively targets osteoclast cells whilst delivering an attached (i.e. chemically conjugated) active drug cargo. METHODS: Using hybridoma technology, we generated a specific monoclonal antibody (mAb) against recombinant human RANK receptor and characterized by SDS PAGE, ELISA, Western Blot and immunocytochemistry, then synthesized osteoclast-targeting bioconjugates of salmon calcitonin (sCT) using this antibody by generating thiol groups on mAb using 2-Iminothiolane and subsequently reacting them with sCT-PEG-MAL synthesised from sCT and NHS-PEG-MAL. To test the efficacy of the conjugate in vitro, osteoclasts were generated from precursor RAW 264.7 cells by dosing with the cytokines macrophage-colony-stimulating factor (M-CSF), and RANK Ligand (RANKL) and TRAP activity assay, Resorption Pit Assay, TRAP staining were performed. Cytotoxicity of the mAb-sCT conjugate was also evaluated in RAW 264.7 cells; sCT bioactivity and CTR binding potential were evaluated by in vitro intracellular cAMP stimulation assay in human T47D breast cancer cells. RESULTS: Generation of antibody against human RANK receptor was confirmed by SDS PAGE, ELISA and Western Blot. Immunocytochemistry confirmed the osteoclast targeting potential of the antibody. Successful conjugation of the antibody with sCT was confirmed by SDS PAGE and ELISA.Multinucleated osteoclast formation was confirmed by staining for tartrate-resistant acid phosphatase (TRAP). Conjugate functionality was confirmed by TRAP activity and Resorption Pit assay, showing the inhibitory effect on osteoclast differentiation. cAMP assay confirmed the retention of calcitonin bioactivity after conjugation. CONCLUSIONS: Our strategy offers the potential for a "universal" osteoclast-targeting platform--one that targets the RANK receptor on osteoclast cells by simply altering the conjugated cargo in order to affect the specific regulation of osteoclast cells.

Synthesis, characterization and in vitro evaluation of a bone targeting delivery system for salmon calcitonin.

Synthetic salmon Calcitonin (sCT) is currently used to treat and manage conditions associated with low bone mass, and elicits its antiresorptive effect by acting upon Calcitonin receptors (CTRs) located on bone-resorbing osteoclast cells. However, CTRs are also widely distributed in many non-skeletal tissues (such as kidney, brain, and lung), and the competitive uptake of available sCT amongst such CTRs likely reduces sCT availability for bone resident osteoclast cells, particularly if the drug is administered systemically and not specifically targeted to bone. Hence, the objective of this study was to synthesize and characterize a bisphosphonate (BP)-mediated bone targeting delivery system for sCT and to determine whether the bioactivity of sCT was retained after BP conjugation. BP-sCT conjugates were synthesized by initially reacting sCT with sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate (sulfo-SMCC) in dimethyl formamide in the presence of triethylamine (TEA) at room temperature. Thiolated (Thiol)-BP was then reacted with the sCT-sulfo-SMCC conjugates to generate sCT-BP conjugates, which were purified by dialysis and assayed using the micro-BCA protein assay. Non-BP containing control sCT-Cysteine conjugates were also synthesized using the same procedure. Reactions were monitored and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF) analysis and Tris-Tricine SDS-PAGE. Conjugates were evaluated for in vitro bone mineral affinity using a hydroxyapatite binding test, for bone mineral specificity using different calcium salt binding affinity assays, and for continued sCT bioactivity after conjugation using an intracellular cAMP stimulation in human T47D breast cancer cells. Our results confirmed that BP-conjugated sCT exhibited significantly greater affinity and specificity for bone mineral over unmodified sCT, and that sCT-BP conjugates retained strong CT bioactivity after conjugation. Our conjugation strategy holds the promise of facilitating the delivery of sCT preferentially to skeletal bony tissues, thereby increasing its local concentration to bone surfaces. This peptide hormone-bisphosphonate drug system represents a new class of antiresorptive drug that has not previously been attempted, nor has a bone targeting formulation of sCT been reported.

Enhanced dissolution of ibuprofen using solid dispersion with poloxamer 407.

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility, and in-vitro ibuprofen release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Comparison of the enhanced solubility, dissolution, AUC, and C(max) of ibuprofen from different poloxamers suggested that the preparation of ibuprofen SDs using P 407 as a meltable hydrophilic polymer carrier could be a promising approach to improve its solubility, dissolution and absorption rate.

Preparation and evaluation of fast dissolving ibuprofen-polyethylene glycol 6000 solid dispersions.

To improve its oral absorption, rapidly dissolving ibuprofen solid dispersions (SD) were prepared in a relatively easy, simple, quick, inexpensive, and reproducible manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). They were evaluated for solubility, in vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. However, no such interactions in the solid state were confirmed by FTIR spectra that showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast-dissolving ibuprofen SDs by low temperature melting method using PEG 6000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.

Enhanced dissolution of ibuprofen using solid dispersion with polyethylene glycol 20000.

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility and in vitro drug release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting toward the lower melting temperature of the drug peak in SDs in DSC study indicated the possibilities of drug-polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low-temperature melting method using polyethylene glycol 20000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution, and absorption rate of ibuprofen.

Preparation and evaluation of immediate release ibuprofen solid dispersions using polyethylene glycol 4000.

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), and evaluated for solubility, in-vitro drug release and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FT-IR spectra showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and Cmax, and a significant decrease in Tmax over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low temperature melting method using polyethylene glycol 4000 (PEG 4000) as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and absorption rate of ibuprofen.