Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo, and in vivo studies.

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first-pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 °C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3-200) showed a quasi-spherical shape (9-12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3-200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model (in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (Cmax = 58.07 ± 5.36 µg/g and AUCt (µg/h*g) = 105.76 ± 12.31) was noted within a short time (tmax = 1 h) compared to clozapine suspension administered by intravenous route (Cmax = 20.99 ± 3.91 µg/g, AUC t (µg/h*g) = 56.89 ± 12.31, and tmax = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapine-CDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose-to-brain delivery of clozapine for the effective treatment of schizophrenia.

In vitro and in vivo evaluation of cyclosporine-graphene oxide laden hydrogel contact lenses.

Drug-eluting contact lens can substitute the multiple eye drop therapy. However, loading hydrophobic drug like cyclosporine in the contact lens is very challenging, due to low drug uptake (via soaking method); and alteration in the swelling and optical properties which restricts its clinical application. To address the above issues, graphene oxide (GO, large surface area with oxygen containing functional groups) was incorporated in the contact lenses during fabrication. These GO-laden contact lenses (SM-GO-Cys) as well as blank contact lenses (SM-Cys) were soaked in the solution of cyclosporine. Alternatively, cyclosporine-laden contact lenses (DL-Cys-20) and cyclosporine-GO-laden contact lenses (DL-Cys-20-GO) were fabricated by adding drug and drug-GO (at various level of GO) during fabrication, respectively. Contact angle and swelling data showed increase in water holding capacity of GO laden contact lenses. Optical property was significantly improved due to molecular dispersion of drug on the surface of GO sheets. The drug uptake and in vitro release profile was improved with GO-laden contact lenses by soaking method (SM-GO-Cys-400n) due to hydrophobic interactions between GO and drug. Adding cyclosporine-GO (DL-Cys-20-GO-800n) during fabrication significantly improved drug release kinetics with higher drug leaching (during extraction and sterilization) due to increased swelling, improved dissolution and molecular dispersion of drug on GO sheets. Ocular irritation and histopathological studies demonstrated the safety of GO-contact lens. The in vivo drug release studies in the rabbit eye showed significant improvement in mean residence time (MRT) and area under the curve (AUC) using DL-Cys-20-GO-800n contact lens compared to eye drop solution with reduction in protein adherence value. The study demonstrated that the incorporation of GO into the contact lens can control the release of cyclosporine as well as improved the lens swelling and transmittance properties.

Proton pump inhibitors and osteoporosis risk: exploring the role of TRPM7 channel.

BACKGROUND: Long-term use of proton pump inhibitors (PPIs) has been linked to an increased risk of osteoporosis, with various indirect mechanisms so far identified. Although no direct underlying mechanism for effect on bone cells have been investigated with the use of PPIs. Melastatin-like transient receptor potential 7 (TRPM7)channel has been engaged in the proliferation of bone cells. TRPM7 channel is regulated by extracellular Mg2+ and Ca2+ level, that further encourages to analyse if any imbalance with pantoprazole usage could alter bone remodelling process mediated by TRPM7. OBJECTIVES: The present study was conducted to investigate the effect of pantoprazole on the calcium and magnesium level, the cations involved in the bone remodelling process, as well as role of the TRPM7 channel in the proliferation of bone cells. METHODS: A cytotoxicity study was carried out to study the effect of pantoprazole on the bone cell using MC3T3-E1 cell line, together with the expression of TRPM7 was determined post-pantoprazole treatment. An in vivo study in rats was carried out for estimation of Ca2+, Mg2+ and Ca2+/Mg2+ ratio as well as bone strength was measured over a duration of 4 weeks and 8 weeks with the treatment of pantoprazole. A pilot-scale clinical study was carried out in patients with a fracture to support the evidence of preliminary findings from in-vitro and in vivo studies. RESULTS: MC3T3-E1 cell line treated with pantoprazole showed decreased cell viability in a dose-dependent manner and reduced expression of TRPM7 channel, evidencing interaction of TRPM7 and pantoprazole in the bone remodelling process. A pilot study conducted on 12 patients having major fractures showed changes in serum Mg2+ and Ca2+ levels over a period of 1 month as well as the animal study also showed ionic imbalance over 8-week treatment with pantoprazole. Bone density measured for the patient at the end of the 1-month treatment was found to be in the osteopenic category, together with the animal study which showed a decrease in femur bone strength for the animal treated with pantoprazole over a period of 8 weeks. CONCLUSION: The study findings proved a negative impact of pantoprazole use on Ca2+ and Mg2+ levels, which can impact TRPM7-mediated bone remodelling which serves to be a possible mechanism for osteoporosis upon pantoprazole use.

Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies.

Clozapine is widely used to treat schizophrenia as an atypical antipsychotic. Low solubility, poor dissolution rate, degradation in the gastrointestinal tract, high hepatic first-pass metabolism, and eventually less drug transfer in the brain are all issues with oral clozapine administration. On account of this poor pharmacokinetic parameters, the authors aimed to develop clozapine nanosuspension using (+)-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinylpyrrolidone K-30 (PVP K-30) and deliver it through the intranasal route. The nanosuspension was prepared by the high-speed homogenization method with 32 full factorial design for optimization of the product. Quality Target Product Profile (QTPP) was enlisted before the product development. The amount of TPGS and speed of homogenizer were selected as independent variables whereas, particle size and drug permeation profile after 24 h (Y2, %) were selected as dependent variables. As per the results of optimization, amount of TPGS and speed of homogenizer were chosen as 0.1% and 7000 rpm, respectively. The particle size of the optimized nanosuspension of clozapine was found to be 281 nm. The conversion of clozapine crystals to an amorphous form was verified by characterization studies (XRD and DSC). The drug permeability study showed 96.15% and 41.12% clozapine release after 24 h from nanosuspension and conventional suspension, respectively. The study of nasal cilio-toxicity (histopathological studies) demonstrated the appropriateness of nanosuspension for intranasal purposes. The single-dose in vivo pharmacokinetic analysis in the rat model showed a substantial increase in the therapeutic concentration of clozapine in the brain tissue in the case of intranasal nanosuspension (dose = 0.05 mg drug/0.1 mL, Cmax = 8.62 ± 0.45 µg/g, tmax = 1 h) compared to conventional oral clozapine suspension (dose = 26.43 mg drug/0.158 mL, Cmax = 1.14 ± 0.12 µg/g, tmax = 1 h).Ultimately, in the case of an intranasal route, a 3.56-fold increase in brain drug concentration was observed with a 528-fold lower drug dose compared with oral administration. The results suggest that clozapine nanosuspension may be used for successful nose-to-brain delivery.

Aortic valve replacement via right minithoracotomy versus median sternotomy: a propensity score analysis.

OBJECTIVE: The aim of this study was to define the relative role of a right minithoracotomy (RT) versus standard median sternotomy (ST) for open aortic valve replacement (AVR). METHODS: A retrospective analysis was performed of all 1348 patients undergoing isolated, open AVR at a single institution during a 14-year period. Because relatively few patients were technically suitable for redo AVR with the RT approach (n = 20), all redo patients (n = 209) were excluded, leaving 1139 patients available for analysis. Patients converting from RT to ST approach (n = 15) were analyzed separately. RESULTS: Relative to ST (n = 672), the RT patients (n = 452) were older with more stenosis but with more recent operation year, lower rate of congestive heart failure, higher ejection fraction, lower rate of endocarditis, and lower rate of renal disease than the ST AVR patients (all P < 0.0001). Right minithoracotomy AVR was associated with longer cardiopulmonary bypass times [157 (25) vs 131 (38), P = 0.0004] and clamp times [103 (20) vs 85 (27), P < 0.0001] but less transfusion (1.4 vs 3.4 U, P = 0.0003), less chest tube output (405 vs 950 mL, P < 0.0001), fewer reoperations for bleeding (0.4% vs 4%, P < 0.0001), shorter length of stay (6 vs 8 days, P = 0.03), and lower rate of atrial fibrillation (15% vs 20%, P = 0.03). Stroke, operative mortality, and survival were not significantly different between the groups. CONCLUSIONS: Given the biases of retrospective propensity-adjusted analysis, these data suggest that RT AVR is a safe alternative to ST AVR in selected patients, with advantages of avoiding sternotomy with associated bleeding, transfusion, and delayed wound healing, at the expense of longer pump and clamp times.

Minithoracotomy versus sternotomy for mitral surgery in patients with chronic renal impairment: a propensity-matched study.

OBJECTIVE: Compared with median sternotomy, a right thoracotomy (RT) approach to mitral surgery is associated with decreased postoperative acute renal failure. Therefore, we examined propensity-matched patients with chronic renal impairment to compare outcomes. METHODS: A retrospective review at a single institution identified patients who underwent mitral valve surgery from 1986 to 2010. After excluding patients who had procedures that were not usually performed through an RT approach, 2306 patients were identified. Of this group, we found 446 patients with preoperative creatinines of 1.3 mg/dL or greater. Using propensity score matching based on comorbidities, operative year, and surgeon, 90 matched patients in each group were included. RESULTS: There was no difference in the median year of operation. Postoperative mortality is 20% lower for the RT group (P = 0.037) using Mantel-Cox statistics. This greater survival in the RT group occurred early within the first year and was maintained on long-term follow-up. The RT approach was also associated with a Cox proportional hazard for mortality of 0.528 (P = 0.006). Incidence of postoperative complications with an RT approach was lower in terms of acute renal failure (10% vs 21%, P = 0.05), stroke (1% vs 9%, P = 0.017), and permanent pacemaker insertion (3% vs 11%, P = 0.044). Right thoracotomy was associated with lower chest tube outputs (503 vs 1333 mL, P < 0.001). CONCLUSIONS: The RT approach was associated with lower postoperative mortality and morbidity in patients with impaired renal function. The RT approach to the mitral valve may be preferred in this high-risk population.

Minimally invasive edge-to-edge mitral repair with or without artificial chordae.

BACKGROUND: This study aims to analyze the midterm outcomes of minimally invasive edge-to-edge mitral valve repair (MVR) with artificial chords (CHORD) or without artificial chords (noCHORD) in patients with mitral regurgitation (MR). METHODS: Records of all patients undergoing edge-to-edge MVR through minithoracotomy at a single institution over a 7-year period were retrospectively reviewed. RESULTS: A total of 186 patients underwent edge-to-edge MVR through minithoracotomy. Disease etiology was posterior prolapse in 73 (39%) and bileaflet prolapse in 77 (41%). Edge-to-edge sutures were used at A1-P1 in 20 patients (11%), A2-P2 in 136 (73%), and A3-P3 in 30 (16%). Annuloplasty rings were placed in 184 patients (99%), with a mean size of 36±5 mm. Mean follow-up was 2 years (range, 0 to 6), with mean mitral gradient 4±2 mm Hg, MR mild or less in 179 of 186 (96%), 4 (2%) late reoperations, and 1 (0.5%) late death. The CHORD patients (n=71) were more likely than the noCHORD patients (n=115) to have extensive posterior leaflet pathology (p<0.01), had longer clamp and pump times (p<0.01) and were less likely to need leaflet resection (p=0.002), but had similar postoperative courses. At 3 years, freedom from moderate MR was less in CHORD versus noCHORD patients (88±6 versus 100%, p=0.001), but freedom from reoperation was similar (96%±3% versus 99%±1%, p=not significant). CONCLUSIONS: Early results suggest that edge-to-edge MVR can be safe and effective in patients with mitral regurgitation. Edge-to-edge MVR combined with artificial chordae may be useful in selected patients, but with some risk of recurrent moderate MR.

Comparison of need for operative therapy in patients with mitral valve prolapse involving both leaflets versus posterior leaflet only.

Mitral valve prolapse may involve 1 leaflet or 2 leaflets, yet management guidelines do not differentiate posterior leaflet (PML) from bileaflet (BML) prolapse. We hypothesized that patients with BML have a prolonged natural history with more severe atrial and ventricular enlargement but less severe mitral regurgitation (MR) compared to patients with PML. Patients with mitral valve prolapse undergoing mitral repair were identified and preoperative characteristics were recorded. Patients with predominant PML prolapse (n = 304) versus BML prolapse (n = 131) were identified based on preoperative echocardiographic and intraoperative findings. Timing of operation was based on standard guidelines. Despite being equally symptomatic, patients with BML differed significantly from those with PML in being younger (54 vs 60 years, p <0.0001), more likely to be women (51% vs 24%, p <0.0001), and having a larger valve (37 vs 32 mm, p <0.0001). Despite similar cardiac function and dimensions, patients with BML had less severe MR (24% vs 13% with <4+ MR, p = 0.01) and less severe pulmonary hypertension (14% vs 31%, p <0.0001) at time of operation. In conclusion, patients with BML often meet indications for mitral valve repair with similar cardiac enlargement but less MR than patients with PML prolapse. Patients with BML prolapse may benefit from timing mitral repair based more on symptomatic 3+ MR or cardiac enlargement and less on presence of severe MR.

Comparison of Minithoracotomy versus Sternotomy in 304 Consecutive Tricuspid Valve Operations.

OBJECTIVE: : The relative outcomes of sternotomy versus thoracotomy for tricuspid valve operation were examined over a 22-year period. METHODS: : Three hundred four consecutive patients undergoing tricuspid valve operation using right minithoracotomy (THORC group; n = 124) versus median sternotomy (STERN group; n = 180) between 1985 and 2007 were retrospectively analyzed. Minithoracotomy used a 6-cm incision with femoral venous cannulation and augmented venous return. Sternotomy patients undergoing aortic valve, coronary bypass, or other procedure not feasible through a right minithoracotomy were excluded. RESULTS: : Both groups were similar except that STERN patients had an earlier operative year. Combined mitral and tricuspid valve operation was performed in 70% (214/304) of patients. The tricuspid valve was repaired in 59% (180/304) of patients. Previous sternotomy was present in 56% (171/304) of patients. The mean cardiopulmonary bypass times were longer in the THORC group (216 vs. 167 minutes, P < 0.0001). THORC was associated with a lower 30-day mortality (2% vs. 11%, P = 0.007), less atrial fibrillation (18% vs. 34%, P = 0.0025), less renal failure (3% vs. 11%, P = 0.016), and shorter length of stay (11 vs. 15 days, P = 0.012), although these differences were less apparent in more recent years. Stroke (3% vs. 2%, P = 0.72), respiratory failure (7% vs. 31%, P = 0.06), and infection rates (11% vs. 16%, P = 0.25) were similar. Five-year survival was also similar (63% vs. 64%, P = 0.84). CONCLUSIONS: : Given the limitations of a large, retrospective experience, minithoracotomy versus sternotomy is associated with low short-term morbidity and mortality, with advantages of avoiding sternotomy and minimizing mediastinal dissection in an otherwise high-risk group of patients.

Aortic valve replacement through right minithoracotomy in 306 consecutive patients.

OBJECTIVE: To define the role and early results of aortic valve surgery through a right minithoracotomy. METHODS: A retrospective analysis was performed on 306 consecutive patients undergoing aortic valve replacement through an 8-cm right minithoracotomy in the second intercostal space. The initial experience was included. The right second and third ribs were detached from the sternum in most cases and repaired at the end of each case. Most operations were performed using anterograde and retrograde cardioplegic arrest with percutaneous femoral venous cannulation and direct aortic cannulation through the incision. Standard instruments were used with direct digital knot tying. RESULTS: Mean age was 65 ± 14 (range, 20-90) years. Aortic valve disease cause was calcific disease in 160 of 306 (52%) patients, bicuspid disease in 95 of 306 (31%) patients, and endocarditis in 9 of 306 (3%) patients. Previous cardiac surgery was present in 13 of 306 (4%) patients. Biologic prostheses were used in 240 of 306 (78%) patients. Median valve size was 23 mm. Mean clamp times and pump times were 103 ± 26 and 158 ± 35 minutes, respectively. Median postoperative length of stay was 5 days. Thirty-day mortality was found in 4 of 306 (1%) cases. There were no deep wound infections or mediastinitis. Stroke occurred in 5 of 306 (1.6%) patients, and new pacemaker required in 11 of 306 (4%) patients. Reoperation for bleeding occurred in 2 of 306 (1%) patients. Conversion to median sternotomy occurred in 15 of 306 (5%) patients caused by chest wall anatomy (n = 7), bleeding (n = 3), coronary disease (n = 2), or aortic disease (n = 3). Patients were allowed to return to driving or preoperative activity in 2 weeks. With a mean follow-up of 2.8 ± 2.2 years, one patient required reoperation for aortic root disease. CONCLUSIONS: Right minithoracotomy is a safe but limited alternative to sternotomy in isolated aortic valve replacement. This approach may be particularly valuable in some higher risk, elderly patients and opens options for a hybrid approach combined with percutaneous coronary angioplasty.

Transaortic endoclamp for mitral valve operation through right minithoracotomy in 369 patients.

OBJECTIVE: : The effects and benefits of a transaortic endoclamp for mitral valve operation through right minithoracotomy have not been established. METHODS: : The records were examined in 671 patients undergoing mitral valve operation using aortic cannulation through a 6-cm right minithoracotomy in the fourth intercostal space. The ascending aorta was cannulated with a 24-Fr cannula through a 12-mm port in the first intercostal space. The experience from 1998 to 2006 with aortic endoclamping (group A, N = 436) was compared with the experience from 2006 to 2009 with external aortic clamping (group B, N = 235). Aortic endoclamping was achieved with a 30 mL endoclamp introduced through the aortic cannula into the ascending aorta to provide aortic endoclamping, anterograde cardioplegia, and root venting. Percutaneous femoral venous cannulation was used. RESULTS: : Group A and group B had similar demographics. Endoclamp availability (group A) resulted in significantly less fibrillatory arrest (no clamping) in 67 of 436 (15%) versus 104 of 235 (44%) patients in group B (P = 0.001). In patients with aortic clamping, endoclamp (group A) versus external clamp (group B) was not a determinant of clamp time or pump time. Hospital and late outcomes were not different between groups. No patient complications could be attributed to the endoclamp. CONCLUSIONS: : Aortic endoclamping requires no more clamp or pump time than external clamping and can provide a more bloodless field than ventricular fibrillation without obstructing hardware. Aortic endoclamping is a safe alternative for mitral surgery through right minithoracotomy.

Results of 141 consecutive minimally invasive tricuspid valve operations: an 11-year experience.

BACKGROUND: Reports of minimally invasive tricuspid valve operations are rare. We reviewed our experience and results of tricuspid valve operation using mini-thoracotomy during an 11-year period. METHODS: Consecutive patients (n = 141) undergoing tricuspid valve operation using mini-thoracotomy were retrospectively analyzed. Access was through a 6-cm right thoracotomy and cardiopulmonary bypass was instituted by means of the femoral artery (n = 16) or ascending aorta (n = 125) with augmented venous return. In most cases, vacuum assist without caval occlusion and snaring the cavae was used to minimize mediastinal dissection. In all cases, the tricuspid valve operation was done with the heart unclamped, and the heart either beating or fibrillating. RESULTS: Seventy-three percent (103 of 141 patients) of the patients underwent combined mitral and tricuspid valve operations. The tricuspid valve was repaired instead of being replaced in 61% (86 of 141 patients). Previous sternotomy was present in 49% (69 of 141 patients). The average patient age was 64 years. Conversion rate to median sternotomy was only 3% (4 of 141 patients). The mean cardiopulmonary bypass time was 216 minutes. Thirty-day mortality was 2.1% (3 of 141 patients). Stroke occurred in 2.8% (4 of 141 patients), and reexploration for bleeding occurred in 5.6% (8 of 141 patients). The stroke rate was 3 of 16 patients (18.8%) using mini-thoracotomy through femoral cannulation versus 1 of 125 patients (0.8%) through aortic cannulation (p = 0.005). CONCLUSIONS: In this largest reported series of patients undergoing tricuspid valve operation, mini-thoracotomy provides excellent short-term morbidity and mortality in these high-risk patients while avoiding redo sternotomy with a low conversion rate. Mini-thoracotomy with aortic cannulation is an attractive alternative approach to the tricuspid valve, particularly in patients with previous sternotomy.

Early Results of Edge-to-Edge Alfieri Mitral Repair Via Right Mini-Thoracotomy in 68 Consecutive Patients.

OBJECTIVE: : To examine early outcomes of mitral valve repair using Alfieri repair via a right mini-thoracotomy approach. METHODS: : Records were examined in 68 consecutive patients undergoing Alfieri mitral repair via 6 cm right mini-thoracotomy. Most repairs were performed under cardioplegic arrest, using percutaneous femoral cannulation and direct aortic cannulation through the right first intercostal space. All patients without hypertrophic cardiomyopathy received rigid ring annuloplasty. The indications for Alfieri repair were extensive prolapse with ring size at least 30 mm. RESULTS: : Mean age was 56 ± 13 (range, 20-80). Mitral disease etiology was Barlow disease in 17 of 68 (25%) patients and myxomatous disease in 47 of 68 (69%). Concurrent procedures were performed in 29 of 68 (43%) patients. Median ring size was 34 mm. Despite extensive leaflet disease, 59 of 68 (87%) patients were repaired without leaflet resection. Chord pairs were inserted on the posterior leaflet in 18 of 68 (26%) patients and anterior leaflet in four patients. There were no 30-day or late deaths. Residual intraoperative mitral regurgitation was absent in 54 of 68 (79%) patients and trace in the remainder. Local echocardiography follow-up at a mean of 99 days showed median residual regurgitation to be trace. Only two patients developed moderate regurgitation. Mean mitral gradient at follow-up was 4 ± 2 mm Hg. Local follow-up showed 28 of 39 (72%) patients to be New York Heart Association class I. CONCLUSIONS: : An edge-to-edge Alfieri repair via mini-thoracotomy can provide excellent short-term results in selected patients with complex myxomatous mitral disease when minimizing the need for leaflet resection.