Formulation, Pharmacokinetics evaluation, and IVIVC Assessment of Gliclazide Multiparticulates in Rat Model.

In vitro and in vivo studies of gliclazide (GLZ)-loaded freeze-dried alginate-gelatin (AL-GL) beads were carried out, aiming to modify its oral bioavailability. Crosslinked freeze-dried GLZ AL-GL beads (particle size: 1.5- and 3.0-mm) were prepared. In vitro evaluation of GLZ AL-GL beads included SEM, DSC, FT-IR, and release rate study in gradient media. In vivo study was single-dose (4 mg/kg), randomized, parallel-group design, two-treatment (T: test GLZ AL-GL beads and R: reference product Diamicron® 30-mg MR tablet) conducted in 96 healthy rats. Each group was subdivided into 2 sub-groups (G1 and G2) having different blood sampling schemes for up to 72 h. Assessment of level A in-vitro-in-vivo correlation (IVIVC) model was carried out. AL-GL beads successfully increased GLZ release rate compared to R. GLZ percent released (Q4h) was 109.34, 86.85, and 43.43% for 1.5-mm and 3.0-mm beads and R, respectively. DSC analysis confirmed the interaction of AL-GL via crosslinking. No chemical interaction of GLZ has occurred as proved by FT-IR. Relative bioavailability (T/R) for AUC0-∞ was 132.45% for G1 and 146.16% for G2. No significant differences between T and R in the primary pharmacokinetic parameters were determined. Tmax values were found to be earlier in the case of G1 than those of G2. A secondary absorption peak of GLZ was clearly detected in the case of R while its sharpness was minimized in T. High IVIVC was established, and hence, the proposed in vitro release model perfectly correlated with the in vivo study. The current study design might be a platform to enable panoramic view for GLZ variability in vivo.

Neuroprotective activity of Ulmus pumila L. in Alzheimer's disease in rats; role of neurotrophic factors.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders which affects the hippocampus and cortical neurons leading to impairment of cognitive ability. Treatment of AD depends mainly on acetylcholinesterase inhibitors, however, a novel therapeutic approach is introduced based on the maintenance of neuronal viability and functionality exerted through neurotrophic factors. In the current study, Ulmus pumila L. leaves alcoholic extract was investigated for its neuroprotective activity in AlCl3-induced AD in rats. Rats were orally treated with AlCl3 (17 mg/kg) for 4 weeks followed by U. pumila extract (150 mg/kg b.wt.) for another 6 weeks. Treatment of neuro-intoxicated rats with U. pumila extract resulted in a significant regulation in neurotrophic factors; brain derived neurotrophic factor and transforming growth factor-ß and pro-inflammatory cytokine; TNF. It also induced an elevation in serum levels of monoamine neurotransmitters; norepinephrine, dopamine and serotonin and a decline in brain acetlycholinesterase activity. U. pumila extract also showed potent antioxidant activity as indicated by the declined malondialdehyde and elevated reduced glutathione, catalase and super oxide dismutase levels in AD rats' brains. Histological improvement was detected in the cerebral cortex, the hippocampus and striatum of the treated rats. The phytochemical analysis of U. pumila extract revealed high contents of flavonoids and phenolics and the major compounds were isolated and chemically characterized. Additionally, U. pumila extract and the isolated compounds exerted a prominent activity in in-vitro acetylcholinesterase inhibition assay with kaempferol-3-O-ß-glucoside being the most potent compound showing IC50 of 29.03 ± 0.0155 µM. A molecular docking study indicated high affinity of kaempferol-3-O-ß-robinobioside on acetylcholine esterase binding site with estimated binding free energy of -8.26 kcal/mol.

Comparison between adenosine and magnesium sulphate as adjuvants for transversus abdominis plane block: a prospective randomized controlled trial.

BACKGROUND: Various adjuvants have been employed during different nerve blocks. We aimed to evaluate the effect of adding adenosine versus magnesium sulfate to bupivacaine on the quality and duration of transversus abdominis plane (TAP) block. METHODS: Participants were randomized to TAP block using either 20 mL of bupivacaine hydrochloride 0.375% + 12 mg adenosine in 2 mL of saline 0.9% (adenosine group), 20 mL of bupivacaine hydrochloride 0.375% + 500 mg magnesium sulphate in 2 mL saline 0.9% (magnesium group) or 20 mL of bupivacaine hydrochloride 0.375% + 2 mL saline 0.9% (control group). Primary outcome measure included postoperative pain as assessed by Visual Analog Scale (VAS) for pain scoring on movement and secondary outcomes included analgesia duration, postoperative morphine need and any adverse effects. RESULTS: VAS in adenosine and magnesium groups was significantly less than in control group at 6 and 12 hours postoperatively whereas it was comparable in adenosine and magnesium groups at all time points. Analgesia duration was significantly longer in adenosine and magnesium groups in comparison to the control group and it was relatively longer in the magnesium group when compared to adenosine group (401 vs. 447 vs. 320 minutes in adenosine, magnesium and control groups, respectively; P=0.003). CONCLUSIONS: Both adenosine and magnesium improved the quality and duration of TAP block, but the duration was relatively longer with magnesium.

Does the addition of magnesium to bupivacaine improve postoperative analgesia of ultrasound-guided thoracic paravertebral block in patients undergoing thoracic surgery?

PURPOSE: Magnesium is a plentiful intracellular cation that has been reported to possess analgesic effect. The present study was aimed to see whether addition of magnesium to bupivacaine in thoracic paravertebral block (TPVB) improved the analgesic effect after thoracic surgery. MATERIALS AND METHODS: Fifty adult patients undergoing elective open thoracic surgery were divided into two equal groups. Group I received 12 ml of 0.5 % bupivacaine plus 0.9 % saline (3 ml) whereas Group II received 12 ml of 0.5 % bupivacaine plus 150 mg magnesium sulphate (in 3 ml 0.9 % saline) for TPVB. The following parameters were assessed: onset, dermatomal levels and duration of sensory block, duration of analgesia, visual analogue scale (VAS) for pain, postoperative intravenous morphine consumption, pulmonary function tests (peak expiratory flow rate [PEFR], forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]) before and 24 h after surgery, and complications from the drugs and technique. RESULTS: Group II patients showed a significantly longer sensory block duration (224.6 ± 59.3 vs 160.1 ± 55.2 min, P < 0.05), longer duration of analgesia (388.8 ± 70.6 vs 222.2 ± 61.6 min, P < 0.05), less VAS during the postoperative 48 h, less need for postoperative morphine (16.2 ± 7.4 vs 29.5 ± 11.1 mg, P < 0.05) and lower incidence of somnolence (0 [0 %] vs 5 [20 %], P < 0.05). Furthermore, postoperative pulmonary function tests (PEFR, FEV1 and FVC) were significantly better in Group II whereas there was no significant difference between both groups regarding the sensory block dermatomal level or hemodynamic data. CONCLUSION: Addition of magnesium to bupivacaine in TPVB improved the analgesic effect of bupivacaine in patients undergoing thoracic surgery.

Effect of adding dexamethasone to bupivacaine on transversus abdominis plane block for abdominal hysterectomy: A prospective randomized controlled trial.

PURPOSE: Different adjuvants have been used to improve the quality and increase the duration of local anesthetics during various nerve block techniques. The current study was aimed to evaluate the effect of adding dexamethasone to bupivacaine on the quality and duration of transversus abdominis plane (TAP) block. METHODS: Sixty adult patients undergoing elective open abdominal hysterectomy were randomly allocated to receive TAP block using 20 mL of bupivacaine hydrochloride 0.25% + 2 mL saline 0.9% (control group, n=30) or 20 mL of bupivacaine hydrochloride 0.25% + 2 mL dexamethasone "8 mg" (dexamethasone group, n=30). The primary outcome was postoperative pain, as evaluated by visual analog scale (VAS) for pain scoring at 1, 2, 4, 12, 24 and 48 h postoperatively, whereas the secondary outcomes were time to first analgesia (TFA), morphine consumption and the occurrence of nausea, vomiting or somnolence. RESULTS: The pain VAS score was significantly lower at the postoperative 2 h (4.9 vs. 28.1, P=0.01), 4 h (12.2 vs. 31.1, P=0.01) and 12 h (15.7 vs. 25.4, P=0.02). Furthermore, TFA was significantly longer in the dexamethasone group (459.8 vs. 325.4 min, P=0.002), with lesser morphine requirements in the postoperative 48 h (4.9 vs. 21.2 mg, P=0.003) and lower incidence of nausea and vomiting (6 vs. 14, P=0.03). No complications attributed to the block were recorded. CONCLUSION: Addition of dexamethasone to bupivacaine in TAP block prolonged the duration of the block and decreased the incidence of nausea and vomiting.

Norepinephrine supplemented with dobutamine or epinephrine for the cardiovascular support of patients with septic shock.

BACKGROUND AND AIMS: Sepsis management remains a great challenge for intensive care medicine. The aim of this study was to evaluate the effect of adding dobutamine versus epinephrine to norepinephrine in treating septic shock patients refractory to fluid therapy. MATERIALS AND METHODS: Sixty adult patients with the diagnosis of septic shock were included in this study. Norepinephrine infusion was started at a dose of 0.05 µg/kg/min, and increased gradually up to 0.1 µg/kg/min. Upon reaching this dose, patients with mean arterial pressure <70 mmHg were further divided randomly into two equal groups. In group I: the patients continued on norepinephrine and dobutamine was added at a starting dose of 3 µg/kg/min and increased in increments of 2 µg/kg/min up to 20 µg/kg/min. In group II: the patients continued on norepinephrine and epinephrine was added in a starting dose of 0.05 µg/kg/ min and increased in increments of 0.03 µg/kg/min up to 0.3 µg/kg/min. RESULTS: Group II patients developed significantly better cardiovascular parameters, lower arterial pH and higher serum lactate and urine output; however, the 28-day mortality and major adverse effects were comparable in both groups. CONCLUSIONS: The addition of epinephrine to norepinephrine has positive effects on the cardiovascular parameters but negative results on the serum lactate concentration and systemic pH compared with the addition of dobutamine to norepinephrine.

Ultrasound-guided single injection infraclavicular brachial plexus block using bupivacaine alone or combined with dexmedetomidine for pain control in upper limb surgery: A prospective randomized controlled trial.

BACKGROUND: Dexmedetomidine, is a selective α2-adrenoceptor agonist that is used as an adjuvant mixed with local anesthetics during regional anesthesia. This study was designed to test the efficacy of adding dexmedetomidine to bupivacaine during placement of infraclavicular brachial plexus blockade (ICB). METHODS: Sixty adult patients were divided into 2 equal groups of 30 subjects each. Patients in Group I received an ICB using 30 mL of 0.33% bupivacaine and Group II patients received 30 mL of 0.33% bupivacaine mixed with 0.75 µg/kg of dexmedetomidine. The following brachial plexus nerve block parameters were assessed: block success rate, sensory onset time and duration, motor block onset time and duration, analgesic pain scores using the verbal rating scale (VRS) for pain, duration of analgesia, and amount of supplemental intravenous (IV) morphine required. RESULTS: There was a statistically significant shorter time to onset of sensory blockade (13.2 vs 19.4 min, P=0.003), longer duration of sensory block (179.4 vs 122.7 min, P=0.002), shorter onset time to achieve motor block (15.3 vs 22.2 min, P=0.003), longer duration of motor block (155.5 vs 105.7 min, P=0.002), lower VRS pain scores, prolonged analgesia (403 vs 233 min, P=0.002), and lower morphine rescue requirements for 48 h after surgery (4.9 (0-8.0) vs 13.6 mg (4.0-16.0) mg, P=0.005). All patients recovered without evidence of sensory or motor deficit. CONCLUSION: ADDING DEXMEDETOMIDINE TO BUPIVACAINE DURING THE PLACEMENT OF AN ICB PROVIDES: (1) enhancement of onset of sensory and motor blockade, (2) prolonged duration of analgesia, (3) increases duration of sensory and motor block, (4) yields lower VRS pain scores, and (5) reduces supplemental opioid requirements.

Alemtuzumab preconditioning allows steroid-calcineurin inhibitor-free regimen in live-donor kidney transplant.

OBJECTIVES: This prospective study was designed to develop a steroid and calcineurin inhibitor-free regimen for kidney transplants using alemtuzumab. MATERIALS AND METHODS: A single dose of alemtuzumab (30 mg) was given preoperatively. Phase 1: Twenty-one patients were randomized into 2 groups; the tacrolimus (n=11) and the sirolimus groups (n=10). Steroids were given for 5 days. Azathioprine (1 mg/kg) was added when white blood cells ≥ 4000 cells/cm(3). Mean follow-up was 48 ± 2.8 and 48.2 ± 1.6 months for the tacrolimus and sirolimus groups. Phase 2: Twenty patients were included and the study design was modified. Tacrolimus was given for 2 months, and was replaced by sirolimus thereafter. The mean follow-up was 28.3 ± 2.1 months. RESULTS: Phase 1: Acute rejection episodes were encountered in 5 patients of the tacrolimus versus 2 cases in the sirolimus group (P = .44). Antibody-mediated rejection was diagnosed in 2 recipients in each group. Four patients were switched from sirolimus to tacrolimus owing to resistant rejection, significant proteinuria, persistent thrombocytopenia, lymphocele, and urinary leakage. One patient was shifted from tacrolimus to sirolimus owing to Kaposi sarcoma. Glomerular filtration rate was significantly higher in the sirolimus group. Currently, 14 patients (8 tacrolimus, and 6 sirolimus) are steroid-free. One patient died from the tacrolimus group owing to fulminant hepatitis. Two grafts were lost in the sirolimus group versus 1 graft in the tacrolimus group. Phase 2: Five patients developed successfully treated borderline changes with no antibody-mediated rejection. Mean serum creatinine was 114.9 ± 17.7 µmol/L. Currently, 17 patients are steroid free and 15 of them are calcineurin inhibitor-free as well. In this phase, only 1 patient died with a functioning graft. CONCLUSIONS: This clinical trial provides a good insight into a potentially effective steroid and calcineurin inhibitor-free protocol with the use of alemtuzumab induction in combination with sirolimus.

Ultrasound-guided continuous infraclavicular brachial plexus block using bupivacaine alone or combined with adenosine for pain control in upper limb surgery.

INTRODUCTION: The infraclavicular brachial plexus block (ICB) is designed to deposit anesthetic high in the plexus, achieving anesthesia of the hand, forearm, elbow, and distal arm. Adenosine is a metabolic intermediate that is involved in nearly all aspects of cell function, including neurotransmission and signal transduction.This study was aimed to show whether addition of adenosine to bupivacaine in ultrasound-guided ICB had an analgesic effect. METHODS: Sixty adult patients were divided into two equal groups, each group included 30 patients. Group I received infraclavicular bupivacaine 0.325% in a volume of 30 ml. Group II received 30 ml of 0.325% bupivacaine + 12 mg adenosine. The block was maintained with an infusion of 10 ml/h. The following parameters were assessed: Success rate, time of the sensory onset, motor block, visual analog scale (VAS), and amount of i.v. pethidine needed. RESULTS: This study showed an analgesic effect of infraclavicular adenosine as evidenced by a statistically significant shorter mean time of onset of the sensory block (16 vs. 20 min, P < 0.05), lower mean VAS score over 48 h (1.7 vs. 2.7, P < 0.05), longer mean time of first parenteral analgesic requirement (299 vs. 255 min, P < 0.05), and lower mean total dose of pethidine needed over 48 h after surgery (25.5 vs. 56.6 mg, P <0.05). All patients got successful infraclavicular block and recovered uneventfully without any sensory or motor deficit. CONCLUSION: Adenosine may provide valuable addition to the therapeutic options in anesthesia and pain management. Further research is required to figure out its exact role.

A comparison between two different alveolar recruitment maneuvers in patients with acute respiratory distress syndrome.

BACKGROUND: Alveolar recruitment is a physiological process that denotes the reopening of previously gasless lung units exposed to positive pressure ventilation. The current study was aimed to compare two recruitment maneuvers, a high continuous positive airway pressure (CPAP), and an extended sigh in patients with ARDS. MATERIALS AND METHODS: Forty patients with acute respiratory distress syndrome were randomly divided into two groups, 20 patients each. Group I received a CPAP of 40 cm H(2)O for 40 seconds and group II received extended sigh (providing a sufficient recruiting pressure × time). In our study, we assessed the effects of both recruitment maneuvers on respiratory mechanics, gas exchange, and hemodynamics. These data were analyzed using two-way analysis of variance (ANOVA) followed by a Student--Newman--Keuls post hoc comparison test. P < 0.05 was considered statistically significant. RESULTS: Both methods improved the compliance, increased arterial oxygenation (PaO(2)), increased the PaO(2)/FiO(2) ratio, and reduced the pulmonary shunt fraction (Q(s)/Q(t)). However, the extended sigh improved both PaO(2) and PaO(2)/FiO(2) ratios more than continuous positive airway pressure. Also the hemodynamic parameters were better maintained during the extended sigh. CONCLUSION: Alveolar recruitment maneuvers are effective in management of mechanically ventilated ARDS patients. We conclude that extended sigh is more effective than continuous positive airway pressure as a recruitment maneuver.

Continuous ambulatory peritoneal dialysis in Egypt: progression despite handicaps.

BACKGROUND: Despite the well-known advantages of continuous ambulatory peritoneal dialysis (CAPD), it continues to be grossly underutilized in many developing countries. However, some developing countries, such as Mexico, use the modality very effectively. In view of this, we started the first CAPD program in Egypt. METHODS: Since its start in 1997, our program has treated 33 patients. Straight double-cuffed Tenckhoff catheters were surgically placed in all patients. Twin-bag systems were used. All patients underwent monthly clinical and biochemical assessment and measurement of Kt/V urea. Peritonitis and exit-site infection rates were monitored. RESULTS: Most treated patients were adult and female. Mean age was 31.7 years and mean follow-up duration was 18 months. Peritonitis rate was 1 episode /21.3 months and was easily managed in most patients. Staphylococcus aureus was the most commonly isolated organism (24%) but 49% of cases were culture negative. There were no exit-site infections. Mean weekly Kt/V urea was 1.78 +/- 0.23. CONCLUSION: We report the successful development of a small CAPD program in Egypt, made possible by well-established financial support, a motivated team of doctors and nurses, and good patient selection and training.

Nail changes in kidney transplant recipients.

BACKGROUND: Nail changes are common complications of end-stage renal disease, and reports of nail changes in kidney transplant recipients (KTR) are rare. Few reports have documented a higher prevalence of onychomycosis in KTR compared with controls, while others found no significant differences. In this study, we investigated the prevalence and nature of nail changes in a large series of KTR. METHODS: Three hundred and two KTR (216 males and 86 females) were included in this study, and the mean transplant duration was 6.57 years (range 1.5 month-23 years). They were screened for the presence of nail changes. Nail clippings were collected when indicated and cultures were performed for patients with suspected onychomycosis. The patients were compared with 302 age- and sex-matched healthy controls (220 males and 82 females). RESULTS: One hundred and twenty-one KTR (40.1%) had nail changes compared with 104 (34.4%) in controls. Onychomycosis, Muehrcke's nail and leuconychia were significantly more common in KTR [23 (7.6%), 13.3 (4.3%), 11 (3.6%), respectively] compared with controls [7 (2.3%), 1(0.3%), 2 (0.66%), P = 0.002, 0.001 and 0.02, respectively]. However, the most frequent nail change among KTR and controls was absent lunula, 90 (29.8%) and 80 (26.5%), respectively P = 0.36. Longitudinal ridging was also a frequent nail pathology among KTR and controls, 21 (6.9%) and 19 (6.3%), respectively, P = 0.74. CONCLUSION: KTR have higher prevalence rates of onychomycosis, Muehrcke's nail and leuconychia than the healthy population. On the other hand, absent lunula could be a normal variation among Egyptian people.

Association and prognostic impact of persistent left ventricular hypertrophy after live-donor kidney transplantation: a prospective study.

AIM: Persistent or de novo left ventricular hypertrophy (LVH) is a risk factor for cardiovascular diseases and congestive heart failure following renal transplantation (RT). Our aim was to determine the associations and impact of persistent LVH on RT outcome. MATERIALS AND METHODS: We included 72 live-donor renal allograft recipients with mean age of 28.5 years who had evidence of LVH at time of transplantation and had stable functioning grafts 1 year after transplantation. Cardiac status of all recipients was assessed before transplantation and at 1 year after transplantation by echocardiography. Recipients were subdivided into two groups according to persistence or regression of LVH 1 year after transplantation. The first group included 33 patients who had persistent LVH. The second group included 39 patients in whom LVH had regressed (control group). Both groups were closely followed for 10 years. RESULTS: Univariate analysis showed that persistent LVH 1 year after RT was significantly associated with high serum creatinine, higher incidence of medical infection, and acute and chronic rejection. Chronic rejection and infection were the only valid associations on multivariate logistic regression analysis. Patient and graft survival were significantly lower in the persistent LVH group (P = 0.012). CONCLUSION: Persistent LVH may be associated with higher incidence of medical infection and chronic rejection that worsen the prognosis for renal transplant recipients.

Basiliximab induction therapy for live donor kidney transplantation: a long-term follow-up of prospective randomized controlled study.

BACKGROUND/AIMS: The effect of basiliximab induction therapy on long-term patient and graft survival is not yet clear. We aimed to evaluate if there is any advantage of routine basiliximab induction on the long-term outcome of living related donor kidney transplantation. METHODS: One hundred adult recipients with their first kidney allograft were randomized into two treatment groups, one group received basiliximab and the second served as a control. All patients received a maintenance triple immunosuppressive therapy (steroids, cyclosporine (CsA) micro-emulsion and azathioprine) and were followed up thoroughly for 7 years. RESULTS: Basiliximab significantly reduced the proportion of patients who experienced acute rejection in the first year (18/50) when compared to the control group (31/50), and in 7 years (28/50) when compared to (37/50) in controls. The cumulative steroid dose used throughout the whole study period was significantly lower in the basiliximab group. The overall incidence of post-transplant complications was comparable among the two treatment groups. There was no significant difference in patient or graft survival; 7 years patient and graft survival were 92, 76% for basiliximab and 92, 80% for the control group, respectively. CONCLUSION: Routine basiliximab induction significantly reduced the incidence of acute rejection without any noticeble beneficial effect on the long-term renal transplantation outcome.

Can intravenous immunoglobulin and simvastatin solve the problem of sensitization in renal transplant candidates?

The value of intravenous immunoglobulin (IVIG) and simvastatin as potential modalities for the treatment of sensitized patients was evaluated by testing the efficacy of these agents on a relatively large cohort of adult hemodialysis patients (11) who were waiting for renal allotransplantation at our center. The patients had persistently positive crossmatches with their living related donors and a panel reactive antibody titer of more than 20%. All patients received IVIG (500 mg/kg per day on alternate days for a total of six doses); panel reactive antibody (PRA) titer and crossmatch testing were carried out after each dose and before each subsequent one. Two months after the last dose, eight patients received simvastatin (20 mg/day) for a period of 2 months; PRA titer and crossmatch testing were carried out every two weeks. Only four patients showed an insignificant reduction of PRA activity (P = 0.36); no patient attained a negative crossmatch. Simvastatin also resulted in an insignificant reduction of anti-human leukocyte antigen (HLA) antibodies in three patients (P = 0.32). We propose that IVIG or simvastatin alone can not effectively inhibit preformed anti-HLA antibodies to allow successful renal transplantation. Further trials on the use of IVIG and simvastatin with other modalities of treatment to desensitize these patients may be warranted.

Management of sensitized patients awaiting renal transplantation: does sequential therapy of intravenous immunoglobulin and simvastatin offer a solution?

The value of intravenous immunoglobulin and simvastatin as potential modalities for the treatment of sensitized patients was studied. We aimed to test their efficacy as solo agents to inhibit anti-human leukocyte antigen (HLA) antibodies. We tested samples from 11 adult hemodialysis patients who were waiting for renal allotransplantation at our center, all of whom had persistently positive crossmatches with their living related donors and panel reactive antibody titers more than 20%. All patients received intravenous immunoglobulin (500 mg/kg/day on alternate days for 6 doses). Panel reactive antibody titer measurement and crossmatch testing were carried out after each dose and before each subsequent one. Two months later, 8 patients received simvastatin (20 mg/day) for 2 months. Panel reactive antibody measurement titer and crossmatch testing were carried out every 2 weeks. Only 4 patients showed an insignificant reduction in panel reactive antibody activity (P=0.36). None of them attained a negative crossmatch. Furthermore, simvastatin also resulted in an insignificant reduction of HLA antibodies in 3 patients (P=0.32). We concluded that intravenous immunoglobulin or simvastatin alone cannot effectively inhibit preformed anti-HLA antibodies to allow successful renal transplantation. Further trials of the use of intravenous immunoglobulin and simvastatin with other modalities to desensitize these patients may be warranted.