Particle size affects pharmacokinetics of milled oxycodone hydrochloride tablet products following nasal insufflation in nondependent,recreational opioid users

This study assessed the impact of product particle sizes (fine: 106–500 µm; coarse: 500–1000 µm) on oxycodone pharmacokinetics (PK) following nasal insufflation of milled oxycodone extended‐release (ER) abuse‐deterrent (AD) tablets using immediate‐release (IR) non‐AD product as reference. Additionally, this study assessed the effects of different excipient to drug ratio (EDR) by comparing two products with fine particle size but different EDRs, again using IR non‐AD as the control. Thirty milligrams of oxycodone were administered in each treatment. Coarsely milled 30 mg ER tablets demonstrated significantly lower maximum plasma concentration (C_max) and partial areas under the concentration‐time curve (AUCs) than those of the finely milled IR tablets. Finely milled ER tablets demonstrated similar C_max and partial AUCs but higher total systemic exposures than those of finely milled IR tablets. Finely milled 80 mg ER tablets were bioequivalent to IR tablet on all parameters. The finely milled 30 mg ER tablet was not bioequivalent to the coarsely milled 30 mg ER tablet and had higher values for all parameters. The finely milled 30 mg ER tablets (EDR 6.9) showed no PK differences with finely milled 80 mg ER tablets (EDR 4.9). No serious adverse events were reported. The study demonstrated a significant effect of particle sizes (106–1000 µm) on PK of milled and insufflated oxycodone ER AD tablets. EDR difference did not have any significant effects on the PK of finely milled oxycodone ER AD tablets. Particle size distribution should be considered when nasal AD properties of opioid drug products are investigated during drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Available literature suggests that product particle sizes of milled and insufflated polyethylene oxide (PEO)‐based abuse deterrent (AD) oxycodone extended release (ER) tablet products could influence pharmacokinetic (PK) parameters of insufflated product. However, study designs in published literature are widely different and the comminuted products have not been adequately characterized. Therefore, the reported results in literature are not consistent.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does manipulation of a given tablet formulation to different particle sizes affect PK parameters of the insufflated comminuted product? If two different tablet’s formulation with different PEO to oxycodone ratios are milled to the same particle size, does the difference in PEO to oxycodone affect PK parameters of the milled and insufflated product?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The study demonstrates a significant effect of particle sizes on PK of milled and insufflated oxycodone ER AD at the dose of 30 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Particle size distribution should be considered in comparative PK studies to evaluate the nasal AD properties of opioid drug products.     

Combined living-related segmental liver and bowel transplantation for megacystis-microcolon-intestinal hypoperistalsis syndrome

Background

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is the most severe form of functional intestinal obstruction in the newborn. To date, multivisceral transplantation has been the only accepted treatment modality for these patients, and the results have met with marginal success. We report the first case of a patient affected by MMIHS and cholestatic liver failure treated by a combined living-related liver and intestinal transplant (CLRLITx).

Case Report

The patient was a 1-year-old Hispanic girl born with MMIHS and maintained on total parenteral nutrition since birth. Once liver failure developed, she was referred for evaluation for possible CLRLITx. The patient's mother volunteered as the donor. The left lateral segment was used for the liver transplant. The intestinal graft consisted of the terminal 180 cm of the ileum with a single vascular pedicle. Initially, the patient continued to have severe gastroparesis; however, by 8 months posttransplant, stomach function had returned to normal. Currently, at 2 years posttransplant, she is tolerating an oral diet with gastric tube supplementation. Results of absorption studies are within normal, and she has shown catch-up growth.

Conclusion

A CLRLITx can be a viable alternative for infants diagnosed with MMIHS. This procedure can help avoid the 25% wait-list mortality for children who are in need of a combined transplant.     

Long-term outcome of a prospective trial of steroid withdrawal after kidney transplantation

BACKGROUND: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. METHODS: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management. RESULTS: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively (P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively (P = .014). CONCLUSIONS: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution.     

Encephalopathy in AIDS patients: evaluation with MR imaging

The presence and extent of encephalopathy were evaluated in 47 patients with AIDS or AIDS-related complex (ARC) by the use of MR imaging. Twenty-nine (62%) of the patients showed some form of white matter disease, exhibited as high signal intensity on T2-weighted images. Focal white matter lesions were seen in 23 (49%) of the patients, while a diffuse white matter process was observed in six patients (13%). Of the 29 patients who had white matter disease on MR scans, 17 (36%) had a suggestion of white matter involvement on an initial CT study. Meanwhile, 12 (26%) of the patients had a normal CT scan on the initial examination. MR findings showed predominant disease in the subinsular and peritrigonal white matter areas. Marked cerebral atrophy was observed in 17 (36%) of 47 patients, cerebellar atrophy in 18 (38%), and brainstem atrophy in seven patients (15%). Pathologic findings showed that toxoplasmosis was present in eight patients (17%), and primary CNS lymphoma was present in three patients (6%). Cryptococcal meningitis was noted in two (4%) of the patients at autopsy, and Mycobacterium tuberculosis was seen in one (2%) of the patients at autopsy. MR imaging has been shown to be a valuable technique for the detection of encephalopathy in AIDS patients.     

Antidepressant effects of magnetic resonance imaging—based stimulation on major depressive disorder: a double-blind randomized clinical trial

Antidepressant effects of magnetic resonance imaging (MRI) based stimulation have been reported in animal studies, but no human studies are available on subjects with major depressive disorder. Here, the efficacy of two diagnostic MRI protocols (echo-planar diffusion-weighted imaging (DWI) and T1-weighted imaging) was assessed in patients with major depressive disorder. In this double-blind randomized clinical trial, 51 patients with clinically proven major depressive disorder were randomly enrolled into three equal groups. All patients were receiving a selective serotonin reuptake inhibitor as the only antidepressant treatment. The first group received echo-planar DW stimulation (DWI group), the second group received T1-weighted stimulation (T1 group), and the third group experienced a similar condition without receiving any magnetic stimulation (sham group). The Hamilton rating scale for depression (HAMD24) and Beck depression inventory (BDI) were used to assess the effect of MR stimulation on depressive symptoms. In comparison to baseline, mean HAMD24 and BDI scores significantly (p?相似文献   

Negative priming in amphetamine psychosis

Amphetamine abuse may lead to a psychotic state, its symptomatology being very similar to what is seen in paranoid schizophrenia. Failure of attentional inhibition of irrelevant information is thought to be associated with the psychotic symptoms in schizophrenia. Negative priming (NP) paradigm is believed to measure this impairment. Several studies have shown impaired NP in schizophrenia. In the present study a spatial NP task was used to assess attentional inhibition in a group of amphetamine-induced psychosis patients. Nineteen patients with amphetamine-induced psychotic disorder and 20 healthy subjects participated in this study. Severity of psychotic symptoms was measured prior to testing using the Brief Psychiatric Rating Scale (BPRS). Patients showed no deficit in NP, and the amount of their NP effect was not significantly different from healthy subjects. Besides, we did not find any correlation between the amount of NP effect and severity of symptoms. Our results may indicate that cognitive mechanisms underlying NP might not be affected in amphetamine psychosis.     

Successful living related simultaneous pancreas-kidney transplant between identical twins

Simultaneous pancreas-kidney transplant from living donors has been recently proposed as an effective therapeutic option in selected uremic patients with type I diabetes. We report the first simultaneous pancreas-kidney transplant performed between identical twins. Posttransplant, the recipient has been maintained on low dose cyclosporine to avoid recurrent auto-immune insulitis. At the 1-year follow-up, both donor and recipient are well with normal renal function and excellent glucose control. Simultaneous pancreas-kidney transplant between identical twins can be performed successfully using cyclosporine to prevent recurrent auto-immune insulitis.     

Staged approach for abdominal wound closure following combined liver and intestinal transplantation from living donors in pediatric patients

Abstract:  Primary closure of the abdominal wall after combined liver and intestine transplantation from a living donor into a pediatric patient is usually not possible, because of the size of the donor organ, graft edema, and preexisting scars or stomas of the abdominal wall. Closure under tension may lead to abdominal compartment syndrome with vascular compromise and necrosis of the transplanted organ. We describe our experience of abdominal wound closure after liver and intestinal transplant in the pediatric patient using a staged approach. From February 2003 to June 2006, we managed five pediatric liver and intestinal living donor transplant recipients. Because of the large post-transplantation abdominal wall defect, a staged technique of abdominal wound closure was utilized. Initially, an absorbable Polygalactin mesh was sutured around the layer of the defect. As soon as adequate granulation tissue was formed over the mesh a STSG was applied. From the wound stand point all five patients were managed successfully with staged wound closure after transplantation. Granulation tissue filled and covered the mesh within 7.6 wk. A STSG was then used to cover the defect. All infants recovered well and none had a significant wound complication in the immediate post-operative period following STSG. At a mean follow-up of 24 months only one patient developed an entero-cutaneous fistula five months post-transplant. Staged abdominal wall coverage with the use of Polygalactin mesh followed by STSG is a simple and effective technique. A closed wound is achieved in a timely fashion with protection of the viscera. Residual ventral hernia will need to be managed in the future with one of several reconstructive techniques.     

Hospital medicine maturity framework: proposing a novel framework for defining stages of hospital medicine in Canada

While hospitalists and hospital medicine programs are proliferating across Canada, there is little written about them. In this article, the authors propose a conceptual framework for defining stages of development and maturity of hospitalist programs in the Canadian healthcare context. In developing this framework, they have not only relied on personal experience as practising hospitalists and healthcare consultants but have also consulted with leaders of hospital medicine across Canada.