In vitro metabolism of new synthetic cannabinoid SDB-006 in human hepatocytes by high-resolution mass spectrometry

The drug abuse epidemic within the United States remains one of the nation’s most serious social challenges, especially among adolescents and young adults. Novel psychoactive substances continuously emerge into the illicit drugs-of-abuse market to evade legislation. In 2013, SDB-006 was detected as a novel synthetic cannabinoid (SC) with high binding affinity to CB₁ (EC₅₀ = 19 nM) and CB₂ (EC₅₀ = 134 nM). Unfortunately, no human metabolism data for SDB-006 are currently available, making it challenging to confirm intake, since all previously investigated SCs were extensively metabolized. The present study aims to recommend appropriate marker metabolites for documenting SDB-006 consumption by investigating its metabolism in human hepatocytes. For metabolite profiling, 10 µM of SDB-006 was incubated in human hepatocytes for 3 h. Metabolite identification in hepatocyte samples was accomplished with high-resolution mass spectrometry via information-dependent data acquisition. Results revealed that SDB-006 was highly metabolized in human hepatocytes. A total of 20 metabolites were characterized, generated mainly from hydroxylation and glucuronidation. Hydroxylation occurred primarily on several positions of the pentyl chain. N-Dealkylation was the other major pathway, including depentylation and debenzylation. Based on our data, we propose 4′-keto-SDB-006 (M19) and pentyl-OH-SDB-006 (M15) as optimal marker metabolites for documenting SDB-006 intake.     

In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)

In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by scientists at Russian and US laboratories. It has been already added to the list of scheduled drugs in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, which makes it challenging to confirm its intake, especially given that all SCs investigated thus far have been found to be extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes, and to confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 µM NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 µM of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201-positive cases were subjected to β-glucuronidase hydrolysis prior to analysis. The identification of metabolites in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs, with an 8.0-min half-life. In human hepatocyte incubation samples, a total of 13 NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was found to be the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after β-glucuronidase hydrolysis. Therefore, based on the results of our study, we recommend M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake.     

The Business Case for Adult Disability Care Coordination

Palsbo SE, Diao G. The business case for adult disability care coordination.

Objective

To analyze the financial performance of a care coordination program.

Design

The study used a retrospective pretest, posttest design of 245 beneficiaries. Physical impairment ranged from slight to severe.

Setting

Minnesota Disability Health Options (MnDHO), a capitated Medicaid program.

Participants

Medicaid beneficiaries ages 18 to 64 with physical disabilities arising from multiple sclerosis, cerebral palsy, spinal cord injury, or brain injury.

Interventions

Not applicable.

Main Outcomes Measures

Change in expenditures, rate of return, and utilization.

Results

Mean MnDHO monthly expenditures including care coordination increased by a factor of 1.75 (P<.001) over the previous expenditures. Increasing age has a multiplier effect on increased expenditures. Hospitalization rates were unchanged, but the average cost per admission and average length of stay dropped significantly (P=.017, P=.032, respectively). For people enrolled at least 3 years, annual reductions in medical costs more than paid for the added cost of care coordination, but the savings in Year 3 were about 20% of the savings in the first 2 years.

Conclusions

Care coordination leads to higher program expenditures for enrollees with moderate physical impairments who encounter access problems, but has little impact on enrollees who are already getting 24-hour care. There is some evidence of adverse selection bias. MnDHO's disability care coordination may not be financially sustainable over the long term.     

Effect of Dermabrasion and ReCell? on Large Superficial Facial Scars Caused by Burn,Trauma and Acnes

Objective To explore the effects of dermabrasion combined with ReCell? on large superficial facial scars caused by burn, trauma and acnes. Methods Nineteen patients with large superficial facial scars were treated by the same surgeon with dermabrasion combined with ReCell?. According to the etiology, patients were classified into post-burning group (n=5), post-traumatic group (n=7) and post-acne group (n=7). Fifteen patients completed the follow-ups, 5 patients in each group. Healing time, complication rate, the preoperative and 18-month-post-operative assessments using Patient Satisfaction Score (PSS), Vancouver Scar Scale (VSS), and Patient and Observer Scar Assessment Scale (POSAS) of each group were analyzed to compare the effect of the combined therapy on outcomes. Results The healing time of post-burning group (19.6±4.0 days), post-traumatic group (15.8±2.6 days), and post-acne group (11.4±3.1 days) varied remarkably (F=7.701,P=0.007). The complication rates were 60%, 20%, and 0 respectively. The post-operative POSAS improved significantly in all groups (P<0.05), where the most significant improvement was shown in the post-acne group (P<0.05). The post-operative PSS and VSS improved only in the post-traumatic group and post-acne group (allP<0.05), where the more significant improvement was also shown in the post-acne group (P<0.05). Conclusions The combined treatment of dermabrasion and ReCell? has remarkable effect on acne scars, moderate effect on traumatic scars and is not suggested for burn scars. POSAS should be applied to assess the therapeutic effects of treatments for large irregular scars.     

Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy

The presence of multiple affected offspring from apparently non-carrier parents is caused by germ line mosaicism. Although germ line mosaicism has been reported for many diseases, figures for recurrence risks are known for only a few of them. In X-linked Duchenne and Becker muscular dystrophies (DMD/BMD), the recurrence risk for non-carrier females due to germ line mosaicism has been estimated to be between 14% and 20% (95% confidence interval 3–30) if the risk haplotype is transmitted. In this study, we have analyzed 318 DMD/BMD cases in which the detected mutation was de novo with the aim of obtaining a better estimate of the 'true' number of germ line mosaics and a more precise recurrence risk. This knowledge is essential for genetic counseling. Our data indicate a recurrence risk of 8.6% (4.8–12.2) if the risk haplotype is transmitted, but there is a remarkable difference between proximal (15.6%) (4.1–27.0) and distal (6.4%) (2.1–10.6) deletions. Overall, most mutations originated in the female. Deletions occur more often on the X chromosome of the maternal grandmother, whereas point mutations occur on the X chromosome of the maternal grandfather. In unhaplotyped de novo DMD/BMD families, the risk of recurrence of the mutation is 4.3%.