Cannabidiol and Cannabidiol Metabolites: Pharmacokinetics,Interaction with Food,and Influence on Liver Function

Cannabidiol (CBD) is widely available and marketed as having therapeutic properties. Over-the-counter CBD is unregulated, many of the therapeutic claims lack scientific support, and controversy exists as to the safety of CBD-liver interaction. The study aims were to compare the pharmacokinetics of commercial CBD and CBD metabolites following the ingestion of five different CBD formulations, determine the influence of CBD on food induced thermogenesis, determine the influence of food on CBD pharmacokinetics, and determine the influence of CBD on markers of liver function. Fourteen males (body mass index ≥ 25 kg/m²) were studied in a placebo-controlled, randomized, crossover design. On five occasions, different CBD formulations were ingested (one per visit). On two additional occasions, CBD or placebo was ingested following a meal. CBD servings were standardized to 30 mg. Considerable pharmacokinetic variability existed between formulations; this pharmacokinetic variability transferred to several of the metabolites. CBD did not influence food induced thermogenesis but did favorably modify early insulin and triglyceride responses. Food appreciably altered the pharmacokinetics of CBD. Finally, CBD did not evoke physiologically relevant changes in markers of liver function. Collectively, these data suggest that consumers should be aware of the appreciable pharmacokinetic differences between commercial CBD formulations, CBD is unlikely to influence the caloric cost of eating but may prove to be of some benefit to initial metabolic responses, consuming CBD with food alters the dynamics of CBD metabolism and increases systemic availability, and low-dose CBD probably does not represent a risk to normal liver function.     

Zoledronic acid improves femoral head sphericity in a rat model of perthes disease.

We hypothesized that the bisphosphonate zoledronic acid (ZA) could improve femoral head sphericity in Perthes disease by changing the balance between bone resorption and new bone formation. This study tests the effect of ZA in an established model of Perthes disease, the spontaneously hypertensive rat (SHR). One hundred and twenty 4-week old SHR rats were divided into three groups of 40: saline monthly, 0.015 mg/kg ZA weekly, or 0.05 mg/kg ZA monthly. At 15 weeks DXA measurements documented that femoral head BMD was increased by 18% in ZA weekly and 21% in ZA monthly compared to controls (p<0.01). Femoral head sphericity in animals with osteonecrosis was improved in ZA-treatment groups (p<0.01) as measured by epiphyseal quotient (EQ). The proportion of "flat" heads (EQ0.40) was significantly reduced from 32% in saline-treated animals to 12% in weekly ZA and 3% in monthly ZA (p<0.01). Histologically there was a similar prevalence of osteonecrosis in all groups. The prevalence of ossification delay was significantly reduced by ZA treatment (p<0.01). Zoledronic acid favorably altered femoral head shape in this spontaneous model of osteonecrosis in growing rats. Translation of these results to Perthes disease could mean that deformity of the femoral head may be modified in children, perhaps reducing the need for surgical intervention in childhood and adult life.     

Is high level of disability an indication for spinal fusion? Analysis of long-term outcome after posterior lumbar interbody fusion using carbon fiber cages

OBJECTIVE: Posterior lumbar interbody fusion is a recognized procedure for the treatment of back pain associated with degenerative disc disease and segmental instability. It allows decompression of the spinal canal and circumferential fusion through a single posterior incision. METHODS: Sixty-five consecutive patients who underwent posterior lumbar interbody fusion using carbon cages and pedicle fixation between 1993 and 2000 were recruited and contacted with a postal survey. Clinical outcome was assessed by the postoperative clinical findings and complications and the fusion rate, which was assessed using the scoring system described by Brantigan and Steffee. Functional outcome was measured by using improvement in the Oswestry Disability Index, return to work, and satisfaction with the surgical outcome. The determinants of functional relief were analyzed against the improvement in disability using multiple regression analysis. RESULTS: The mean postoperative duration at the time of the study was 4.4 years. Overall radiologic fusion rate was 98%. There was a significant improvement in Oswestry Disability Index (P < 0.01). There was 84% satisfaction with the surgical procedure and 61% return to predisease activity level and full employment. We found preoperative level of disability to be the best determinant of functional recovery irrespective of age or the degree of psychological morbidity and litigation (P < 0.01). CONCLUSION: The combination of posterior lumbar interbody fusion and posterior instrumented fusion is a safe and effective method of achieving circumferential segmental fusion. A direct relationship between preoperative level of disability and functional recovery suggests that disability should be measured preoperatively and spinal fusion should be performed to alleviate disability caused by degenerative spine.     

Extracorporeal membrane oxygenation in infants with meconium aspiration syndrome: a decade of experience with venovenous ECMO

Background

Despite the emergence of new therapies for respiratory failure of the newborn with meconium aspiration syndrome (MAS), extracorporeal membrane oxygenation (ECMO) has a significant role as a rescue modality in these infants. Our objective was to compare the use of venovenous (VV) vs venoarterial (VA) ECMO in newborns with MAS who need ECMO and to ascertain the impact of new therapies in these infants during the last decade. We also evaluated how disease severity or time of ECMO initiation affected mortality and morbidity.

Methods

A report of 12 years experience (1990-2002) of a single center, comparing VV and VA ECMO, is given. Venovenous ECMO was the preferred rescue modality for respiratory failure unresponsive to maximal medical therapy. Venoarterial ECMO was used only when the placement of a VV ECMO 14-F catheter was not possible; 128 patients met ECMO criteria, 114 were treated with VV ECMO, and 12 with VA ECMO. Two patients were converted from VV to VA ECMO.

Results

Venovenous and VA ECMO patients had comparable birth weight (mean ± SEM, 3.48 ± 0.05 vs 3.35 ± 0.15 kg) and gestational age (40.3 ± 0.1 vs 40.7 ± 0.3 weeks). Before ECMO, there was no difference between VV and VA ECMO patients in oxygenation index (60 ± 3 vs 63 ± 8), mean airway pressure (19.5 ± 0.4 vs 20.8 ± 1.5 cm H₂O), alveolar-arterial O₂ gradient (630 ± 2 vs 632 ± 4 torr), ECMO cannulation age (median [25th-75th percentiles], 23 [14-47] vs 26 [14-123] hours), or in the % of patients who needed vasopressors/inotropes (98% vs 100%). From November 1994, inhaled nitric oxide (NO) was available. Before VV ECMO, 67% of the patients received NO, 24% received surfactant, and 48% were treated with high-frequency ventilation (HFV). There was no significant difference between VV and VA ECMO patients in survival rate (94% vs 92%), ECMO duration (88 [64-116] vs 94 [55-130] hours), time of extubation (9 [7-11] vs 14 [9-15] days), age at discharge (23 [18-30] vs 27 [15-41] days), or incidence of short-term intracranial complications (5.3% vs 16.7%). For the total cohort of 126 infants, indices of disease severity (oxygenation index, alveolar-arterial O₂ gradient, mean airway pressure) did not correlate with outcome measures. Delay in ECMO initiation (>96 hours) was associated with prolonged mechanical ventilation and hospitalization (P < .01). New therapies (NO, HFV, surfactant) in the second part of the decade were associated with a longer ECMO duration (98 [80-131] vs 87 [60-116] hours; P < .05), no delay in ECMO initiation time (23 [10-40] vs 24 [14-52] hours), and no significant change in survival (97% vs 92.5%). No patient was treated with VA ECMO after 1994.

Conclusions

Venovenous ECMO is as reliable as VA ECMO in newborns with MAS in severe respiratory failure who need ECMO. Delay in ECMO initiation may result in prolonged mechanical ventilation and increased length of hospital stay. The emergence of new conventional therapies (NO, HFV, surfactant) and particularly increased experience enable sole use of VV ECMO with no significant change in survival in infants with MAS.     

Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe,in subcutaneous and orthotopic tumors

IntroductionThe α_vβ₃ integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of α_vβ₃-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with α_vβ₃-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with ^99mTc. In an effort to begin to address this limitation, we evaluated the tumor uptake of ^99mTc-NC100692, a cyclic RGD peptide that binds to α_vβ₃ with ~ 1-nM affinity, in an α_vβ₃-positive tumor model as well as its in vivo specificity.MethodsMicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for α_vβ₃, to block and displace ^99mTc-NC100692 in an orthotopic U87 glioma tumor. The specificity of ^99mTc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of ^99mTc-NC100692 with that of the non-specific structural analogue ^99mTc-AH-111744 and by blocking uptake of ^99mTc-NC100692 with excess unlabeled NC100692.ResultsMicroSPECT imaging studies demonstrated that uptake of ^99mTc-NC100692 in the intracranial tumor model was both blocked and displaced by the α_vβ₃-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of ^99mTc-NC100692 at 1 h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for ^99mTc-AH-111744 (p < 0.001). Blocking ^99mTc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01).ConclusionThese results confirm that ^99mTc-NC100692 does, in fact, target the α_vβ₃ integrin and may, therefore, be useful in identifying patients prior to anti-α_vβ₃ therapy as well as monitoring the response of these patients to therapy.     

The use of chest computed tomography versus chest X-ray in patients with major blunt trauma

INTRODUCTION: Computed tomography (CT) scans are often used in the evaluation of patients with blunt trauma. This study identifies the clinical features associated with further diagnostic information obtained on a CT chest scan compared with a standard chest X-ray in patients sustaining blunt trauma to the chest. METHODS: A 2-year retrospective survey of 141 patients who attended a Level 1 trauma centre for blunt trauma and had a chest CT scan and a chest X-ray as part of an initial assessment was undertaken. Data extracted from the medical record included vital signs, laboratory findings, interventions and the type and severity of injury. RESULTS: The CT chest scan is significantly more likely to provide further diagnostic information for the management of blunt trauma compared to a chest X-ray in patients with chest wall tenderness (OR=6.73, 95% CI=2.56, 17.70, p<0.001), reduced air-entry (OR=4.48, 95% CI=1.33, 15.02, p=0.015) and/or abnormal respiratory effort (OR=4.05, 95% CI=1.28, 12.66, p=0.017). CT scan was significantly more effective than routine chest X-ray in detecting lung contusions, pneumothoraces, mediastinal haematomas, as well as fractured ribs, scapulas, sternums and vertebrae. CONCLUSION: In alert patients without evidence of chest wall tenderness, reduced air-entry or abnormal respiratory effort, selective use of CT chest scanning as a screening tool could be adopted. This is supported by the fact that most chest injuries can be treated with simple observation. Intubated patients, in most instances, should receive a routine CT chest scan in their first assessment.