Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Minimally disruptive decompression and transforaminal lumbar interbody fusion.

BACKGROUND: Posterior spinal procedures through tubular exposures have been described. However, tubes restrain visibility and require co-axial instrument manipulation, increasing difficulty and potentially compromising surgical results. An independent-blade retractor system overcomes the obstacles of working through a tube and has been used to perform minimally-disruptive decompression and instrumented tranforaminal lumbar interbody fusion (TLIF). PURPOSE: To evaluate the advantages to patient recovery and surgical efficacy of this technique. METHODS/RESULTS: Retrospective review of technique employing a minimally-disruptive approach to decompression and transforaminal lumber interbody fusion (TLIF). CONCLUSIONS: Minimally-disruptive decompression and instrumented TLIF can be performed in a safe and effective manner using an independent-blade retractor system. Relative to traditional-open techniques, surgical goals can be accomplished, but with the benefits of minimally-disruptive surgery.     

166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.     

Etomidate for Rapid-sequence Intubation in Young Children: Hemodynamic Effects and Adverse Events

OBJECTIVES: Physicians commonly use etomidate for adult rapid-sequence intubation (RSI), but the manufacturer does not recommend its use for children under 10 years of age due to a lack of data. The authors present their experience with etomidate for pediatric RSI in order to further develop its risk-benefit profile in this age group. METHODS: Trained abstractors reviewed the medical records for all children under 10 years old who received etomidate for RSI between July 1996 and April 2001. RESULTS: 105 children, with an average age of 3 (+/-2.9) years, received a median dose of 0.32 (+/-0.12) mg/kg of etomidate. The systolic blood pressure increased an average of 4 mm Hg (95% CI = -3.3 to 9.2); the diastolic blood pressure increased 7 mm Hg (95% CI = -3.1 to 11) within 10 minutes of receiving etomidate. The heart rate increased an average of 10 beats/min (95% CI = 4.0 to 17.4). Complications included three patients who vomited within 10 minutes of etomidate administration. There were no cases of documented myoclonus, status epilepticus, or new-onset seizures. Thirty-eight patients received corticosteroids during the hospital course, none for suspected adrenal insufficiency. Three patients died, all from severe brain injury. CONCLUSIONS: In children less than 10 years old, etomidate seems to produce minimal hemodynamic changes, and appears to have a low risk of clinically important adrenal insufficiency, myoclonus, and status epilepticus. The association between etomidate and emesis (observed in less than 3% of enrolled patients) remains unclear. For clinical situations in which minimal blood pressure changes during RSI are critical, etomidate appears to have a favorable risk-benefit profile for children under 10 years old.