Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.

Brain morphological changes and early marijuana use: a magnetic resonance and positron emission tomography study.

BACKGROUND: The focus of this report is on the possible role that the age of first use of marijuana may play on brain morphology and function. METHODS: Magnetic resonance imaging (MRI) and positron emission tomography (PET) were utilized to study 57 subjects. Brain volume measures (whole brain, gray matter, white matter and lateral ventricle volumes), global cerebral blood flow (CBF) and body size were evaluated. RESULTS: There are three primary findings related to age of first use of marijuana. Subjects who started using marijuana before age 17, compared to those who started later, had smaller whole brain and percent cortical gray matter and larger percent white matter volumes. Functionally, males who started using marijuana before 17 had significantly higher CBF than other males. Both males and females who started younger were physically smaller in height and weight, with the effects being greater in males. CONCLUSIONS: These findings suggest that the age at which exposure to marijuana begins is important. Early adolescence may be a critical period for effects that are not present when exposure begins later. These results are discussed in light of reported effects of marijuana on gonadal and pituitary hormones.

Aging and recognition memory: changes in regional cerebral blood flow associated with components of reaction time distributions.

We used H(2)15O positron emission tomography (PET) to measure age-related changes in regional cerebral blood flow (rCBF) during a verbal recognition memory task. Twelve young adults (20 to 29 years) and 12 older adults (62 to 79 years) participated. Separate PET scans were conducted during Encoding, Baseline, and Retrieval conditions. Each of the conditions involved viewing a series of 64 words and making a two-choice response manually. The complete reaction time (RT) distributions in each task condition were characterized in terms of an ex-Gaussian model (convolution of exponential and Gaussian functions). Parameter estimates were obtained for the mean of the exponential component (tau), representing a task-specific decision process and the mean of the Gaussian component (mu) representing residual sensory coding and response processes. Independently of age group, both tau and mu were higher in the Encoding and Retrieval conditions than in the Baseline condition, and tau was higher during Retrieval than during Encoding. Age-related slowing in task performance was evident primarily in mu. For young adults, rCBF activation in the right prefrontal cortex, in the Retrieval condition, was correlated positively with mu but not with tau. For older adults, rCBF changes (both increases and decreases) in several cortical regions were correlated with both mu and tau. The data suggest that the attentional demands of this task are relatively greater for older adults and consequently lead to the recruitment of additional neural systems during task performance.

Adult age differences in the functional neuroanatomy of verbal recognition memory.

Adult age differences are frequently observed in the performance of memory tasks, but the changes in neural function mediating these differences are largely unknown. We used (H2)15O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) during Encoding, Baseline, and Retrieval conditions of a recognition memory task. Twelve young adults (20-29 years) and 12 older adults (62-79 years) participated. During each task condition, participants made a two-choice manual response to each of 64 words. Analyses of the performance data yielded evidence of age-related slowing of encoding and retrieval processes, and an age-related decline in the accuracy of yes/no recognition (d'). The rCBF activation associated with both encoding and retrieval was greater for older adults than for young adults, but this pattern was more clearly evident for memory retrieval. For young adults, rCBF activation during retrieval occurred primarily in right prefrontal cortex, whereas older adults exhibited a more bilateral pattern of prefrontal activation. Regression analyses predicting reaction time in the memory task from regional PET counts confirmed that the neural system mediating memory retrieval is more widely distributed for older adults than for young adults. Both age groups exhibited some decrease in rCBF activation in the second half of the test session, relative to the first half. The practice-related decrease in rCBF activation was more prominent for young adults, suggesting that the older adults' recruitment of additional neural systems reflects a more continual allocation of attention to support task performance.

Detection of Recurrent Brain Tumor. Comparison of MR Registered Camera-Based and Dedicated PET Images.

The purpose of this study is to compare the quality of images and the results of camera-based and dedicated position emission tomography (PET) in the same patients with suspected recurrent or persistent brain tumor after therapy. Both PET studies were interpreted using registration with contrast-enhanced magnetic resonance imaging (MRI) studies. Twenty-three patients with 24 contrast-enhancing lesions by MRI were included. Camera-based PET images were more difficult to register and resulted in less accurate automated determination of the edge because of image noise. Dedicated PET images demonstrated better gray matter to white matter discrimination in every patient. Camera-based PET identified tumor in 17 of 19 lesions that were abnormal for tumor by dedicated PET. Camera-based PET identified absence of tumor in 4 of 5 lesions considered negative for tumor by dedicated PET. Thus, despite the limitations related to camera-based PET, the overall concordance of interpretation using MRI registered images is good.

Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion size in male rats.

This study was undertaken to determine the effects of estrogen and testosterone on cerebral ischemic lesion size induced by middle cerebral artery (MCA) occlusion in male rats. Rats were gonadectomized and treated with testosterone, estrogen, or testosterone plus estrogen filled Silastic pellets. The animals were divided into 6 groups: intact, intact + estrogen (E2), castrate, castrate + testosterone (T), castrate + E2, and castrate + T + E2. One week after treatment, cerebral ischemia was induced by MCA occlusion for 40 min, followed by reperfusion. After 24 h, rats were sacrificed and slices were then stained to assess lesion size. The presence of testosterone increased and the removal of testosterone decreased lesion size. A strong positive correlation (r2 = 0.922) between plasma testosterone concentrations and ischemic lesion size was observed. Estradiol treatment reduced ischemic area. In summary, the present study provides evidence that testosterone exacerbates and estrogens ameliorate ischemic brain damage in an animal model of cerebral ischemia.

Selective and divided visual attention: age-related changes in regional cerebral blood flow measured by H2(15)O PET.

Regional cerebral blood flow (rCBF) was measured using H2(15)O and positron emission tomography (PET) to test the hypothesis that age-related changes in the pattern of rCBF activation would be greater under divided attention conditions than under selective attention conditions. Subjects were 24 right-handed men: 12 young adults (age 21-28 years), and 12 older adults (age 60-77 years). Measurement of rCBF was obtained during performance of three visual search task conditions, each of which involved viewing a series of nine-letter displays and making a two-choice button press response to each display. Analyses of subjects' mean reaction time and error rate confirmed that older adults' search performance was disproportionately impaired when it was necessary to divide attention among the display positions. The rCBF data indicated that attending selectively to a target letter in a known (central) location was not associated with cortical activation for either age group. The requirement to divide attention among the display positions led to rCBF activation in occipitotemporal, occipitoparietal, and prefrontal cortical regions. In the divided-attention condition, rCBF activation in the occipitotemporal pathway was relatively greater for young adults; activation in prefrontal regions was relatively greater for older adults. These differences in rCBF activation were related to search reaction time and suggest that, when attention was divided, young adults' performance relied primarily on letter identification processes, whereas older adults required the recruitment of additional forms of task control.

Pilot study of positron emission tomography in patients with advanced head and neck cancer receiving radiotherapy and chemotherapy.

BACKGROUND: Positron emission tomography (PET) provides a noninvasive modality for evaluating the biochemical processes of normal and pathologic tissue. Preliminary reports of F-18 fluorodeoxyglucose (FDG) PET indicate its potential usefulness in evaluating head and neck tumors. The current study was performed to explore the relationship between changes in tumor FDG metabolism and local control in patients receiving hyperfractionated radiotherapy and concurrent chemotherapy. METHODS: The study group consisted of six patients with locally advanced, nonmetastatic squamous cell carcinoma of the head and neck. FDG studies were performed prior to, during, and 24 months post-therapy. Ratios of tumor to nontumor FDG uptake in regions of interest (ROI) were compared. RESULTS: All pretherapy studies demonstrated a focal hypermetabolic abnormality corresponding to the known tumor. The pretherapy tumor to nontumor FDG ratios declined significantly during therapy (p < 0.05) with a similar continued trend post-therapy (p < 0.07). CONCLUSION: The treatment-induced decrease in tumor hypermetabolism as seen on serial FDG PET parallels the clinical response in squamous carcinoma of the head and neck. Two-year follow-up scans also suggest that continued low tumor to nontumor ratios reflect eradication of local disease. Because of its high cost, a study of larger numbers of patients is necessary to better define the role of PET in the management of head and neck cancer.

An interactive, computer-based atlas of neurologic positron emission tomographic studies for use in teaching.

Recent developments in personal computer hardware and software allow the manipulation of radiologic images. We developed an interactive, computer-based atlas of clinical neurologic positron emission tomographic studies for use as an educational resource. A personal computer and multimedia software were used to assemble the clinical case studies. For each clinical case, the user had available the clinical history, positron emission tomographic and correlative anatomic images, study interpretation, discussion, and references. The clinical cases were selected for their educational value, either as a representative example of an abnormality or for their ability to illustrate a common pitfall in positron emission tomographic imaging of the brain.

Cerebral glucose utilization in motor neuron disease.

Positron emission tomography with fluorodeoxyglucose F 18 (18F-fluorodeoxyglucose) was used to examine regional cerebral glucose metabolism in individuals with motor neuron disease. Motor neuron disease involves selective loss of motor neurons, large pyramidal cells in the motor cortex, and corticospinal tract degeneration. We postulated that the local cerebral metabolic rate of glucose should correlate with this regional neuronal cell loss. Glucose metabolism values in patients with motor neuron disease were reduced compared with those of controls in several regions; however, when corrected for multiple comparisons, no significant difference was observed between patients with motor neuron disease and age-matched controls. No correlation was noted between the local cerebral metabolic rate of glucose and duration or severity of illness. Correlation between metabolic changes with objective findings on neurologic examination, including motor weakness and tendon reflexes, provided interesting results, including a decline in glucose metabolism with progressive weakness and upper motor neuron dysfunction. Moreover, in supplementary motor areas, there appears to be an increase in regional glucose metabolism as the neurologic condition deteriorates, possibly representing increased metabolic activity of the motor association cortex in response to primary loss of pyramidal cells.

The effects of carbidopa administration on 6-[18F]fluoro-L-dopa kinetics in positron emission tomography.

Carbidopa (L-alpha-hydrazino-alpha-methyl-b-(3,4-dihydroxyphenyl) propionic acid is a known inhibitor of aromatic amino acid decarboxylase. In both humans and monkeys, we studied the effects of carbidopa on plasma and brain kinetics of 6-[18F]fluoro-L-DOPA (FDOPA), an analog of L-DOPA used for PET studies of the central dopaminergic system. Pretreatment with carbidopa resulted in increases in the plasma levels of FDOPA and 3-O-methyl-6-[18F]fluoro-L-DOPA (3-OMFD). Total striatal and cerebellar activities measured with PET were also increased. Furthermore, increases observed in the specific striatal activity (striatum minus cerebellum total activity) were correlated with increases in the plasma FDOPA curve. Carbidopa pretreatment did not affect the influx rate constant (K) for FDOPA from plasma to striatum in humans as determined by Patlak graphical analysis. Thus, an increase in measured striatal tomographic activity was secondary to the increase in plasma FDOPA levels rather than as a result of changes in the FDOPA influx rate constant.

Primary surgical repair of severe peripheral marginal ectasia in Terrien's marginal degeneration.

We have developed a safe, successful, and simple procedure for repairing the severe peripheral marginal ectasia in Terrien's marginal degeneration. The area of ectasia is incised along its thinnest paralimbal dimension down to Descemet's membrane. Ectatic stroma along both sides of the incision is then undermined until normal-thickness stroma is reached. After excision of excess ectatic stroma, if necessary, the normal-thickness stroma is then sutured together, primarily with 9-0 Prolene. The sutures are left in place permanently, and the remaining refractive error is corrected with spectacles or contact lenses. This technique substantially improved visual acuity in three of four patients and decreased corneal astigmatism in all four. Although one eye required resuturing, there were no complications in any case.

A variant of fibrous dysplasia (osteofibrous dysplasia).

We are reporting the cases of five patients with a tumor-like lesion that has recently been called osteofibrous dysplasia but has also been called osteogenic fibroma, monostotic cortical fibrous dysplasia, and a variant of fibrous dysplasia. The lesions in our patients developed in childhood and were located in the diaphysis of the tibia, which was bowed anteriorly. The structural stability of the limb was not affected. In four patients the lesion recurred after a biopsy and curettage was performed in childhood. No further surgical procedure was done until the patients reached skeletal maturity. The lesion in one patient was biopsied at the age of twenty-one years. No subsequent treatment was recommended.

Dumbbell neuroblastomas in children.

A "dumbbell" neuroblastoma is a malignant neoplasm usually primary in the mediastinum or retroperitoneum with posterior extension through an intervertebral foramen to additional tumor within the spinal canal. Neurologic deficits are found in almost all cases. Nineteen patients with such tumors were reviewed with respect to diagnosis, management, and results. Treatment consisted of prompt laminectomy with total or subtotal excision of the extradural tumor. The primary tumor in the mediastinum or retroperitoneal area was removed at a second stage. All patients received postoperative radiation therapy. Eleven of the 17 patients observed more than two years are free of disease, a cure rate much higher than the overall experience with neuroblastoma. Substantial recovery of neurologic function occurred in most, but kyphoscoliotic deformities were a disturbingly frequent late complication.