Identification, characterization, and implications of species-dependent plasma protein binding for the oral Hedgehog pathway inhibitor vismodegib (GDC-0449)

Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is ≥95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug concentrations and α-1-acid glycoprotein (AAG) in a phase I study. Biophysical and cellular techniques have been used to reveal that vismodegib strongly binds to human AAG (K(D) = 13 μM) and binds albumin with lower affinity (K(D) = 120 μM). Additionally, binding to rat AAG is reduced ～20-fold relative to human, whereas the binding affinity to rat and human albumin was similar. Molecular docking studies reveal the reason for the signficiant species dependence on binding. These data highlight the utility of biophysical techniques in creating a comprehensive picture of protein binding across species.     

Impact of parent and teacher concordance on diagnosing attention deficit hyperactivity disorder and its sub-types

Objective  This study examines the extent to which parents and teachers agree on the diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) and its subtypes, as per the DSM IV criteria. It assesses whether the extent of agreement between informants improves by making the ADHD criteria more flexible. Methods  Parents and teachers of 119 clinic-referred sample of children (mean age=8.4 years, S.D= 2.48) with disruptive behavioral symptoms completed the Vanderbilt Attention Deficit Hyperactivity Disorder Diagnostic Parent and Teacher Rating Scales, respectively. Concordance of parent and teacher reports for the presence or absence of diagnosis of ADHD and type of ADHD was examined by percent agreement and the kappa statistics. Results  Of the 119 children referred for disruptive behavior disorders, 96 (80.6%) met criteria for any type of ADHD according to the parents’ report; and only 68 (57.1%) met criteria according to the teachers’ report. Parent and teacher agreement for the diagnosis of any type of ADHD was only 52% :(k= .11, n.s); and the agreement regarding diagnosis of sub-type was even poorer. Making the criteria more flexible vis-à-vis impairment or number of symptoms did not improve agreement between the informants. Conclusion  Clear guidelines are needed to reconcile the differences between informants in order to promote uniform diagnostic practices among clinicians working with children having ADHD.     

“Getting physical”: the management of neuropsychiatric disorders using novel physical treatments

Objective

To summarize and review the utility of physical interventions in the treatment of psychiatric disorders.

Methods

A systematic review of the literature pertaining to novel physical interventions, namely, transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, and neurosurgery, was conducted using MEDLINE, EMBASE, and PSYCHLIT. Bibliographies of papers were scrutinized for further relevant references along with literature known to the authors.

Results

Currently available physical interventions worldwide are reviewed with respect to efficacy, applications, and putative indications. Physical interventions have experienced a resurgence of interest for both the investigation of brain function and the treatment of neuropsychiatric disorders. The widespread availability of neuroimaging technology has advanced our understanding of brain function and allowed closer examination of the effects of physical treatments. Clinically, transcranial magnetic stimulation seems likely to have a role in the management of depression, and its use in other neuropsychiatric disorders appears promising. Following on from its success in the management of intractable epilepsy, vagus nerve stimulation is undergoing evaluation in the treatment of depression with some success in refractory cases. Deep brain stimulation has improved mood in patients with Parkinson’s disease and may also relieve symptoms of obsessive-compulsive disorder. Neurosurgery has re-invented itself by way of increased technical sophistication, and although further assessment of its efficacy and clinical utility is still needed, its widespread practice reflects its increasing acceptance as a viable treatment of last resort.

Conclusion

It is clear that physical treatments are here to stay and “getting physical” offers a useful addition to the neuropsychiatrist’s therapeutic armamentarium. However, like all new treatments these interventions need to remain under rigorous scientific scrutiny to determine accurately their immediate and long-term effects.     

Evaluation of the cost of CA-125 measurement,physical exam,and imaging in the diagnosis of recurrent ovarian cancer

Objective

Ovarian cancer accounts for 50% of deaths from gynecologic malignancies. We sought to determine the cost of common methods of surveillance of women with ovarian cancer in first clinical remission. The current standard for post treatment surveillance is the National Comprehensive Cancer Network (NCCN) guidelines.

Methods

We retrospectively determined how recurrence was initially detected at our institution and a cost model was created and applied to the United States population to calculate surveillance costs using the Surveillance Epidemiology & End Results (SEER) database.

Results

57% (n = 60) of first recurrences were identified by increasing CA 125 level. Routine office visit identified 27% (n = 29) of recurrences, and 15% (n = 16) were diagnosed initially with CT scan. In 5% (5/105), CT abnormality was the only finding. 95% (100/105) of patients had either elevated CA 125 or office visit findings at time of recurrence. Of the 22,000 women diagnosed with ovarian cancer yearly, 60% (n = 13,266) will have advanced disease and are likely to recur. The surveillance cost for this population for 2 years using our model is $32,500,000 using NCCN guidelines and $58,000,000 if one CT scan is obtained.

Conclusions

Our data suggests that following NCCN guidelines will detect 95% of recurrences. An additional $26 million will be needed to identify the 5% of women with recurrence seen on CT only. Post treatment surveillance of ovarian cancer patients contributes significantly to health care costs. Use of CT scan to follow these patients largely increases cost with only a small increase in recurrence detection.