Lawrence Tamarkin

Phase I and Pharmacokinetic Studies of CYT-6091, a Novel PEGylated Colloidal Gold-rhTNF Nanomedicine

Purpose: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients. Experimental Design: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart. Results: Doses from 50 μg/m2 to 600 μg/m2 were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m2, did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNFs dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue. Conclusions: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers. Clin Cancer Res; 16(24); 6139–49. ©2010 AACR.

Seasonal Affective Disorder and Phototherapy

Recognition that the timing of depressive episodes is related to the seasons goes back at least to Hippocrates (circa 400 B.C.),’ who noted that “melancholia occurs in the spring.” In the last 150 years many researchers have noted seasonal variations in affective episodes and in suicide, an indirect reflection of the incidence of depression. The suicide data, well reviewed by Kevan2 and A ~ c h o f f , ~ show a peak incidence in late spring and early summer. The incidence of depressive episodes is highest in spring and fall, whereas mania seems to occur most frequently in late summer.‘ Several authors have correkted the incidence of these occurrences with climatic variables such as sunshine and temperature and have shown statistically significant relationship^.^*^-^ Such survey studies, however, cannot establish a causal link between environmental influences and psychopathology. In order to probe the mechanisms by means of which these seasonal rhythms might be mediated, we have adopted a different strategy. We have recruited and studied a population of patients who have a history of extreme seasonal vulnerability to changes in mood and behavior. In this paper we summarize our experience with these patients and their condition, and discuss our interventions in their seasonal rhythms, and the extensive animal literature on which these interventions were patterned.

Nanomedicines: addressing the scientific and regulatory gap.

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared to materials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation.

Neurobiology of Seasonal Affective Disorder and Phototherapy

I. To whom all correspondence should be addressed, at the Clinical Psychobiology Branch, NIMH. Building 1.0/Room 4S-239, 9000 Rockville Pike, Bethesda. Maryland 20892. The investigation of the biochemical basis of seasonal affective disorder (SAD) and light therapy is a new field. As with any body of knowledge undergoing rapid expansion, the data, though interesting, are incomplete and at times even conflicting. In this paper, we attempt to organize and synthesize the information currently available into a coherent and understandable form.

Supersensitivity to melatonin suppression by light in young people at high risk for affective disorder. A preliminary report

Affective illness aggregates in families and appears to be heritable. Bipolar affective patients have been found to be supersensitive to the suppressive effect of light on the nocturnal secretion of melatonin, both in ill and well states. We tested young people aged 15 to 25 years with one manic-depressive parent (n = 18), major affective disorder on both sides of the family (n = 7), and age-matched controls (n = 20). The subjects in the high-risk groups were more likely to show supersensitivity in melatonin response to light at night than controls. Follow-up studies are necessary to assess the predictive value of this response.

The correlation between human plasma melatonin levels and urinary 6-hydroxymelatonin excretion

A significant correlation (0.76) has been found between nighttime peak plasma melatonin levels and the 24-h urinary excretion totals for conjugated 6-hydroxymelatonin for a group of 22 women. This study validates the comparison of plasma levels of the hormone or urinary levels of its metabolite to assess pineal gland production of melatonin in humans.

Translational considerations for cancer nanomedicine

There are many important considerations during preclinical development of cancer nanomedicines, including: 1) unique aspects of animal study design; 2) the difficulties in evaluating biological potency, especially for complex formulations; 3) the importance of analytical methods that can determine platform stability in vivo, and differentiate bound and free active pharmaceutical ingredient (API) in biological matrices; and 4) the appropriateness of current dose scaling techniques for estimation of clinical first-in-man dose from preclinical data. Biologics share many commonalities with nanotechnology products with regard to complexity and biological attributes, and can, in some cases, provide context for dealing with these preclinical issues. In other instances, such as the case of in vivo stability analysis, new approaches are required. This paper will discuss the significance of these preclinical issues, and present examples of current methods and best practices for addressing them. Where possible, these recommendations are justified using the existing regulatory guidance literature.

Chronic Clorgyline Treatment of Syrian Hamsters: An Analysis of Effects on the Circadian Pacemaker

Clorgyline, a type A monoamine oxidase inhibitor with antidepressant properties when administered to depressed patients, is often associated with disturbances of the human sleep-wake cycle. In order to assess its effects on the mammalian circadian system, this drug was administered chronically to Syrian hamsters. It was found to affect the hamster circadian system in four specific ways. Clorgyline increased the intrinsic period of wheel-running ac tivity, altered the phase response curve to brief light pulses, altered the educed waveform of running activity in animals maintained in light-dark cycles or constant darkness, and in creased the activity-rest ratio in animals maintained in constant darkness. Our data support the interpretation that clorgyline exhibits direct or indirect input to the circadian pacemaker and alters the processing of photic information to the pacemaker.

Plasma melatonin and the hormone-dependency of human breast cancer.

We studied the 24-hour plasma melatonin profile in three groups of women: normal individuals, women with breast cancer, and women at high risk for breast cancer, to determine the relationship of plasma melatonin to this malignancy. The mean daytime (nadir) and mean nighttime (peak) plasma levels for the normal subjects were 9.1 pg/mL and 70.9 pg/mL, respectively. The mean daytime and nighttime plasma levels, and the range of melatonin day to night differences for women with breast cancer and women at high risk for breast cancer were comparable to each other and to the normal subjects, with no statistically significant differences noted. The patients with breast cancer demonstrated a striking correlation between the melatonin diurnal rhythm and the steroid receptor content of the primary tumor. Women with estrogen (ER) or progesterone (PR) receptor-positive tumors had a significantly lower mean plasma melatonin day to night difference than did patients with ER- or PR-negative tumors. Further, a strong inverse correlation was observed between the plasma melatonin concentration and the quantities of ER and PR in the primary tumor: the lower the plasma melatonin concentration the greater the amount of either receptor in the primary tumor. Plasma melatonin did not correlate with tumor glucocorticoid receptor content or stage of breast cancer among these patients, or with menopausal status, age, parity, or the plasma levels of estrone, estradiol, progesterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH) among all individuals studied. Plasma melatonin was also independent of the degree of risk for breast cancer among the high-risk patients. These findings suggest an important relationship between the plasma melatonin diurnal rhythm and the hormone dependency of human breast cancer, and may have implications for both the prognosis and treatment of this malignancy.

Photic regulation of the melatonin rhythm: monkey and man are not the same

Laboratory of Clinical Psychopharmacology, Division of Special Mental Health Research, Intramural Research Program, National Institute Mental Health, Saint Elizabeths Hospital, Washington D.C. 20032 and (S.M.R., L.T. and D.C.K.) Section of Neuroendocrinology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md. 20014 (U.S.A.)