Phillip Schwartz | Harvard University (original) (raw)

Papers by Phillip Schwartz

Neurology, 1989

We evaluated the neuroprotective effect of MK-801, a noncompetitive, selective N-methyl-D-asparta... more We evaluated the neuroprotective effect of MK-801, a noncompetitive, selective N-methyl-D-aspartate receptor antagonist, in a neonatal hypoxic-ischemic animal model. Seven-day-old rats underwent bilateral ligation of the carotid arteries followed by exposure to an 8% oxygen atmosphere for 1 hr. We sacrificed the animals 72 hrs later and assessed the hypoxic-ischemic brain damage histologically. MK-801 (10 mg/kg), administered IP 0.5 hr before the hypoxia, completely prevented hypoxic-ischemic infarction in cerebral cortex, while treatment immediately and 1 hr after the end of the hypoxia resulted in 76% and 52% reduction in the infarcted area, respectively. MK-801, given 0.5 hr before and immediately after the insult, reduced striatal damage and, given 0.5 hr before, attenuated neuronal necrosis in hippocampal regions. These results show that in neonates MK-801 is neuroprotective even when administered up to 1 hr after the end of a hypoxic-ischemic insult.

Neurology, 1993

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspa... more Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% ± 7% of neocortex in unmedicated rats to 32% ± 8%, 51% ± 12%, 38% ± 19%, and 53% ± 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells ...

European Journal of Pharmacology, 1992

The neuroprotectivc effects of felbamatc were tested in a model of incomplete cerebral ischcmia a... more The neuroprotectivc effects of felbamatc were tested in a model of incomplete cerebral ischcmia and hypoxia in 7-day-old rat pups. Felbamatc pretreatment (300 mg/kg) reduced the surface of infarcted cortex following bilateral carotid ligation, by 42-49% compared to saline and dimethylsulfoxide (DMSO) controls, respectively. The number of necrotic neurons in the dentate gyrus was reduced by 77% over both DMSO controls and saline controls. These results suggest that felbamate deserves further evaluation for its therapeutic potential in hypoxia-ischemia.

Development, 2002

During development of the nervous system, neural progenitors arise in proliferative zones, then e... more During development of the nervous system, neural progenitors arise in proliferative zones, then exit the cell cycle and migrate away from these zones. Here we show that migration of cerebellar granule cells out of their proliferative zone, the external granule cell layer (EGL), is impaired in Bdnf–/– mice. The reason for impaired migration is that BDNF directly and acutely stimulates granule cell migration. Purified Bdnf–/– granule cells show defects in initiation of migration along glial fibers and in Boyden chamber assays. This phenotype can be rescued by exogenous BDNF. Using time-lapse video microscopy we find that BDNF is acutely motogenic as it stimulates migration of individual granule cells immediately after addition. The stimulation of migration reflects both a chemokinetic and chemotactic effect of BDNF. Collectively, these data demonstrate that BDNF is directly motogenic for granule cells and provides a directional cue promoting migration from the EGL to the internal gran...

Molecular and Cellular Biology, 1994

Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (H... more Human proenkephalin gene transcription is transactivated by human T-cell leukemia virus type I (HTLV-I) Tax in human Jurkat T lymphocytes. This transactivation was further enhanced in Jurkat cells treated with concanavalin A, cyclic AMP, or 12-O-tetradecanoylphorbol-13-acetate. Deletion and cis-element transfer analyses of the human proenkephalin promoter identified a cyclic AMP-responsive AP-1 element (-92 to -86) as both necessary and sufficient to confer Tax-dependent transactivation. Different AP-1 or cyclic AMP-responsive element-binding protein (CREB)/activating transcription factor (ATF) proteins which bind this element were expressed in murine teratocarcinoma F9 cells to identify those capable of mediating Tax-dependent transactivation of human proenkephalin gene transcription. Although CREB, c-Fos, c-Jun, and JunD did not have significant effects, JunB inhibited the Tax-dependent transactivation. In contrast, ATF3 dramatically induced Tax-dependent transactivation, which wa...

Proceedings of the National Academy of Sciences, 2013

Significance Covalent kinase inhibition strategies are reemerging, but critical gaps in the under... more Significance Covalent kinase inhibition strategies are reemerging, but critical gaps in the understanding of molecular determinants of potency still persist. A kinetic approach is developed to describe the components of overall inhibitor potency (reversible binding and chemical reactivity). Detailed kinetic descriptions of EGFR covalent drugs are provided. Reversible interactions of covalent inhibitors are found to be essential to biochemical and cellular potency. A dynamic linkage between available affinity and necessary reactivity is proposed. Cysteine oxidation is an emerging type of posttranslational modification. Specific oxidation of the EGF receptor cysteine nucleophile causes highly variable effects on inhibitor potency. Two mechanisms of drug resistance are identified (reversible cysteine–inhibitor warhead interactions and specific cysteine oxidation) as well as a rational framework for understanding and designing covalent inhibitors.

Molecular Psychiatry, 1998

Cerebellar pathology in BDNF −/− mice: the classic view of neurotrophins is changing Recent studi... more Cerebellar pathology in BDNF −/− mice: the classic view of neurotrophins is changing Recent studies of neurotrophin knockout mice shed light on the distinct requirements for neurotrophins in the central as compared to the peripheral nervous system. These findings reveal pleiotropic roles for neurotrophins including roles in neuronal patterning and differentiation.

Bioorganic Chemistry, 2011

Protein kinases are fascinating biological catalysts with a rapidly expanding knowledge base, a g... more Protein kinases are fascinating biological catalysts with a rapidly expanding knowledge base, a growing appreciation in cell regulatory control, and an ascendant role in successful therapeutic intervention. To better understand protein kinases, the molecular underpinnings of phosphoryl group transfer, protein phosphorylation, and inhibitor interactions are examined. This analysis begins with a survey of phosphate group and phosphoprotein properties which provide context to the evolutionary selection of phosphorylation as a central mechanism for biological regulation of most cellular processes. Next, the kinetic and catalytic mechanisms of protein kinases are examined with respect to model aqueous systems to define the elements of catalysis. A brief structural biology overview further delves into the molecular basis of catalysis and regulation of catalytic activity. Concomitant with a prominent role in normal physiology, protein kinases have important roles in the disease state. To facilitate effective kinase drug discovery, classic and emerging approaches for characterizing kinase inhibitors are evaluated including biochemical assay design, inhibitor mechanism of action analysis, and proper kinetic treatment of irreversible inhibitors. As the resulting protein kinase inhibitors can modulate intended and unintended targets, profiling methods are discussed which can illuminate a more complete range of an inhibitor's biological activities to enable more meaningful cellular studies and more effective clinical studies. Taken as a whole, a wealth of protein kinase biochemistry knowledge is available, yet it is clear that a substantial extent of our understanding in this field remains to be discovered which should yield many new opportunities for therapeutic intervention.

European Journal of Neuroscience, 2007

Neurotrophins are a large class of trophic factors located throughout the central nervous system.... more Neurotrophins are a large class of trophic factors located throughout the central nervous system. While the role of neurotrophins in neuronal survival and axon guidance is well known, their secondary role in modulating synaptic transmission and cell firing properties is largely unexplored. In this study we examined the expression of neurotrophins in the mouse medial nucleus of the trapezoid body (MNTB) and investigated the effect of exogenous brain‐derived neurotrophic factor (BDNF) application on the firing properties of MNTB principal cells. The expression levels of nerve growth factor, BDNF, neurotrophin‐3, neurotrophin‐4/5 and major receptor tyrosine kinase B was found to be moderate to high at postnatal day 12, indicating that the neurotrophins may have a role following synaptogenesis. A 2‐h exposure to exogenous BDNF (100 ng/mL) had a significant effect on principal cell firing properties and voltage‐gated potassium currents. Importantly, preincubation in BDNF increased the in...

An orally administered PTH may have prodigious advantages in the treatment of hypoparathyroidism ... more An orally administered PTH may have prodigious advantages in the treatment of hypoparathyroidism and osteoporosis. Unfortunately, the oral delivery of biologic macromolecules is characterized by a negligible bioavailability and a high dose-to-dose variability in absorption, resulting in difficulty in accurately titrating the drug effect. We present clinical study data of a novel oral peptide delivery technology demonstrating an enhanced bioavailability with reduced Cmax variability. Methods: A Phase I, open label crossover pharmacokinetic (PK) study to assess the safety and PK of oral PTH (1-34) in ten healthy male adult volunteers was conducted. The PK profile of a fixed dose - 1.5mg PTH (1-34) of three different oral formulations was compared. PTH (1-34) levels in the plasma of subjects was analyzed at a number of time points post administration, utilizing a PTH (1-34) immunoassay (IDS; Bolden, UK). In parallel, to assess the pharmacodynamic (PD) effect, serum calcium of subjects ...

Background: PTH(1-34) (Teriparatide) is an anabolic agent used in treatment of osteoporosis. It p... more Background: PTH(1-34) (Teriparatide) is an anabolic agent used in treatment of osteoporosis. It promotes bone formation and reduces the risk of vertebral and some non-vertebral fractures. The route of administration by daily subcutaneous (sc) injection can cause problems in certain patients. A new oral delivery system for human PTH(1-34) has been developed as a possible treatment option. Galitzer et al. presented pre-clinical data (ASBMR 2012, MO0402) and first-in-human results (ASBMR 2013, FR0378) on safety, tolerability and absorption dynamics of oral PTH(1-34) in various dosages. We now describe the pharmacokinetics (PK) of oral PTH(1-34) compared to sc and placebo in healthy subjects. Objective: A single-center, double blinded, triple crossover study was designed to compare the 1.8 mg optimal dose of oral PTH(1-34) against standard dosage of teriparatide injection and oral placebo. Method: The study was conducted following and in accordance with the Hadassah Medical Center ethic...

International Journal of Pharmaceutics: X, 2021

Please cite this article as: G. Burshtein, C. Itin, J.C.Y. Tang, et al., The combined effect of p... more Please cite this article as: G. Burshtein, C. Itin, J.C.Y. Tang, et al., The combined effect of permeation enhancement and proteolysis inhibition on the systemic exposure of orally administrated peptides: Salcaprozate sodium, soybean trypsin inhibitor, and teriparatide study in pigs, (2021),

Journal of Bone and Mineral Research, 2021

The standard treatment of primary hypoparathyroidism with oral calcium supplementation and calcit... more The standard treatment of primary hypoparathyroidism with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015 human PTH(1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral human PTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily, for 16 consecutive weeks and changes in calcium supplementation and alfacalcidol use, albuminadjusted serum calcium (ACa), serum phosphate, urinary calcium excretion and quality of life decreased (23%; p=0.0003) 2-hours following the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%; p= 0.07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p=0.03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism.

Neuron, 1997

Division of Neuroscience Mice with a targeted gene deletion of BDNF provide Children's Hospital a... more Division of Neuroscience Mice with a targeted gene deletion of BDNF provide Children's Hospital a good example of the discrepancy between the effects Boston, Massachusetts 02115 of a neurotrophin in the central and peripheral nervous systems. Histologic studies have indicated that BDNFresponsive neurons in the retina, cerebral cortex, hippo-Summary campus, and cerebellum all survive in the absence of BDNF; this is in contrast to the striking loss of BDNFresponsive neurons in PNS structures such as the dorsal While target-derived neurotrophins are required for root ganglia (Ernfors et al., 1994; Jones et al., 1994). the survival of developing neurons in the PNS, the Several explanations have been offered to explain this functions of neurotrophins in the CNS are unclear. discrepancy (Snider, 1994). First, it is possible that other Mice with a targeted gene deletion of brain-derived neurotrophins capable of binding and activating the neurotrophic factor (BDNF) exhibit a wide-based gait. BDNF receptor, TrkB, compensate for the absence of Consistent with this behavioral evidence of cerebellar BDNF in mutant animals in the CNS. Alternatively, there dysfunction, there is increased death of granule cells, may be redundancy among the neurotrophin receptors, stunted growth of Purkinje cell dendrites, impaired so that no single neurotrophin or receptor is required formation of horizontal layers, and defects in the rosfor survival of CNS neurons. A third possibility is that tral-caudal foliation pattern. These abnormalities are BDNF is necessary for normal development of the peaccompanied by decreased Trk activation in granule ripheral but not the central nervous system. Finally, the and Purkinje cells of mutant animals, indicating that critical functions of BDNF in CNS development may be both cell types are direct targets for BDNF. These distinct from its activity as a survival factor, such that data suggest that BDNF acts as an anterograde or responsive cells remain viable in the absence of neuroan autocrine-paracrine factor to regulate survival and trophin. For example, BDNF might act to regulate synmorphologic differentiation of developing CNS neuapse formation or cell morphology (McAllister et al., rons, and thereby affects neural patterning. 1995, 1996; Snider and Lichtman, 1996). We have chosen to focus on the cerebellum as a system in which to investigate the role of BDNF in the