Keith R Pennypacker

US Patent:

20070160975, Jul 12, 2007

Filed:

Jan 9, 2007

Appl. No.:

11/621196

Inventors:

Javier Cuevas - Lutz FL, US
Keith Pennypacker - Wesley Chapel FL, US

Assignee:

UNIVERSITY OF SOUTH FLORIDA - Tampa FL

International Classification:

C12Q 1/00
G01N 33/567

US Classification:

435004000, 435007200

Abstract:

A method of in vitro screening for compounds for treating strokes at delayed timepoints of administration following the onset of stroke. In a first aspect the method includes the step of contacting neurons with azide/deoxyglucose to induce ischemia, contacting with a compound of interest at a later timepoint and assessing neuronal death. A reduction in neuronal death at the later timepoint relative to one or more controls indicates the compound of interest is a candidate for stroke treatment in vivo at delayed timepoints. In another aspect the method includes the step of contacting neurons with an inflammatory agent, such as a lipopolysaccharide, contacting with a compound of interest and assessing the inflammatory response. The methods allow for screening of compounds at higher throughput and lower cost than in vivo methods currently used. Compounds exhibiting promise in the in vitro system can be further characterized by traditional in vivo screening.

US Patent:

20110201688, Aug 18, 2011

Filed:

Apr 20, 2011

Appl. No.:

13/090828

Inventors:

Keith Pennypacker - Wesley Chapel FL, US
Javier Cuevas - Lutz FL, US
Jon Antilla - Tampa FL, US

Assignee:

UNIVERSITY OF SOUTH FLORIDA - Tampa FL

International Classification:

A61K 31/155
C07C 279/18
C07C 277/06
A61P 9/10

US Classification:

514634, 564238, 564239

Abstract:

1,3 di-o-tolylguanidine (DTG) was examined as anti-stroke drug with a broad therapeutic window. DTG activates sigma 1 and 2 receptors. Administration of DTG at 24 hours post-stroke to rats reduces neurodegeneration by 85%; this is the only pharmacological agent that has been used successfully at this delayed timepoint. Treatment with DTG provides protection of neurons exposed to hypoxia and blocks activation of immune cells that are responsible for delayed neurodegeneration associated with stroke. Disclosed is an altered DTG structure, placing a bromide at the para position to increase tissue penetrance and efficacy. Results show that N,N′-di-p-bromophenyl guanidine protects cultured neurons under hypoxic conditions but is more potent than DTG. Moreover, N,N′-di-p-bromophenyl guanidine is as least as efficacious as DTG in treating rats 24 hours after experimental stroke.

US Patent:

20130129673, May 23, 2013

Filed:

Aug 27, 2012

Appl. No.:

13/595130

Inventors:

Keith Ronald Pennypacker - Wesley Chapel FL, US
Alison Elizabeth Willing - Tampa FL, US

Assignee:

UNIVERSITY OF SOUTH FLORIDA - Tampa FL

International Classification:

A61K 38/20
G01N 33/68
A61K 38/19

US Classification:

424 852, 424 851, 435 74, 435 721, 435 71, 506 9, 435 612

Abstract:

Oligodendrocytes (OLs), the predominant cell type found in cerebral white matter, are essential for structural integrity and proper neural signaling. Very little is known concerning stroke-induced OL dysfunction. Infusion of human umbilical cord blood (HUCB) cells protects striatal white matter tracts in vivo and directly protects mature primary OL cultures from oxygen glucose deprivation (OGD). Microarray studies of RNA prepared from OL cultures subjected to OGD and treated with HUCB cells showed an increase in the expression of 33 genes associated with OL proliferation, survival, and repair functions, such as myelination. Immunohistochemistry showed antioxidant protein expression was upregluated in the ipsilateral white matter tracts of rats infused with HUCB cells 48 hrs after middle cerebral artery occlusion (MCAO). These results show expression of genes induced by HUCB cell therapy that could confer oligoprotection from ischemia.

US Patent:

20140080885, Mar 20, 2014

Filed:

Sep 13, 2013

Appl. No.:

14/026165

Inventors:

Keith R. Pennypacker - Wesley Chapel FL, US
Shyam S. Mohapatra - Tampa FL, US

Assignee:

University of South Florida (A Florida Non-Profit Corporation) - Tampa FL

International Classification:

A61K 31/403

US Classification:

514411

Abstract:

Embodiments of the present disclosure provide methods of treating a traumatic brain injury with an agent. In particular, embodiments of the present disclosure provide for methods of treating a traumatic brain injury using an agent such as ()-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine or an isomer, a tautomer, or a prodrug thereof, or pharmaceutically acceptable salt each of these.

US Patent:

20070123556, May 31, 2007

Filed:

Jun 6, 2006

Appl. No.:

11/422505

Inventors:

Keith Pennypacker - Wesley Chapel FL, US
Javier Cuevas - Lutz FL, US

Assignee:

UNIVERSITY OF SOUTH FLORIDA - Tampa FL

International Classification:

A61K 31/473
A61K 31/195
A61K 31/155

US Classification:

514289000, 514634000, 514561000

Abstract:

A method of post-stroke treatment at delayed timepoints with sigma receptor agonists. Sigma receptors are promising targets for neuroprotection following ischemia. One of the key components in the demise of neurons following ischemic injury is the disruption of intracellular calcium homeostasis. The sigma receptor agonist, DTG, was shown to depress [Ca]elevations observed in response to ischemia induced by sodium azide and glucose deprivation. Two sigma receptor antagonists, metaphit and BD-1047, were shown to blunt the ability of DTG to inhibit ischemia-evoked increases in [Ca]. DTG inhibition of ischemia-induced increases in [Ca]was mimicked by the sigma-1 receptor-selective agonists, carbetapentane, (+)-pentazocine and PRE-084, but not by the sigma-2 selective agonist, ibogaine, showing that activation of sigma-1 receptors is responsible for the effects. Activation of sigma receptors can ameliorate [Ca]dysregulation associated with ischemia in cortical neurons, providing neuroprotective properties. The effects of 1,3-di-o-tolyguanidine (DTG), a high affinity sigma receptor agonist, as a potential treatment for decreasing infarct area at delayed time points was further examined in rats. DTG treatment significantly reduced infarct area in both cortical/striatal and cortical/hippocampal regions by >80%, relative to control rats. These findings were confirmed by immunohistochemical experiments using the neuronal marker, mouse anti-neuronal nuclei monoclonal antibody (NeuN), which showed that application of DTG significantly increased the number of viable neurons in these regions. Furthermore, DTG blocked the inflammatory response evoked by MCAO, as indicated by decreases in the number of reactive astrocytes and activated microglia/macrophages detected by immunostaining for glial fibrillary acidic protein (GFAP) and binding of isolectin IB4, respectively. Thus, the sigma receptor-selective agonist, DTG, can enhance neuronal survival when administered 24 hr after an ischemic stroke. In addition, the efficacy of sigma receptors for stroke treatment at delayed time points is likely the result of combined neuroprotective and anti-inflammatory properties of these receptors.

US Patent:

20160151311, Jun 2, 2016

Filed:

Feb 4, 2016

Appl. No.:

15/015796

Inventors:

Keith R. Pennypacker - Wesley Chapel FL, US
Alison Willing - Tampa FL, US
Javier Cuevas - Lutz FL, US
Jon C. Antilla - Tampa FL, US

Assignee:

University of South Florida - Tampa FL

International Classification:

A61K 31/155

Abstract:

A method of treating stroke by administration of a novel sigma agonist is presented. Twenty-four hours after MCAO, systemic administration of several novel sigma agonists including: Bromo-DTG; Chloro-DTG; N,N′-di-1-Naphthylguanidine hydrochloride (NAGH); N,N′-di-p-Nitrophenylguanidine HCL (NAD) or vehicle were injected subcutaneously daily for 3 days. Rats treated with Bromo-DTG and Chloro-DTG had no significant improvements in any of the motor or cognitive tests while NAGH treated rats showed improved vertical movement and had significantly less motor asymmetry and bias than vehicle treated rats. Sigma receptor agonist NAGH also was found to exert its long-term neuroprotective effects by preserving both gray matter and white matter tracts. Both NAD and NAGH, when administered 24 hours after experimental stroke, reduced neural damage and enhanced behavioral recovery thirty days later which suggests that NAGH and NAD potentially extend the therapeutic window of stroke several fold over the current treatments.

US Patent:

20150238502, Aug 27, 2015

Filed:

Oct 17, 2013

Appl. No.:

14/433172

Inventors:

- Tampa FL, US
Keith Pennypacker - Wesley Chapel FL, US

Assignee:

University of South Florida - Tampa FL

International Classification:

A61K 31/55
A61K 38/48
C07D 487/04

Abstract:

Provided herein is a method of treating a subject believed to have suffered a stroke. This method comprises administering to the subject therapeutically effective amount of a composition comprising conivaptan or an active derivative, stereoisomer, pro-drug, or pharmaceutically acceptable salt thereof.

US Patent:

20150051291, Feb 19, 2015

Filed:

Nov 3, 2014

Appl. No.:

14/531296

Inventors:

Keith R. Pennypacker - Wesley Chapel FL, US
Alison Willing - Tampa FL, US
Javier Cuevas - Lutz FL, US
Jon C. Antilla - Tampa FL, US

Assignee:

UNIVERSITY OF SOUTH FLORIDA - Tampa FL

International Classification:

C07C 279/18

US Classification:

514634, 564238

Abstract:

A composition and method of treating stroke by administration of a novel sigma agonist is presented. Twenty-four hours after MCAO, systemic administration of several novel sigma agonists including: Bromo-DTG; Chloro-DTG; N,N′-di-1-Naphthylguanidine hydrochloride (NAGH); N,N′-di-p-Nitrophenylguanidine HCL (NAD) or vehicle were injected subcutaneously daily for 3 days. Rats treated with Bromo-DTG and Chloro-DTG had no significant improvements in any of the motor or cognitive tests while NAGH treated rats showed improved vertical movement and had significantly less motor asymmetry and bias than vehicle treated rats. Sigma receptor agonist NAGH also was found to exert its long-term neuroprotective effects by preserving both gray matter and white matter tracts. Both NAD and NAGH, when administered 24 hours after experimental stroke, reduced neural damage and enhanced behavioral recovery thirty days later which suggests that NAGH and NAD potentially extend the therapeutic window of stroke several fold over the current treatments.