Thomas P Dooley

Thomas P Dooley
Trends in Pharma Development LLC

PhD

About

93
Publications
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Introduction
I am focused on the discover and development of pharmaceutical and biomedical products, and most notably repurposing of old active pharmaceutical ingredients (APIs) into new products with new medical indications. Recent examples of repurposed APIs include Cetirizine (Zyrtec) + Famotidine (Pepcid) for the treatment of COVID-19 and Atenolol + Scopolamine for the treatment of anxiety disorders. In LivFul I am working on insect repellents, wound dressings, and a Metabolic Syndrome treatment.

Publications

Publications (93)
Article
Full-text available
A patented new class of anti-anxiety medications consists of a beta blocker plus an antimuscarinic agent to inhibit the sympathetic and parasympathetic symptoms of anxiety disorders, respectively. The PanX® medications are non-benzodiazepines to address the unmet medical need for fast-acting and effective anxiolytics, without using active ingredien...
Article
https://www.sciencedirect.com/science/article/abs/pii/S2468171719300110 There is an unmet medical need for fast-acting, effective, non-dependent and non-addicting anxiolytic treatments, in lieu of benzodiazepines. Compounded tablets of PanX® Atenolol - Scopolamine HBr were administered orally in eight patients with complex diagnoses receiving resi...
Article
Full-text available
High density chitosan membranes were produced via a novel manufacturing process and used as implantable resorbable surgical membranes. The innovative method utilizes the following three sequential steps: (1) casting an acidic chitosan solution within a silicon mold, followed by freezing; (2) neutralizing the frozen acidic chitosan solution in alkal...
Article
Full-text available
Background The objective of this in vivo study is to evaluate in five rat models the pharmacologic effects and toxicity of a commercial hydro-alcoholic extract, GlucoMedix®, derived from Stevia rebaudiana and the pentacyclic chemotype of Uncaria Tomentosa (Willd.) DC, for use as a treatment for metabolic syndrome. The extract contains phytochemical...
Article
Full-text available
Background GlucoMedix® is an all-natural phytotherapy consisting of a hydro-alcoholic extract of Stevia rebaudiana (Bertoni) Bertoni and pentacyclic chemotype Uncaria tomentosa (Willd. Ex Schult.) DC. The nutraceutical product has potential for the treatment of hyperglycemia in type 2 diabetes and Metabolic Syndrome. Methods Six adult Hispanic typ...
Preprint
Full-text available
Background: The objective of this in vivo study is to evaluate in five rat models the pharmacologic effects and toxicity of a commercial hydro-alcoholic extract, GlucoMedix®, derived from Stevia rebaudiana and the pentacyclic chemotype of Uncaria Tomentosa (Willd.) DC, for use as a treatment for Metabolic Syndrome. The extract contains phytochemica...
Article
Background: The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, a...
Preprint
Full-text available
Background: The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, a...
Article
Full-text available
OBJECTIVE: Patients often experience anxiety in anticipation of medical procedures. A new class of anti-anxiety medications, PanX®, has been developed as alternatives to benzodiazepines, and are combinations of beta blockers and antimuscarinic motion sickness agents. An atenolol - scopolamine HBr drug combination was tested in an open label physici...
Article
Full-text available
Benzodiazepines are the standard-of-care for the “as needed” treatment of acute anxiety episodes. Although effective, they pose considerable risks of dependence, addiction, abuse, and death when used with opioids. A patented new class of anxiolytics has been developed that are drug combinations of a beta blocker and an antimuscarinic agent intended...
Article
Full-text available
A new class of anti-anxiety medications has been developed and patented that are dual drug combinations of a beta blocker and an antimuscarinic agent. The PanX® drug combinations were designed as pro re nata (prn) alternatives to addictive benzodiazepines, without the use of addictive Controlled Substances. The beta blocker (beta adrenergic recepto...
Article
Novel topical dermatologic or cosme-ceutical agents are needed to treat cutaneous hyperpigmentation, since most currently available products typically contain hydroquinone (HQ), which has significant disadvantages. Although most studies have found HQ therapies to be efficacious, this compound is highly toxic and mutagenic to mammalian cells. Skin p...
Article
Here we present methods of gene expression profiling using nylon filter deoxyribonucleic acid (DNA) microarrays and radiolabeled and nonradiolabeled hybridization probes. DermArray(R) nylon filter DNA microarrays were designed specifically for use in dermatology research. A patent-pending method was used to select approx 4400 highly informative, se...
Chapter
Here we present methods of gene expression profiling using nylon filter deoxyribonucleic acid (DNA) microarrays and radiolabeled and nonradiolabeled hybridization probes. DermArray® nylon filter DNA microarrays were designed specifically for use in dermatology research. A patent-pending method was used to select approx 4400 highly informative, sequ...
Article
Full-text available
This study established the utility of cross-species application of the cDNA microarray technique for investigating differential gene expression. Using both total RNA and mRNA samples recovered from two opossum cell lines derived from UVB-induced melanoma, we analyzed expression of ca. 4400 genes on the human DermArray DNA microarrays. The signals g...
Article
Full-text available
Potential biomarkers for Crohn's disease (CD) and ulcerative colitis (UC) were identified from two sets of full thickness pathologic samples utilizing DermArray and PharmArray DNA microarrays relative to uninvolved (Un) colon or normal colon. Seven of the over-expressed genes were verified using quantitative RT-PCR (i.e., TMPT, FABP1, IFI27, LCN2,...
Article
Full-text available
Squamous cell carcinoma (SCC) is the second most common form of skin cancer in Caucasians. Here we report on the identification of biomarkers of human cutaneous SCC cell lines in vitro and tissue samples in vivo using DermArray and PharmArray DNA microarrays, consisting of ca. 7400 unique human cDNAs. Differentially expressed genes were identified...
Article
Full-text available
In this article, some of the advantages and limitations of DNA microarray technologies for gene expression profiling are summarized. As a model experiment, DermArray DNA microarrays were utilized to identify potential biomarkers of cultured normal human melanocytes in two different experimental comparisons. In the first case, melanocyte RNA was com...
Article
Full-text available
DNA microarrays may be used to identify potential molecular targets for drug discovery. Yet, DNA microarray experiments provide massive amounts of data. To limit the choice of potential molecular targets, it may be desirable to eliminate genes coincidentally up-regulated in tissues implicated in absorption, distribution, metabolism, and excretion (...
Article
Full-text available
Biomarker genes of human skin-derived cells were identified by new simple bioinformatic methods and DNA microarray analysis utilizing in vitro cultures of normal neonatal human epidermal keratinocytes, melanocytes, and dermal fibroblasts. A survey of 4405 human cDNAs was performed using DermArray DNA microarrays. Biomarkers were rank ordered by "li...
Article
Full-text available
The wild-type agouti-banding pattern for hair is well characterized in lower mammals such as mice. The switch between eumelanin and pheomelanin in bands in the hair results from the interaction of alpha-melanocyte stimulating hormone and agouti signal protein through the melanocortin 1 receptor on melanocytes. However, such banding patterns have no...
Article
The bioavailability of drugs administered topically or orally depends on their metabolism by epithelial enzymes such as the cytosolic sulfotransferases (SULT). Reverse transcriptase-polymerase chain reaction (RT-PCR) methods were established to detect expression of 8 SULT genes and 4 arylsulfatase (ARS) genes in human tissues of epithelial origin a...
Article
Cytosolic sulfotransferases (ST) catalyze the sulfation of various phenolic agents, catecholamines, thyroid hormones, steroids, drugs, and procarcinogens, usually resulting in the inactivation and subsequent excretion of the compound. My laboratory's efforts have focused on the cloning of the human phenol-sulfating (PST) members of this gene superf...
Article
To discover safe and effective topical skin-lightening agents, we have evaluated alkyl esters of the natural product gentisic acid (GA), which is related to our lead compound methyl gentisate (MG), and four putative tyrosinase inhibitors, utilizing mammalian melanocyte cell cultures and cell-free extracts. Desirable characteristics include the abil...
Conference Paper
Full-text available
We have established cell lines from benign cutaneous melanocytic lesions and from melanoma-affected lymph nodes of Monodelphis domestica, the laboratory opossum (a South American marsupial now widely maintained in captive colonies for experimental purposes). Unlike melanoma cell lines currently available from humans and other mammals, the opossum l...
Article
We have established cell lines from benign cutaneous melanocytic lesions and from melanoma-affected lymph nodes of Monodelphis domestica, the laboratory opossum (a South American marsupial now widely maintained in captive colonies for experimental purposes). Unlike melanoma cell lines currently available from humans and other mammals, the opossum l...
Article
Cytosolic phenol sulfotransferases (PST) catalyze the sulfation/sulfonation of various phenolic agents, including catecholamines, thyroid hormones, and drugs (e.g., minoxidil and acetaminophen), which usually results in the inactivation and subsequent excretion of the compound. Our recent efforts have focused on the cloning and sequencing of the hu...
Article
Phenol sulfotransferases (PST) catalyze the sulfonation of catecholamines, thyroid hormones and phenolic drugs. At least two major forms of human PST enzyme have been characterized biochemically from liver, platelets and other tissues, the phenol-preferring PST (P-PST) and the monoamine neurotransmitter-preferring PST (M-PST). Molecular cloning eff...
Article
Dihydrofolate reductase is an essential bacterial enzyme necessary for the maintenance of intracellular folate pools in a biochemically active reduced state. In this report, the Mycobacterium avium folA gene was identified by functional genetic complementation, sequenced, and expressed for the first time. It has an open reading frame of 543 bp with...
Article
The authors have devised a simple method for the detection of drug–DNA interaction and sequence selectivity in vitro (1).The method is based on the inhibition or termination of bacterial DNA polymerase(s) when it encounters modified DNA sequences. The DNA polymerase inhibition assay (PIA) has been successfully employed to study a variety of DNA bin...
Article
A family of human phenol sulfotransferase genes has been suggested by the cloning of numerous cDNA isolates from different tissues. We have previously cloned and sequenced the STM gene encoding the monoamine neurotransmitter-preferring sulfotransferase, M-PST, and a portion of the STP1 gene encoding the phenol-preferring isozyme, P-PST1 (BBRC 205,...
Article
Intersexual opossums (Monodelphis domestica) from a large captive colony are described. These are the first naturally existing New World (didelphoid) intersexual marsupials for which reproductive phenotype and sex chromosome constitution are reported. One animal was XX, two were XY, and two were XO; all had lower body weight than normal males or fe...
Article
Full-text available
The cornified envelope is a layer of transglutaminase cross-linked protein that is deposited under the plasma membrane of keratinocytes in the outermost layers of the epidermis. We present the sequence of one of the cornified envelope precursors, a protein with an apparent molecular mass of 210 kD. The 210-kD protein is translated from a 6.5-kb mRN...
Article
Full-text available
A group of specialized mesenchymal cells located at the root of the mammalian hair follicle, known as the follicular or dermal papillary cells, are involved in regulating the hair cycle, during which keratinocytes of the lower follicle undergo proliferation, degeneration and regrowth. Using the arbitrarily primed-PCR approach, we have identified a...
Article
Metastatic melanoma cells, clonally derived from an affected lymph node of an ultraviolet-irradiated laboratory opossum, were allografted subcutaneously into suckling young, juveniles and adults to determine their tumorigenicity and metastatic potential. All injected 1- and 3-week-old suckling young survived well beyond weaning at 8 weeks. One died...
Article
Human tissues possess at least four distinct forms of cytosolic ST, three of which are involved in the sulfation of steroids. DHEA-ST is responsible for the majority of hydroxysteroid and bile acid sulfation in human tissues and abundant levels of the enzyme are present in human liver and adrenal tissues. In the adult human adrenal, DHEA-ST has bee...
Article
Rhodanese (thiosulfate sulfurtransferase) is expressed at high levels in liver and is involved in the detoxification of cyanide. The full-length cDNA corresponding to the mouse rhodanese gene (Tst), which is located on chromosome 15, was cloned by PCR amplification of a liver cDNA library and subjected to DNA sequencing. Alignment of the rhodanese...
Article
Metastatic melanoma cell lines were derived from a lymph node of a laboratory opossum, Monodelphis domestica, which had been exposed to mid-wavelength ultraviolet radiation (UVB) initially as a suckling young, and subsequently as a shaved juvenile and adult. The melanoma cell lines were dendritic and pigmented in vitro and contained a t(6;8)(p13;q1...
Article
An in vivo nude mouse graft model and an in vitro collagen matrix culture system were used to study interactions of immature hair follicle buds from newborn mice with clonally derived AdE1A-12S-immortalized rat whisker dermal papilla cell lines. Of the 19 available dermal papilla cell lines, four consistently supported good hair follicle developmen...
Article
We have sequenced a large proportion of the open reading frames (ORFs) of two phenol sulphotransferase gene transcripts (STP and STM) from three patients with Batten disease. This was done using reverse transcription and PCR amplification of total RNA followed by direct sequencing of the PCR products. No mutations or changes have been observed in e...
Article
Batten disease (juvenile-onset neuronal ceroid lipofuscinosis; JNCL) is an autosomal recessive neurodegenerative disorder, characterized by the cytosomal accumulation of autofluorescent proteolipopigments in neurons and other cell types. The Batten disease gene (CLN3) has not yet been identified, but has been mapped to a small region of human chrom...
Article
Full-text available
The gene that is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease--CLN3--has been localized to 16p12, and the mutation shows a strong association with alleles of microsatellite markers D16S298, D16S299, and D16S288. Recently, haplotype analysis of a Batten patient from a consanguineous relationship indicated homozygosit...
Article
The gene encoding human phenol-preferring phenol sulfotransferase (STP) has been cloned and mapped to chromosome 16p. A HindIII RFLP in this gene is described.
Article
The human monoamine neurotransmitter-preferring phenol sulfotransferase (M-PST) plays an essential role in the sulfation of catecholamines, such as dopamine. The cDNA encoding M-PST has been reported, and we have recently identified cosmid clones from human chromosome 16p11.2 for this gene, STM. Plasmid subclones derived from the STM cosmid clones...
Article
Full-text available
Rhodanese (thiosulfate sulfurtransferase) is expressed as high levels in liver and involved in the detoxification of cyanide. The full-length cDNA corresponding to the mouse rhodanese gene (Tst), which is located on chromosome 15, was cloned by PCR amplification of a liver cDNA library and subjected to DNA sequencing. Alignment of the rhodanese cDN...
Article
The cytosolic phenol sulphotransferase gene (STP) was mapped to a region of chromosome 16, within the interval defined by human-rodent somatic cell hybrid breakpoints CY160(D) and CY12, which contains FRA16E. YAC and cosmid clones from this 16p interval were screened for the presence of STP. Two non-overlapping cosmid contigs were identified which...
Article
Full-text available
Litters of suckling young of the laboratory opossum (Monodelphis domestica) were irradiated with UV light from sunlamps with a spectral emission peak at 302 nm (UVB) to induce melanocytic nevi. Total doses of 0.87-5.0 kJ/m2 were divided equally among up to 14 exposures during the 19 days from birth. Of 358 sucklings exposed, 217 survived to weaning...
Article
Full-text available
The cytosolic phenol sulphotransferase gene (STP) was mapped to a region of chromosome 16, within the interval defined by human-rodent somatic cell hybrid breakpoints CY160(D) and CY12, which contains FRA16E. YAC and cosmid clones from this 16p interval were screened for the presence of STP. Two non-overlapping cosmid contigs were identified which...
Article
An in vitro cell culture assay was developed to identify inhibitors of melanogenesis and agents which produce cytostatic or cytotoxic effects specifically in melanocytes. A total of 50 compounds related to tyrosine, dihydroxyphenylalanine, and hydroquinone (HQ) were tested in vitro in order to determine their effects upon a murine melanocyte cell l...
Article
The oncogenic transformation of epidermal melanocytes produces primary cutaneous melanoma. In this article, previously published cytogenetic, biochemical, molecular biology, and cell biology studies of cutaneous melanoma oncogenesis are reviewed. A variety of laboratory animal models have been developed for studies of the induction of melanoma, inc...
Article
The gray short-tailed opossum, Monodelphis domestica, develops dermal melanocytic nevi (MN) after long-term chronic exposure to UVB (midwavelength ultraviolet radiation) alone. We developed cell lines from six UVB-induced dermal benign melanocytic lesion biopsies. One of the MN was determined histologically to be a benign melanoma (BM), whereas the...
Article
The authors have recently cloned a cDNA encoding the human phenol-preferring phenol sulfotransferase (P-PST) enzyme. An oligonucleotide primer pair based on the human STP (representing sulfotransferase, phenol-preferring) cDNA sequence was synthesized and was employed in polymerase chain reaction (PCR) amplification of human genomic DNA to identify...
Article
The distribution of topically applied toremifene (0.5-1 mg/day for 5 days) in the ultraviolet B (UVB)-induced Monodelphis domestica opossum melanoma model was examined. The mean concentration of toremifene measured in the skin was 1200 nmol/g, or > 500 times that detected in any other tissues (blood, brain, liver, testicles, heart, uterus, eyes). I...
Article
High selectivity for covalent reaction at adenine N-3 within duplex DNA is a distinguishing feature of the CC-1065 and duocarmycin classes of natural products. Studies of the base and sequence selectivity exhibited by duocarmycins and CC-1065-based alkylating agents have focused on characterization of the predominant covalent adenine adducts that a...
Article
We developed and evaluated an in vivo athymic nude mouse model for tumor growth, angiogenesis, metastasis, and antineoplastic drug development. Melanoma cell lines expressing beta-galactosidase encoded by the Escherichia coli lac Z gene have been created by infecting an immortal murine melanocyte cell line with a recombinant retrovirus expressing t...
Article
Full-text available
A cDNA encoding the human liver phenol-sulfating form of phenol sulfotransferase (P-PST) has been isolated and characterized from a lambda Uni-Zap XR human liver cDNA library. P-PST is the major form of phenol sulfotransferase involved in drug and xenobiotic metabolism in human liver. P-PST is also responsible for the sulfation and activation of mi...
Article
Full-text available
A cDNA encoding minoxidil sulfotransferase (Mx-ST), a rat liver cytosolic sulfotransferase that catalyzes the 3'-phosphoadenosine 5'-phosphosulfate-dependent sulfate conjugation of minoxidil and p-nitrophenol, has been isolated from a lambda gt11 cDNA library constructed from poly(A)+ RNA isolated from female Sprague-Dawley rat liver. The largest c...
Article
The cDNA encoding full-length human p11 calpactin I light chain has been cloned and subjected to DNA sequencing. The open reading frame specifies a 97-amino-acid residue protein that surprisingly is identical to the p11 sequences of two mammalian ungulate species, cow and pig. However, the previously reported p11 polypeptide sequences of mouse and...
Article
Involucrin is a precursor of the insoluble protein envelope that is assembled in the outermost layers of the epidermis. The coding sequence of the protein contains a number of short tandem repeats that have been greatly altered during mammalian evolution. We have characterised eight mouse monoclonal antibodies raised against human involucrin, all o...
Article
CC-1065, a cyclopropylpyrroloindole (CPI), is a highly potent antitumor DNA-alkylating agent. We have devised a simple method to detect CPI bonding sites on double-stranded DNA (dsDNA). The technique utilizes a modified form of bacteriophage T7 polymerase, Sequenase, to synthesize a radiolabeled nascent strand from dsDNA that has been reacted in vi...