Gad Consulting Services

Cary, NC, United States

Gad Consulting Services

Cary, NC, United States

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Sullivan Jr. D.W.,Gad Consulting Services | Gad S.C.,Gad Consulting Services | Julien M.,Gattefosse
Food and Chemical Toxicology | Year: 2014

Transcutol® (Diethylene glycol monoethyl ether, DEGEE), CAS # 111-90-0, is commonly used as a vehicle in the formulation or manufacturing process of pharmaceuticals, cosmetics, and food additives. This paper presents unpublished nonclinical safety data using a form of DEGEE which includes a significantly decreased level of impurities, specifically ethylene glycol and diethylene glycol. It also reviews the history of use, regulatory status, and previously published toxicity data for DEGEE. The review supports that DEGEE is well tolerated across animal species and gender with toxicity occurring only at levels well above those intended for human use. At high levels of exposure, the kidney is identified as the critical target organ of DEGEE toxicity. DEGEE is negative for genotoxicity in in vitro and in vivo studies. Subchronic and chronic toxicity studies produced no reports of preneoplastic changes in organs, but the animal data is insufficient to allow a definitive opinion as to carcinogenicity. In silico data suggested that DEGEE is not carcinogenic or genotoxic. Developmental toxicity was seen in rats but only at levels 200 times greater than the estimated oral Permissible Daily Exposure Level of 10. mg/kg/day. The nonclinical data along with the long history of DEGEE use as a vehicle and solvent by multiple routes provide evidence of its safety. Furthermore, the novel data discussed herein provides evidence that toxicity previously associated with high levels of DEGEE in nonclinical studies conducted prior to 1990 could possibly be attributed to the presence of significant amounts of ethylene glycol or other impurities. © 2014 Elsevier Ltd.


PubMed | BioMimetix JV LLC, Calvert Labs, Duke University and Gad Consulting Services
Type: Journal Article | Journal: International journal of toxicology | Year: 2016

BMX-001, a manganese porphyrin that has anti-inflammatory, antioxidant, and antitumor properties, is being developed as a potential therapeutic for high-grade glioma (HGG) and head and neck (H&N) cancer. An IND has been opened for BMX-001 in the treatment of HGG (NCT02655601) and another is in preparation for H&N. The safety of BMX-001 has been evaluated in a battery of nonclinical Good Laboratory Practice (GLP)-compliant studies. Systemic toxicity has been evaluated using the intended cGMP product administered subcutaneously for periods of up to 5 weeks in both the mouse and the monkey and included toxicokinetic evaluations to characterize systemic exposure and tissue distribution and clearance of BMX-001. In additional GLP studies, BMX-001 was not irritating to the skin or eye and caused no changes in cardiac rate or rhythm or blood pressure. Mixed results for genotoxicity were seen with the weight of evidence indicating that BMX-001 poses no genotoxic risk in humans. In systemic mouse and monkey studies, loading/maintenance dose no observed adverse effect levels were 12/2 mg/kg/dose and 6/2 mg/kg/dose, respectively, with maintenance doses administered every 3 days after the initial loading dose. Systemic data were used to determine a Food and Drug Administration-approved safe starting dose for the initial clinical study in patients with HGG. BMX-001 was detected in analyzed tissues, including the brain, persisting well past the short plasma clearance period. The highest levels of BMX-001 were seen in the liver and kidneys, with amounts in these tissues returning to close to undetectable levels after a 2-week cessation of dosing.


Kagan M.L.,Qualitas Health Ltd | Sullivan D.W.,Jr | Gad S.C.,Gad Consulting Services | Ballou C.M.,Gad Consulting Services
International journal of toxicology | Year: 2014

Almega PL is an eicosapentaenoic acid-rich ω-3 oil that is isolated from Nannochloropsis oculata algae and developed as a dietary supplement. The safety of the algal oil was evaluated in 14- and 90-day studies in Sprague-Dawley rats by oral gavage at dose levels of 0, 250, 500, and 2500 mg/kg/d and 0, 200, 400, and 2000 mg/kg/d, respectively. No mortalities occurred and no signs of toxicity were observed during the studies. No treatment-related effects were seen for body weight, food consumption, ophthalmology, neurological effects, urinalysis, clinical pathology, gross pathology, organ weights, or histopathology. Although statistically significant effects were noted for some end points, none were considered to be of toxicological significance. The no observed adverse effect level for Almega PL was 2000 mg/kg/d. Additionally, Almega PL was not mutagenic in Salmonella typhimurium or Escherichia coli, did not induce chromosome aberrations in Chinese hamster ovary cells, and did not induce genotoxic effects in vivo in rat bone marrow erythrocytes. © The Author(s) 2014.


Sullivan D.W.,Gad Consulting Services | Gad S.C.,Gad Consulting Services | Laulicht B.,Perosphere | Bakhru S.,Perosphere | Steiner S.,Perosphere
International Journal of Toxicology | Year: 2015

A new molecular entity, PER977 (di-arginine piperazine), is in clinical development as an anticoagulant reversal agent for new oral anticoagulants and heparins. The good laboratory practices (GLP)-compliant studies were conducted to evaluate the toxicity of PER977 and its primary metabolite, 1,4-bis(3-aminopropyl)piperazine (BAP). PER977 and BAP were negative for systemic toxicity in dogs and rats. PER977 was rapidly eliminated from the blood with little to no accumulation. PER977 was negative for genotoxicity and did not alter neurological, respiratory, or cardiovascular function. Maximum tolerated doses for PER977 were 40 (rat) and 35 mg/kg (dog), and greater than 80 mg/kg (rat) for BAP. The no observable adverse effect level (NOAEL) for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/d. For BAP, the NOAELs for 14-day intravenous exposure to rats and dogs were 5 and 20 mg/kg, respectively. Based on these results, a safe and conservative dose level of 19.4 mg/d was used for the PER977 first in human study. © The Author(s) 2015.


PubMed | NephroGenex, Calvert Labs and Gad Consulting Services
Type: | Journal: Human & experimental toxicology | Year: 2016

Pyridorin


PubMed | Gad Consulting Services
Type: Journal Article | Journal: International journal of toxicology | Year: 2016

This survey serves as the ninth in a series of toxicology salary surveys conducted at 3-year intervals and beginning in 1988. An electronic survey instrument was distributed to 5919 individuals including members of the Society of Toxicology, American College of Toxicology, and 23 additional professional organizations. Question items inquired about gender, age, degree, years of experience, certifications held, areas of specialization, society membership, employment and income. Overall, 1293 responses were received (response rate 21.8%). The results of the 2014 survey provide insight into the job market and career path for current and future toxicologists.


PubMed | Calvert Laboratories, Sinclair Laboratories, BASi Laboratories, MPI Laboratories and Gad Consulting Services
Type: Journal Article | Journal: International journal of toxicology | Year: 2016

Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this authors 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection.


PubMed | Perosphere and Gad Consulting Services
Type: Journal Article | Journal: International journal of toxicology | Year: 2015

A new molecular entity, PER977 (di-arginine piperazine), is in clinical development as an anticoagulant reversal agent for new oral anticoagulants and heparins. The good laboratory practices (GLP)-compliant studies were conducted to evaluate the toxicity of PER977 and its primary metabolite, 1,4-bis(3-aminopropyl)piperazine (BAP). PER977 and BAP were negative for systemic toxicity in dogs and rats. PER977 was rapidly eliminated from the blood with little to no accumulation. PER977 was negative for genotoxicity and did not alter neurological, respiratory, or cardiovascular function. Maximum tolerated doses for PER977 were 40 (rat) and 35 mg/kg (dog), and greater than 80 mg/kg (rat) for BAP. The no observable adverse effect level (NOAEL) for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/d. For BAP, the NOAELs for 14-day intravenous exposure to rats and dogs were 5 and 20 mg/kg, respectively. Based on these results, a safe and conservative dose level of 19.4 mg/d was used for the PER977 first in human study.


PubMed | University of Warmia and Mazury, ADAMED Sp. z o.o., Biologics and Gad Consulting Services
Type: Journal Article | Journal: International journal of toxicology | Year: 2014

The minimal inhibitory concentration (MIC) of an antimicrobial agent for a microbial population (MIC(50, obs) and MIC(90, obs)) is an interpolated value determined for antibacterial drugs by in vitro methods. Many studies have tried to determine the correlation between the MIC(50, obs) or MIC(90, obs) value and the physicochemical parameters to allow quantitaive structure activity relationship (QSAR) predictions of efficacy. A rigorous evaluation of approaches to this problem is presented here. In order to find a correlation between chemical structure and the derivatives of the MIC values for 9 indicatory bacterial strains, it is necessary to employ a number of physicochemical parameters in combination. Only an arithmetic expression composed of many features illustrating the chemical structure of the molecule can be linked to the MIC(50, obs) value. This article demonstrated that, despite the complexity of the MIC value used as the end point, it is possible to validate the model in a limited extent.


PubMed | Gad Consulting Services, Nanospectra Biosciences, Inc. and Yeshiva University
Type: Clinical Trial | Journal: International journal of toxicology | Year: 2016

To evaluate the clinical safety profile for the use of gold nanoshells in patients with human prostate cancer. This follows on the nonclinical safety assessment of the AuroShell particles reported previously. Twenty-two patients, with biopsy diagnosed prostate cancer, underwent nanoshell infusion and subsequent radical prostatectomy (RRP). Fifteen of these patients had prostates that were additionally irradiated by a single-fiber laser ablation in each prostate hemisphere prior to RRP. Patients in the study were assessed at 9 time points through 6 months postinfusion. Adverse events were recorded as reported by the patients and from clinical observation. Blood and urine samples were collected at each patient visit and subjected to chemical (16 tests), hematological (23 tests), immunological (3 tests, including total PSA), and urinalysis (8 tests) evaluation. Temperature of the anterior rectal wall at the level of the prostate was measured. The study, recorded 2 adverse events that were judged attributable to the nanoparticle infusion: (1) an allergic reaction resulting in itching, which resolved with intravenous antihistamines, and (2) in a separate patient, a transient burning sensation in the epigastrium. blood/hematology/urinalysis assays indicated no device-related changes. No change in temperature of the anterior rectal wall was recorded in any of the patients. The clinical safety profile of AuroShell particles is excellent, matching nonclinical findings. A recent consensus statement suggested that the published literature does not support a preference for any ablation technique over another.(1) Now that clinical safety has been confirmed, treatment efficacy of the combined infusion plus laser ablation in prostate will be evaluated in future studies using imaging modalities directing the laser against identified prostate tumors.

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