Gad Consulting Services

Cary, NC, United States

Gad Consulting Services

Cary, NC, United States
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Jaroszewski J.J.,University of Warmia and Mazury | Gad S.C.,Gad Consulting Services | Feder M.,ADAMED Sp. Z O.o.
International Journal of Toxicology | Year: 2012

The correlation between 52 physicochemical parameters and mean residence time (MRT) for 27 drugs used in human and dog were investigated. The physicochemical parameter values calculated provided a basis for deriving a series of arithmetic expressions, which were used to build a mathematical model describing the relationship between them and the MRT values. From the entire set of analyzed parameters, a subset of 14 was identified that contributed to the derivation of an arithmetic expression:Log(PSA-WPSA+ACID)×[XLogP-(LogKp- EA×Ln(Caco2+AMINE+SAF)))]++(AMIDE+IP-FG)-Ln(MW+PISA)the value of which is highly correlated with the MRT value in dogs (P <.001) and allowed prediction of the MRT predicted (MRT(pred)). In humans, no correlation was found that allowed the calculation of MRT(pred). These results indicate that predicting the pharmacokinetics of any specific drug for humans based on pharmacokinetic data obtained in the dog should be undertaken with knowledge of the inherent limitations. © 2011 American College of Toxicology.


Gad S.C.,Gad Consulting Services | Sharp K.L.,Nanospectra Biosciences, Inc. | Montgomery C.,ComPath Biomedical | Payne J.D.,Nanospectra Biosciences, Inc. | Goodrich G.P.,Nanospectra Biosciences, Inc.
International Journal of Toxicology | Year: 2012

Gold nanoshells (155 nm in diameter with a coating of polyethylene glycol 5000) were evaluated for preclinical biocompatibility, toxicity, and biodistribution as part of a program to develop an injectable device for use in the photothermal ablation of tumors. The evaluation started with a complete good laboratory practice (GLP) compliant International Organization for Standardization (ISO)-10993 biocompatibility program, including cytotoxicity, pyrogenicity (US Pharmacopeia [USP] method in the rabbit), genotoxicity (bacterial mutagenicity, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus), in vitro hemolysis, intracutaneous reactivity in the rabbit, sensitization (in the guinea pig maximization assay), and USP/ISO acute systemic toxicity in the mouse. There was no indication of toxicity in any of the studies. Subsequently, nanoshells were evaluated in vivo by intravenous (iv) infusion using a trehalose/water solution in a series of studies in mice, Sprague-Dawley rats, and Beagle dogs to assess toxicity for time durations of up to 404 days. Over the course of 14 GLP studies, the gold nanoshells were well tolerated and, when injected iv, no toxicities or bioincompatibilities were identified. © 2012 The Author(s).


Stern J.M.,Yeshiva University | Kibanov Solomonov V.V.,S.A. de C.V | Sazykina E.,S.A. de C.V | Schwartz J.A.,Nanospectra Biosciences, Inc. | And 2 more authors.
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. © The Author(s) 2015.


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.


Gad S.C.,Gad Consulting Services | Sullivan D.W.,Gad Consulting Services
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. © American College of Toxicology.


Gad S.C.,Gad Consulting Services | Sullivan D.W.,Gad Consulting Services | Crapo J.D.,National Jewish Health | Spainhour C.B.,Calvert Labs
International Journal of Toxicology | Year: 2013

Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP or BMX-010; CASRN 219818-60-7) is a manganese porphyrin compound developed as a potential drug substance for use as a radioprotective and for the ex vivo treatment of cells, tissues, and organs intended for transplantation. In preparation for an investigational new drug filing, a full good laboratory practice nonclinical safety assessment was conducted in order to evaluate the safety of MnTE-2-PyP and included the performance of in vitro genotoxicity studies, local tissue tolerance evaluation, safety pharmacology core battery studies, and single- and repeat-dose intravenous (iv) toxicity studies in mice and monkeys. The MnTE-2-PyP was determined not to be genotoxic or hemolytic, did not demonstrate flocculation or elicit adverse pharmacologic effects on respiration, the central nervous system (CNS), and had limited transitory effects on the cardiovascular system only at levels well above the therapeutic target dose. The intended iv clinical solution did not cause venous irritation in rabbits. The no observed adverse effect level (NOAEL) in mice was determined to be 10 mg/kg/day after 18 consecutive days of bolus iv dosing once daily in the morning. The NOAEL in monkeys after 14 days of bolus iv dosing in the morning was determined to be 5 mg/kg/day. At doses relevant to clinical use in humans, neither study revealed any indication of any specific target organ toxicity, including the classic heme porphyrin kidney, liver, CNS, or cardiac toxicities, or manganese toxicity. Mortality seen shortly after dosing in individual animals at higher doses was not accompanied by any organ or clinical pathology indications, suggesting a functional pharmacological-mediated effect. Based on the results of these studies, a conservative safe initial starting clinical dose of 5.0 mg (0.083 mg/kg in a 60 kg adult) was proposed for the initiation of human trials. Because of patent life issues, use of MnTE-2-PyP as a transplantation aid or radioprotective agent is not currently being pursued past the preclinical stages. It serves as a model for the clinical development of this class of drugs. © The Author(s) 2013.


Gad S.C.,Gad Consulting Services | Sullivan Jr. D.W.,Gad Consulting Services
International Journal of Toxicology | Year: 2013

This survey serves as the eighth in a series of toxicology salary surveys conducted at 3-year intervals and beginning in 1988. An electronic survey instrument was distributed to 5800 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, 2057 responses were received (response rate 35.5%). The results of the 2012 survey provide insight into the job market and career path for current and future toxicologists. © 2013 The Author(s).


Kagan M.L.,Qualitas Health Ltd | Sullivan D.W.,Gad Consulting Services | 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. © 2014, SAGE Publications. All rights reserved.


Gad S.C.,Gad Consulting Services
Neurobiology of Disease | Year: 2014

As our recognition and understanding of diseases and disorders of the central nervous system (CNS) become more insightful, and society's concerns for the safety, efficacy, and use of such drugs become more acute, the regulatory requirements and expectations around assessing potential safety of the drug have continued to become more complex. Currently, these concerns and requirements are addressed in a time phased manner, attempting to match the advance of spending rate on assessing safety issues in alignment with advancing the moiety through development of the therapeutics.This article seeks to communicate all the critical but frequently overlooked aspects of current and pending regulatory requirements including the lesser known parts associated with impurities, active metabolites, and distribution of active components to (and subsequent clearance from) the population brain.While there are some exciting developments in treating CNS diseases with stem cells and some protein based therapies ( Aboody et al., 2011), drugs meant to favorably effect, prevent, or cure a disease process within the central nervous system (CNS) are primarily small molecule and must meet a number of regulatory and scientifically mandated criteria to establish that their safety in clinical use is acceptable. This is initially done in in vivo animals or in in vitro preparations. The starting place for such nonclinical safety assessment requires some fundamental assumptions about the potential therapeutic ( Ball et al., 2007; Gad, 2009; ICH S6, 2004; ICH M3 (R2), 2008). The first assumption is that the primary intended route of therapeutic administration is oral, as is indeed the case for the vast majority of both current and for most potential new drugs. Most aspects of nonclinical safety assessment do not depend on route, and we will consider the situations where the use of other routes influences requirements for nonclinical safety assessment, and why.A second general case assumption in the usual case is that drug administration frequency (or regimen) is once daily, though this assumption is less frequently made (in real life) than the oral route assumption.Regulations, costs, and acceptance of risks ( Enna and Williams, 2009) along with adherence to the phased process of clinical drug development have caused the task or flow of performances of regulatory nonclinical safety assessment studies to be considered as occurring in three sequential parts (once the initial candidate screening and lead selection phase are complete). These are the studies (1) done to allow initiation of clinical trials, (2) done to allow initiation of clinical trials sufficient to support a marketing application, and (3) required to allow a marketing application. Employment of new technologies, such as in vivo imaging has aided, to both help understand specificity of delivery to target tissue sites and mechanisms of both action and undesirable actions. © 2013 Elsevier Inc.


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.

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