Analysis of the cannabinoid content of strains available in the New Jersey Medicinal Marijuana Program.

Background: The six licensed operators in the New Jersey Medicinal Marijuana Program submit their strains of cannabis flower to a single laboratory, administered by the state's Department of Health, for testing. The results of these tests are made available by the State on a web page for patients, allowing a study of the range of cannabinoid profiles available in the program.

Methods: Reports on cannabinoid concentrations were collected from 245 test reports released by the State lab; the relative quantities of cannabinoids on all strains was evaluated, as well as trends in the strain types being tested.

Evaluation of the Toxicity and Neurological Effects of Fulranumab in Adult Cynomolgus Monkeys.

Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab.

Preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals: strategy, challenges, current practices.

Evaluation of pharmaceutical agents in children is now conducted earlier in the drug development process. An important consideration for this pediatric use is how to assess and support its safety. This article is a collaborative effort of industry toxicologists to review strategies, challenges, and current practice regarding preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals.

Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog.

The ontogeny of drug metabolizing enzymes and transporters in the rat.

Knowledge of the ontogeny of the various systems involved in distribution and elimination of drugs is important for adequate interpretation of the findings during safety studies in juvenile animals. The present study was designed to collect information on plasma concentrations of total protein and albumin, enzyme activity and mRNA expression of cytochrome P450 isoenzymes (CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A1/2, and CYP4A1), carboxylesterase and thyroxin glucuronidation (T4-GT) activity in liver microsomes, and mRNA expression of transporters (Mdr1a/b, Mrp1-3 and 6, Bsep and Bcrp, Oct1-2, Oat1-3 and Oatp1a4) in liver, kidney and brain tissue during development in Sprague-Dawley rats. Enzyme activities were determined by measuring the metabolism of marker substrates; expression of mRNAs was assessed using RTq-PCR.

Real life juvenile toxicity case studies: the good, the bad and the ugly.

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use.

Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.

Objective: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats.

Methods: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats.

Gas chromatographic method using nitrogen-phosphorus detection for the measurement of tramadol and its O-desmethyl metabolite in plasma and brain tissue of mice and rats.

A method that allows the measurement of plasma and brain levels of the centrally-acting analgesic tramadol and its major metabolite (O-desmethyl tramadol) in mice and rats was developed using gas chromatography equipped with nitrogen-phosphorus detection (GC-NPD). Plasma samples were extracted with methyl tert.-butyl ether (MTBE) and were injected directly into the GC system.

Determination of the adsorption of tramadol hydrochloride by activated charcoal in vitro and in vivo.

Although tramadol is one of the most widely used centrally acting analgesics worldwide, no literature is available regarding adsorption of tramadol HCl powder or tablets (Ultram; 50 mg tramadol HCl per tablet) by activated charcoal (AC) for use as potential adjunct treatment of overdose. The present study incorporated a novel combination of in vitro and in vivo methods to investigate this question. Based on a binding curve of tramadol UV absorbance (UV(a); 225 nm) plotted against the amount of AC, the ratio of amount of tramadol completely adsorbed by AC was 0.

Spontaneous transformation of cultured rat liver (TRL 1215) cells is associated with down-regulation of metallothionein: implications for sensitivity to cadmium cytotoxicity and genotoxicity.

Previously, we found cadmium (Cd) to be effective in suppressing liver and lung tumors in rodents. Thus, this study investigated the susceptibility of cultured cells to Cd during spontaneous transformation. The TRL 1215 cell line is an epithelial-like liver cell normally nontumorigenic.

The experimental toxicology of tramadol: an overview.

The experimental toxicological findings of tramadol are reviewed and discussed. Tramadol is a centrally acting analgesic. In acute toxicity studies, LD50 values are estimated to be around 300-350 mg/kg body weight (rat, mouse, oral administration).

Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression.

Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming S-adenosyl-methionine (SAM) in the process. The fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis. Here we test the hypothesis that arsenic-induced initiation results from DNA hypomethylation caused by continuous methyl depletion.

Development of connections within and between areas V1 and V2 of macaque monkeys.

We have investigated the development of intrinsic and interareal connections in areas V1 and V2 of the macaque monkey using postmortem transport of the lipophilic fluorescent tracer diI, applied to brains fixed at different pre- and postnatal ages. Intrinsic connections in the deep layers of V1 are evident on embryonic day 108 (E108), but are not robust in the superficial layers until around E118, when migration is largely complete. Both intrinsic horizontal projections and extrinsic projections to V2 initially have a continuous distribution.

Computerized mappings of the cerebral cortex: a multiresolution flattening method and a surface-based coordinate system.

We present a new method for generating two-dimensional maps of the cerebral cortex. Our computerized, two-stage flattening method takes as its input any well-defined representation of a surface within the three-dimensional cortex. The first stage rapidly converts this surface to a topologically correct two-dimensional map, without regard for the amount of distortion introduced.

Minimal basal activity and lack of metal-induced activation of the metallothionein gene correlates with lobe-specific sensitivity to the carcinogenic effects of cadmium in the rat prostate.

Metallothionein (MT), a high-affinity metal-binding protein, is known to detoxicate cadmium and may play an important role in cadmium carcinogenesis. In the rat, the ventral lobe of the prostate is sensitive to cadmium carcinogenesis, while the dorsolateral lobe is refractory. The possibility exists that the basis of this lobe-specific sensitivity may lie in the expression of the MT gene.

Sensitivity to cadmium-induced genotoxicity in rat testicular cells is associated with minimal expression of the metallothionein gene.

Cadmium is a carcinogenic metal. Although the mechanism of tumor induction is unknown, DNA/metal interactions may be involved. Metallothionein can protect against cadmium toxicity in our previous work it was shown to reduce cadmium genotoxicity in cultured cells.

Apparent quiescence of the metallothionein gene in the rat ventral prostate: association with cadmium-induced prostate tumors in rats.

Several chronic studies in rats indicating that cadmium exposure can induce tumors of the ventral prostate have recently been completed in our laboratory. In one such study, a single dose of cadmium, s.c.

Enhanced metallothionein gene expression is associated with protection from cadmium-induced genotoxicity in cultured rat liver cells.

Metallothioneins (MTs) are low-molecular-weight, cysteine-rich proteins that appear to play an important role in the cellular defense system against cadmium toxicity. Although substantial evidence exists demonstrating a reduction in cadmium toxicity concomitant with MT induction, little is known about the possible effects of stimulation of MT synthesis on cadmium-induced genotoxicity. Thus, the alkaline elution technique was used to assess single-strand DNA damage (SSD) in TRL-1215 cells, a liver-derived cell line shown to have inducible MT gene expression.

Hierarchical organization of areas in rat visual cortex.

To test the hypothesis that areas within rat visual cortex are organized in a multilevel hierarchy, we have employed Phaseolus vulgaris leucoagglutinin as an anterograde axonal tracer to visualize the laminar patterns of connections between different cortical areas. For identification of cortical areas, we used a combination of markers that included callosal connections, the patterns of inputs and outputs to ipsilateral cortical and subcortical targets, and geographical location. Projections from area 17 to every identified extrastriate target area extend throughout all layers of cortex and include layer 4.

Protective effects of selenium on cadmium toxicity in rats: role of altered toxicokinetics and metallothionein.

Selenium prevents the toxicity of the carcinogenic metal cadmium through undefined mechanisms. In this study, we determined the effects of selenium on cadmium toxicokinetics and on the ability of cadmium to induce metallothionein, a metal-binding protein that is thought to confer tolerance to cadmium toxicity. To assess the acute protective effects of selenium, male Wistar (WF/NCr) rats were given selenium (as SeO2; 10 mumol/kg, sc) at -24, 0, and +24 h relative to cadmium (as CdCl2; 45 mumol/kg, sc).

Repair of X-ray induced DNA strand damage by isolated rat splenic lymphocytes.

Although a number of chemicals can alter DNA repair function, little is known about the effect of chronic, low dose exposure to environmental agents on DNA repair capacity. Lymphocytes provide a potential target population to study the effects of chronic exposures to low doses of toxic chemicals since they are an easily obtainable cell population. Prior to investigating the repair capacity of chemically exposed lymphocytes, the repair by chemically naive lymphocytes has been characterized.

Cadmium-induced DNA strand damage in cultured liver cells: reduction in cadmium genotoxicity following zinc pretreatment.

It is well established that zinc can decrease the carcinogenicity and toxicity of cadmium. In some tissues this may be due to the induction of metallothionein (MT). Therefore, in the present investigation, the effect of zinc pretreatment on cadmium-induced DNA strand damage was determined.

Toxicological principles of metal carcinogenesis with special emphasis on cadmium.

Metals are an important and emerging class of carcinogens. At least three metals, specifically nickel, chromium, and arsenic, are confirmed human carcinogens, and several more are suspected to have carcinogenic potential in man. Considering that the list of known human carcinogens of any type is very small, it becomes clear that metals make up a substantial portion of the list.

Cadmium exposure in rats and tumours of the prostate.

Recently, we completed three chronic studies in rats indicating that cadmium exposure can induce tumours of the prostate. In the first study, s.c.

Differential DNA-protein crosslinking in lymphocytes and liver following chronic drinking water exposure of rats to potassium chromate.

Carcinogenic chromium (VI) compounds are persistent environmental contaminants with potential for human exposure through drinking water. One lesion associated with chromium (VI) exposure is the formation of DNA-protein crosslinks (DPC). In an attempt to develop markers of chromium exposure, the formation of DPC in lymphocytes was investigated.