Oral Cannabidiol Treatment in Two Postmenopausal Women with Osteopenia: A Case Series.

Introduction: Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of oral CBD administration on bone turnover. Materials and Methods: Two postmenopausal women with osteopenia (T-score=-1 to -2.5) were randomized to receive 100 or 300 mg CBD daily (oral, bis in die [twice per day]) for 12 weeks. Serum markers of bone resorption (carboxyl-terminal collagen crosslinks [CTx]) and bone formation (procollagen type 1 N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BSAP], and osteocalcin [OC]); safety measures; plasma concentrations of CBD and metabolites; sleep disturbance; symptoms of depression, anxiety, and stress; and quality of life, were assessed. Results: CBD was well tolerated, with no clinically significant change in vital signs, hematology, chemistry, or urinalysis, and no adverse events reported. Reductions (% change vs. baseline) in CTx (-8.5%, -28.1%), P1NP (-9.9%, -39.5%), BSAP (-12.7%, -74.8%), and OC (-16.0%, -6.7%) were observed after 12 weeks of oral administration of 100 or 300 mg CBD daily, respectively. The two participants self-reported consuming 95.3% and 98.8% of CBD doses, respectively. CBD and select metabolites were measurable in plasma after 4 and 12 weeks of CBD treatment. No notable changes in sleep disturbance, depression, anxiety, stress, or quality of life were observed. Conclusions: CBD was well tolerated after 12 weeks of twice-daily oral administration and was associated with reduction in measured markers of bone turnover. Compliance with CBD treatment was good. Large-scale randomized clinical trials into the bone protective effects of CBD in postmenopausal women are warranted.

Pretreatment of donor pigs with a diet rich in soybean oil increases the yield of isolated islets.

INTRODUCTION: The pig is considered the donor species of choice for islet xenotransplantation. However, isolation of porcine islets is difficult, particularly from young pigs. Early life exposure to a high-fat diet (HFD) reportedly encourages islet ß-cell expansion in neonatal rodents and improves islet viability in culture from pretreated weanling pigs. In this study, we examined the influence of young donor pretreatment with a soybean oil-enriched HFD on porcine islet mass and yield after islet isolation. MATERIALS AND METHODS: Postweaning and between days 70 and 250, pigs were fed either a standard diet (control group; n = 5) or an HFD (experimental group; n = 6). Biochemical blood parameters and acute C-peptide response to intravenous glucose were monitored before pancreas procurement. The study was blinded to objectively evaluate the influence of treated diet. After procurement, pancreas biopsy samples were taken from control and pretreated donor pigs to assess islet number by using a dithizone scoring method and histologic islet area fraction determination. Control and HFD donor pig islets were isolated by using our standard isolation protocol to determine islet yield. Islet isolation characteristics and islet quality were assessed in both groups, and the results were compared. RESULTS: There were no significant differences in the donor characteristics (age, body weight, glucose disposal rate, acute C-peptide response to intravenous glucose, cholesterol, and aspartate aminotransferase) except fasting blood glucose level between the control and treatment groups (84 ± 6 vs 99 ± 12 mg/dL; P = .0317). The stimulated insulin and C-peptide levels between groups were similar. However, the dithizone score was slightly higher in the treatment group compared with the control group (95.4 ± 38.5 vs 62.6 ± 23.9; P = .1208). Digestion time, digested pancreas weight, pellet volume, and the fragility index were similar in both groups. However, the average islet count (islet equivalent number/g pancreas) at the digest level was significantly higher in the HFD group than in the control group (1578 ± 994 vs 738 ± 202; P = .0344). The functional viability of 2- and 7 day-cultured islets, as assessed by using oxygen consumption rate corrected for DNA, was similar in both groups. CONCLUSIONS: Pretreatment of pigs with HFD enriched with soybean oil could potentially be used to improve the islet mass in donor pigs. Further studies are needed to confirm and optimize the use of HFD for the purpose of increasing islet yield from young donor pigs.

Pharmacology and toxicity of a potent "nonclassical" 2,4-diamino quinazoline folate antagonist, trimetrexate, in normal dogs.

The pharmacology of trimetrexate (JB-11, NSC 249008, 2,4-diamino-5-methyl-5-[(3,4,5-trimethoxyanilino)methyl]quinazoline), an antitumor agent effective against several mouse tumors, was studied in normal dogs. A high-performance liquid chromatographic technique with electrochemical detection, dihydrofolate reductase inhibition assay, and 14C-labeled drug were used to measure plasma disappearance, tissue distribution, excretion, and metabolism of the drug at doses from 0.5 to 6 mg/kg. Doses of 2 mg/kg were well tolerated without toxicity. Higher doses (3 to 6 mg/kg) produced mainly intestinal toxicity without significant hematological or liver abnormalities. The 6-mg/kg dose caused severe bloody diarrhea. After administration of 3 mg/kg, plasma concentrations of trimetrexate were 1 microM and were equal to or greater than 0.1 microM at 1 and 24 hr, respectively. The predominant pharmacokinetics of trimetrexate plasma disappearance was an elimination phase with a t1/2 of 3.5 hr. Concentrations in the cerebrospinal fluid were 2 to 5% of that in plasma and were maximum within 1 to 2 hr after i.v. administration. Highest tissue concentrations of drug were measured in liver and kidney; lowest were found in brain and lung. A dose equivalent to 3 mg/kg in humans (on a sq m basis) should produce adequate plasma concentrations (greater than 0.1 microM) for therapeutic effects.