Evaluation of bone and kidney toxicity of BT2-peg2, a potential carrier for the targeted delivery of antibiotics to bone.

Previous studies have demonstrated that the bone targeting agent BT2-peg2 (BT2-minipeg2, ), when conjugated to vancomycin and delivered systemically by intravenous (IV) or intraperitoneal (IP) injection accumulates in bone to a greater degree than vancomycin alone, but that this accumulation is associated with severe nephrotoxicity. To determine whether this nephrotoxicity could be attributed to BT2-peg2 itself, we used a rat model to assess the distribution and toxicity of BT2-peg2 after IP injection of 11 mg/kg twice daily for 21 days. The results demonstrated that BT2-peg2 accumulates in bone but there was no evidence of nephrotoxicity or any histopathological abnormalities in the bone.

A pharmacokinetic study of morphine-6-O-sulfate in rat plasma and brain.

Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d was used as internal standard.

Stability studies of potent opioid analgesic, morphine-6-O-sulfate in various buffers and biological matrices by HPLC-DAD analysis.

The 6-O-sulfate ester of morphine (M6S) has previously been shown to be an analgesic with greater potency and fewer side effects than morphine. However, being a sulfate ester derivative of morphine, the question exists as to whether this compound is stable in biological fluids and tissues with regard to pH- and esterase-mediated degradation. To date, no studies have focused on the stability profile of M6S across the physiologically relevant pH range of 1.

Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia.

A series of carbamate derivatives of the antileukemic sesquiterpene melampomagnolide B (MMB) has been synthesized utilizing a 1,2,4-triazole carbamate conjugate of MMB as an intermediate synthon. Five imidazole- and benzimidazole-carbamate analogs of MMB (8a-8e) were prepared and evaluated for anti-leukemic activity against cultured M9 ENL1 AML cells. All the analogs exhibited improved anti-leukemic activity (EC=0.

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone.

We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome.

Pharmacokinetics of the novel nicotinic receptor antagonist N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide in the rat.

Plasma and brain concentrations of the nicotinic acetylcholine receptor antagonist and blood-brain barrier choline transporter substrate, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), were analyzed by liquid beta-scintillation spectrometry after administration of [14CH3]bPiDDB to male Sprague-Dawley rats. Plasma concentrations of [14CH3]bPiDDB were determined at 10 time points over 3 h. Absolute plasma bioavailabilities (1, 3, and 5.