Synthesis of 2-diphospho-myo-inositol 1,3,4,5,6-pentakisphosphate and a photocaged analogue.

Diphosphoinositol polyphosphates (inositol pyrophosphates, X-InsP7) are a family of second messengers with important roles in eukaryotic biology. Their chemical synthesis and modification remains a challenging task due to the high density of phosphate groups arranged around the myo-inositol core. Here, a novel approach is presented that facilitates the incorporation of the diphosphate in the 2-position (2-InsP7) and that enables the introduction of a photocage subunit.

Nucleoside diphosphate prodrugs.

Nucleoside analogs are widely applied in antiviral and antitumor therapy. A severe limitation of these compounds arises from the need of biotransformation to the eventually active nucleoside triphosphates by stepwise addition of phosphate by kinases. This problem can be circumvented by employing reversibly masked nucleotides (prodrugs). However, the known concepts to bypass enzyme activation have almost exclusively been applied to nucleoside monophosphates. Here, we report on the transfer of the bis-(acyloxybenzyl)-concept (BAB-concept) from nucleoside monophosphates to nucleoside diphosphates (NDP) of the anti HIV drugs AZT and d4T. After successful synthesis and isolation of the compounds (BAB-NDPs), it was shown that these compounds exhibit promising hydrolytic properties ranging from high stability at physiological pH to very low stability in cellular extracts. Furthermore, we demonstrated that for some of the compounds a selective cleavage mechanism resulted in the exclusive delivery of the corresponding nucleoside diphosphate within 15 minutes without any degradation of the pyrophosphate unit, which is a unique result in the field of NDP-prodrugs.

Bupivacaine toxicity secondary to continuous cervical epidural infusion. Case report.

BACKGROUND AND OBJECTIVES: A case is described of bupivacaine toxicity after continuous cervical epidural infusion in a patient with intractable cancer pain. The patient had several periods of generalized tonic clonic seizures. Serial venous blood samples were taken after the first signs of toxicity. The highest total plasma bupivacaine level was 20.3 micrograms/mL. The corresponding free bupivacaine concentration was not determined. The highest measured free bupivacaine concentration was 1.21 micrograms/mL, corresponding with a total plasma bupivacaine level of 6.7 micrograms/mL. There were no signs of cardiovascular toxicity. The patient recovered after treatment without adverse sequelae. METHODS: A plasma concentration-time curve was constructed. There was a rise in the plasma concentration of bupivacaine after the continuous infusion was stopped. RESULTS: Total body clearance of bupivacaine was 20 mL/min and elimination half-life was 27 hours. CONCLUSIONS: The case emphasizes the importance of serial plasma concentrations of bupivacaine after continuous epidural infusion and the value of free bupivacaine concentration versus total bupivacaine concentration.

Continuous high thoracic epidural administration of morphine with bupivacaine after thoracotomy.

BACKGROUND AND OBJECTIVES: The purpose of the study is to determine the ideal concentration of morphine when given with bupivacaine as a continuous high thoracic epidural infusion for postthoracotomy pain. METHODS: In a prospective study, 60 patients scheduled for thoracic surgery received a high thoracic epidural catheter. Postoperative analgesia was provided by a continuous epidural infusion for 3 days. The patients were randomly divided into two groups: group 1 (loading dose 1 mg morphine epidurally and continuous infusion of bupivacaine 0.75% + 0.2 mg/mL morphine at an infusion rate of 0.8 mL/hr); group 2 (loading dose 0.5 mg morphine epidurally and continuous infusion of bupivacaine 0.75% + 0.1 mg/mL morphine at an infusion rate of 0.8 mL/hr). RESULTS: The visual analog scales were not different at rest but with exercise in group 1 there was better pain relief than in group 2. The number of patients requiring supplementation of analgesia in group 2 (n = 42) was six times that of group 1 (n = 7). PaCO2 increased in both groups during the first postoperative day. There was no difference in the incidence of side effects between the two groups. CONCLUSIONS: Continuous high thoracic epidural administration 0.2 mg/mL morphine in bupivacaine 0.75% at an infusion rate of 0.8 mL/hr with a loading dose of 1 mg morphine is an effective dose for postthoracotomy pain relief in rest, and more important, during exercise.