Mary C. Ritz

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

Abstract The concurrent influence of multiple neurotransmitter systems in mediating cocaine-induced convulsions is predicted by the results of previous receptor binding studies. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alters the occurrence of cocaine-induced convulsions. The 5-HT reuptake inhibitor fluoxetine enhanced the occurrence and severity of convulsions produced by 100 mg/kg (−) cocaine, while the 5-HT2 receptor antagonists cinanserin, ketanserin and pirenperone antagonized cocaine-induced convulsions in a dose-dependent manner. Further, the M1 receptor antagonist pirenzepine antagonized cocaine-induced convulsions, but atropine did not. In addition, both the (+) and (−) stereoisomers of the sigma ligand SKF 10047 significantly attenuated cocaine-induced convulsions. (+)SKF 10047 was more potent than (−)SKF 10047 in this effect, suggesting a stereoselective effect at sigma receptor sites. In contrast, DA and NE neurotransmission do not appear to modulate the proconvulsant effects of cocaine in a specific, dose-dependent manner. Thus, of the CNS binding sites with which cocaine is known to interact, the results are consistent with the conclusion that 5-HT transporters and 5-HT2 receptor sites appear to be direct and primary sites related to cocaine-induced convulsions, while M1 and sigma binding sites appear to play important but secondary and modulatory roles in this response.

Cocaine toxicity: concurrent influence of dopaminergic, muscarinic and sigma receptors in mediating cocaine-induced lethality

Abstract The concurrent influence of dopaminergic, sigma and muscarinic neurotransmitter systems in mediating cocaine-induced lethality is predicted by previous receptor binding results from our laboratories. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alter the occurrence of cocaine-induced lethality in C57BL/6J mice. The dopamine reuptake inhibitor bupropion increased the number of occurrences of lethality produced by (−) cocaine, while the dopaminergic D1 antagonist SCH 23390, the muscarinic M1 antagonist pirenzepine, and the sigma ligand (+) SKF 10047 all significantly, but only partially, antagonized (−) cocaine-induced lethality. In addition, the protective effects against lethality of the drug combinations SCH 23390 + pirenzepine or SCH 23390 + SKF 10047 were greater than any of these drugs used alone. These results are consistent with those from the previous receptor binding studies, and provide converging supportive evidence that the lethal effects of cocaine depend upon concurrent interactions with dopaminergic, muscarinic M1 and sigma receptor sites.

The Provant® Wound Closure System Induces Activation of p44/42 MAP Kinase in Normal Cultured Human Fibroblasts

Healing of wounds to closure can be broken down into four phases: acute inflammation, granulation tissue formation, epithelialization, and tissue remodeling.1 Chronic wounds—such as pressure ulcers—arise when one of these phases is interrupted. The Provant Wound Closure System, based on Cell Proliferation Induction (CPI) technology, was developed as a novel bioactive approach to the serious need for effective wound treatment. Clinical trials show that Provant decreases time to closure for chronic wounds by 50%.2 CPI technology makes use of a specific radiofrequency stimulus to induce proliferation of fibroblasts, epithelial cells,3 and lymphocytes.4 These effects occur under isothermal conditions.4,5 Because the response to CPI is mitogenic, mitogen-activated protein (MAP) kinase pathways might play a role. These pathways mediate many cellular processes, such as cell replication, transcription, and programmed cell death.6–8 There are three major pathways, all characterized by the final kinase in the respective cascades: p38 MAP kinase, p44/42 MAP kinase, and the c-Jun N-terminal kinase (JNK). The p44/42 MAP kinase pathway is known for its mitogenic effects while the other kinases have been implicated in stress-induced pathways.9

PROVANT Wound-Closure System accelerates closure of pressure wounds in a randomized, double-blind, placebo-controlled trial.

Treating pressure ulcers in the United States costs 5 to 8.5 billion dollars annually.1,2 A study of Medicare claims found that hospitals lose more than

Pulsed electromagnetic energy treatment apparatus and method

200 million per year treating pressure ulcers.3 Clearly, there is a need for more effective treatment, but an effective solution has remained elusive. However, a better understanding of wound physiology and the cell biology of wound healing have identified new strategies for achieving wound closure. Previous reports have shown that the Provant Wound Closure System (PROVANT®) is effective in closing pressure wounds compared to average population rates. The purpose of this prospective, randomized, placebo-controlled, doubleblinded trial was to investigate under rigorously controlled conditions the clinical efficacy of PROVANT for the treatment of pressure wounds. PROVANT is based upon Cell Proliferation Induction (CPI®), a biophysical technology that uses radiofrequency stimuli to induce fibroblast and epithelial cell proliferation.4,5