Molecular guidance systems for nuclear-tipped magic bullets:
Clinical experiences in thyroid cancer treatment using recombinant TSH DRIEDGER AA Division of Nuclear Medicine, University of Western Ontario, London, Canada
Background: It is a prerequisite of 131I therapy of differentiated thyroid cancers (DTC) that the sodium iodide symporter be activated in order to maximize iodine uptake. For more than 60 years this was achieved by withholding thyroid hormone replacement for several weeks until thyroid stimulating hormone (TSH) rose into the hypothyroid range. This method of patient preparation is associated with significant side effects in many instances and it prolongs patient time away from work and other normal activities.
Methods: First therapeutic uses were in compassionate care settings with patients who could not be safely rendered hypothyroid (Robbins et al). An international prospective, randomized trial was later performed to compare TSH withdrawal with rhTSH administration. In our own centre, we have also considered the cost implications of the two protocols.
Results: In a retrospective cohort of 115 compassionate care patients it was found that about 40% benefited clinically from rhTSH-stimulated radioiodine therapy. The prospective, randomized trial obtained equivalent clinical outcomes in the two arms at 6-8 months post therapy (Pacini et al, 2006). Further, dosimetry showed that identical administered doses of 131I resulted in a 30% lower whole body radiation dose to those patients who received rhTSH, since euthyroid kidneys maintain function whereas hypothyroidism lowers glomerular filtration rates by 30%. Longer follow up has confirmed that clinical outcomes remain comparable in the prospective study for at least 3 years (Elisei, 2008) and in a separate retrospective cohort to 8.5 years (Rachinsky, 2008). rhTSH use is economically favorable in that time away from employment is reduced.
Conclusions: 1. rhTSH and endogenous TSH are equally effective in preparation of DTC patients for 131I therapy. 2. Further, since circulating radioiodine is excreted more quickly, radiation safety issues are also truncated in time compared to the case of 131I given to hypothyroid patients. 3. In many jurisdictions the cost of rhTSH is an issue for resource-limited health care programs. Cost-effectiveness evaluations show that rhTSH utilization is associated with significantly reduced morbidity, less time away from work and that it is cost-effective in radioiodine therapy protocols.
Interactions of liposomal vesicles with bacterial cells and antimicrobial activity of liposomal antibiotics. DRULIS-KAWA Z1, DOROTKIEWICZ-JACH A1, and GUBERNATOR J2 1Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego 63/77 51-148 Wroclaw, Poland,
2Institute of Biochemistry and Molecular Biology, University of Wroclaw, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland,
3Academic Centre for Biotechnology of Supramolecular Lipid Aggregates, Przybyszewskiego 63/77, 51-148 Wroclaw, Poland
Liposomes have significant effect as antibiotic carriers on improving drug distribution and decreasing a drug's toxic properties. Liposomal drug formulations were developed to increase the bactericidal efficacy of antibiotics by promoting effective interaction between bacteria and liposomes. Various liposomes containing fluroquinolones and aminoglycosides demonstrated reductions in minimum inhibitory concentrations (MICs) compared with the free drug against Gram-positive and Gram-negative bacteria The antimicrobial activity of PC:Chol:DOTAP cationic liposomes containing meropenem, gentamicin and ciprofloxacin were tested in vitro on Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli strains. Ciprofloxacin loaded liposomes exhibited a 2-4 times higher antimicrobial activity compared with the free drug. The bacterial sensitivity to liposomal meropenem were similar as to free antibiotic. The least effective were the liposomes containing gentamicin. The interactions between cationic liposomal formulations (PC:Chol:DOTAP 3:4:3) and examined bacterial cells were tested by fluorescent microscopy. The study was undertaken because different antimicrobial results had been obtained for liposomal antibiotics. The interactions were examined using PE-Rhodamine-labelled liposomes. Some of the strains exhibited red-light emission (fusion with vesicles or vesicles surrounding the cell) and some showed negative reaction (no red-light emission). The microscopic studies showed interactions of all Klebsiella pneumoniae and E.coli strains with tested liposomal formulations. Significant variation were noticed for Pseudomonas aeruginosa strains. Surprisingly the fusion effect were observed for isolates resistant to liposomal antibiotics. It seems that the efficacy of liposomal drugs strongly dependent on both the outer membrane structure of bacterial cell (interactions that may lead to fusion) and mechanism of bacterial drug resistance. It suggests that if the bacterial resistance mechanism is highly effective even direct drug insertion into the bacterial cell does not significantly change the antimicrobial susceptibility to antibiotics.
Mast cells infiltrate the thalamus as part of the CNS nociceptive response DUBAYLE D*, MENETREY D
CNRS UMR 8119, Neurophysique et Physiologie
Université Paris Descartes, UFR Biomédicale, 45 rue des Saints Pères, 75270 Paris Cedex 06, France
Abstract
Mast cells (MCs) accessing brain parenchyma through the blood-brain barrier in healthy animals are limited to pre-cortical sensory relays, the olfactory bulb and thalamus. We have demonstrated that the unilateral repetitive stimulation of the abdominal skin generates controlateral thalamic asymmetry in the distribution of MCs in the rostralmost part of the midline thalamus, the paraventricular pars anterior and reuniens nuclei subregion of animals injected with cyclophosphamide, in strict relation with cystitis genesis. Data are probably related to abnormal visceral/somatic interactions. Thalamic MC asymmetry is restricted to the brain region associated with visceral/vagal inputs, via the nucleus of the solitary tract, and somatic inputs, via the medial contingent of the spinothalamic tract inputs, and takes its origin from abdominal skin where cystitis generates secondary abdominal skin hyperesthesia leading to referred pain in man. We suggest thalamic MCs may play a role in integrative and cognitive sensory processes, including some aspects of visceral pain.
* Corresponding author. Tel.: +33 1 42 86 22 82; Fax: +33 1 49 27 90 62
E-mail: david.dubayle@univ-paris5.fr
High Dose Ascorbic Acid in Burn Resuscitation DUBICK MA US Army Institute of Surgical Research, San Antonio, TX 78234, USA
Background: Despite improvements in critical care, the resuscitation of patients with burn injuries remains a challenge. Numerous formulas and guidelines have been developed to reduce under- and over-resuscitation, yet they have not been fully successful. Few studies have incorporated the use of adjuncts to address specific mechanisms associated with burn during the early phases of resuscitation. For example, thermal injury is known to be associated with capillary leakage and tissue edema that increases the challenge of fluid resuscitation for treating the developing hypovolemia. It has been postulated that free radical generation associated with thermal injury is an important mediator in the development of this capillary leakage and burn patients are known to present with a reduced antioxidant status.
Methods: Over the past 10-15 years, a series of studies in experimental animals and humans have explored the use of high doses of ascorbic acid in reducing fluid requirements and tissue edema associated with burns. Animal studies have been performed in rats, guinea pigs and sheep at doses as high as 640 mg/kg/24 hr in lactated Ringer’s solution. Studies in humans have infused doses of 66 mg/kg. Primary endpoints in all studies have been total fluid infusion and fluid balance. Secondary endpoints have included hemodynamics and antioxidant status.
Results: Studies in experimental animals have reported significant reductions in fluid requirements to achieve equal hemodynamic benefit as long as the vitamin C was infused within 6 hr of the burn injury. Studies in humans reported reduced fluid requirements, less burn wound edema and reduced ventilator days. No overt toxicity was noted in any study.
Conclusions: To date the data suggest that doses up to 66 mg/kg/hr infused for 8-24 hr after burn injury in humans may be effective in reducing fluid needs and tissue edema, and such doses have produced no overt acute toxicity. As an antioxidant vitamin, ascorbic acid has been investigated as a therapeutic agent in several disease states. This presentation will review evidence to suggest that ascorbic acid can be used as a ‘magic bullet’ as part of early burn resuscitation practices.
