BACKGROUND AND OBJECTIVE: Previous studies have shown that photomechanical waves transiently permeabilize the stratum corneum in vivo. The aim of the present work was to investigate the potential of photomechanical waves for systemic drug delivery. STUDY DESIGN/MATERIALS AND METHODS: Photomechanical waves were generated by ablation of a polystyrene target by a Q-switched ruby laser. Systemic insulin delivery in a streptozotocin-diabetic rat model was monitored by measuring the blood glucose level. RESULTS: After photomechanical insulin delivery, the blood glucose decreased 80 +/- 3% and remained below 200 mg/dl for more than 3 hours. Whereas in control experiments (for which insulin was applied without photomechanical waves), there was no dramatic change in the blood glucose (standard deviation of measurements over 4 hours was 7%). CONCLUSION: The application of the photomechanical waves allowed approximately 6-kDa protein molecules (insulin) to pass through the stratum corneum and into the systemic circulation. 相似文献
BACKGROUND AND OBJECTIVE: Bacteria that cause infection of vascular prosthetic grafts produce an exopolysaccharide matrix known as biofilm. Growth in biofilms protects the bacteria from leukocytes, antibodies and antimicrobial drugs. Laser-generated shock waves (SW) can disrupt biofilms and increase drug penetration. This study investigates the possibility of increasing antibiotic delivery and sterilization of vascular prosthetic graft. STUDY DESIGN/MATERIALS AND METHODS: Strains of Staphylococcus epidermidis and S. aureus were isolated from infected prosthetic grafts obtained directly from patients. Dacron grafts were inoculated with the isolated bacteria, which were allowed to form adherent bacterial colonies. The colonized grafts underwent the following treatments: (a) antibiotic (vancomycin) alone; (b) antibiotic and SW (c) saline only; and (d) saline and SW. Six hours after treatment, the grafts were sonicated, the effluent was cultured and the colony forming units (CFU) were counted. RESULTS: CFU recovered from control grafts colonized by S. epidermidis were comparable: saline, 3.05 x 10(8) and saline+SW 3.31 x 10(8). The number of S. epidermidis CFU diminished to 7.61 x 10(6) after antibiotic treatment but the combined antibiotic+SW treatment synergistically decreased CFU number to 1.27 x 10(4) (P<0.001). S. aureus showed a higher susceptibility to the antibiotic: 2.26 x 10(6) CFU; antibiotic +SW treatment also had an incremental effect: 8.27 x 10(4) CFU (P<0.001). CONCLUSIONS: This study demonstrates that laser-generated shock waves have no effects alone, but can enhance the effectiveness of antibiotics against bacteria associated with prosthetic vascular graft biofilms, suggesting that this treatment may be of value as adjunctive therapy for prosthetic graft infections. 相似文献
We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5. 相似文献
Background. As a result of the clinical benefit observed in angina patients treated by transmyocardial revascularization (TMR) with a laser, interest in mechanical TMR has been renewed. Although the injury induced by mechanical TMR is similar to laser TMR, the resultant impact on myocardial contractility is unknown. The purpose of this study was to determine whether mechanical TMR improves ventricular function as compared with laser TMR in chronically ischemic myocardium.
Methods. After establishing an area of chronic myocardial ischemia, 25 domestic pigs were randomized to treatment by: excimer laser (group I), a hot needle (50°C) (group II), a normothermic needle (group III), an ultrasonic needle (40 KHz) (group IV), or no treatment (group V). All devices create a transmural channel of the same diameter; 22 ± 1 transmural channels were created in each animal. Regional myocardial contractility was assessed by measuring ventricular wall thickening at rest and with dobutamine stress echocardiography. Six weeks after revascularization, the animals were restudied at rest and with stress. Postsacrifice and histologic analysis of angiogenesis and TMR effects was then assessed.
Results. Laser TMR provided significant recovery of ischemic myocardial function. This improvement in contractility after laser TMR was a 75% increase over the baseline function of the ischemic zone (p < 0.01). Mechanical TMR provided no significant improvement in function posttreatment. In fact, TMR achieved with an ultrasonic needle demonstrated a 40% worsening of the contractility versus the pretreatment baseline (p < 0.05). Histologic analysis demonstrated a significant increase in new blood vessels in the ischemic zone after laser TMR, which was not demonstrated for any of the other groups (p < 0.05). Additionally, evaluation of the mechanical TMR channels demonstrated significant scarring, which correlated with the functional results.
Conclusions. Using devices to create an injury analogous to the laser, mechanical TMR failed to improve the function of chronically ischemic myocardium. Only laser TMR significantly improved myocardial function. 相似文献
The uptake of choline into cholinergic neurons for acetylcholine (ACh) synthesis is by a specific, high-affinity, sodium- and temperature-dependent transport mechanism (HAChU). Of several quaternary quinuclidinol derivatives tested, the N-allyl derivative proved to be most potent. Though the methyl, ethyl, and isopropyl derivatives were less potent at comparable concentrations, at higher concentrations they also maximally inhibited HAChU. The benzyl, hydroxyethyl, and methoxyethyl derivatives failed to inhibit HAChU by greater than 50% at concentrations up to 100 microM. N-Allyl-3-quinuclidinol (NAQ) proved to be a specific inhibitor of HAChU (IC50 = 0.9 microM) and a poor inhibitor of both sodium-independent transport (IC50 = 680 microM) and choline acetyltransferase activity (Ki = 200 microM). The NAQ exhibited noncompetitive type inhibition compared with N-methyl-3-quinuclidinol, a competitive inhibitor of HAChU. Thus, substitution at the N-functional group not only alters potency, but may change the mechanism by which inhibition is produced. The optical isomers of NAQ and several derivatives were prepared and employed to examine the stereochemical selectivity for inhibition of choline uptake. The S(+)-isomer of NAQ (IC50 = 0.1 microM) had approximately 100-fold greater inhibitory activity for HAChU than the corresponding R(-)-isomer (IC50 = 10 microM). With all other quinuclidinols tested, the S(+)-isomers were also more potent than the corresponding R(-)-isomers. In an effort to obtain a tertiary inhibitor of HAChU that would be expected to cross the blood-brain barrier following peripheral administration, 3-biphenyl-3-quinuclidinol (BHQ) and 3-naphthyl-3-quinuclidinol (NHQ) were synthesized and evaluated.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献