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PubMed1981

Liposome-mediated delivery of deoxyribonucleic acid to cells: enhanced efficiency of delivery related to lipid composition and incubation conditions.

Delivery of liposome-encapsulated simian virus 40 (SV40) DNA to African green monkey Related to been used as a probe to study liposome--cell interactions and to determine conditions which favor the intracellular delivery of liposome contents to cells. The efficiency of DNA delivery by various liposome preparations (monitored by infectivity assays) was found to be dependent both on the magnitude of vesicle binding to cells and on the resistance of liposomes to cell-induced leakage of contents. Acidic phospholipids were much more effective in both binding and delivery, and phosphatidylserine (PS) was the best in both aspects. The inclusion of 50 mol % cholesterol in liposomes reduces the cell-induced leakage of vesicle contents (2--5-fold) and substantially enhances the delivery of DNA to cells (2--10-fold). Following incubation of cells with negatively charged liposomes containing SV40 DNA, infectivity can be enhanced greatly by brief exposure of the cells to glycerol solutions. In contrast, only slight enhancement by glycerol was observed for SV40 DNA encapsulated in neutral or positively charged liposomes. The results of competition experiments between empty phosphatidylcholine liposomes and DNA-containing PS liposomes also suggest possible differences in the interaction of neutral and negatively charged liposome preparations with cells. Morphological studies indicate that the glycerol treatment stimulates membrane ruffling and vacuolization and suggest that the enhanced uptake of liposomes occurs by an endocytosis-like process. Results obtained with metabolic inhibitors are also consistent with the interpretation that the enhancement of liposome delivery in glycerol-treated cells occurs via an energy-dependent endocytotic pathway. Pretreatment of cells with chloroquine, a drug which alters lysosomal activity, further enhanced infectivity in glycerol-treated cells (4-fold). This observation suggests the involvement of a lysosomal processing step at some point in the expression of liposome-encapsulated DNA and, more importantly, illustrates the possibility of altering cellular mechanism to engineer more efficient delivery by liposomes. Under optimal conditions determined in this study, the efficiency of liposome-mediated SV40 DNA delivery was increased more than 1000-fold over that obtained by simply incubating cells with liposomes. It is also demonstrated that these conditions enhance delivery of other molecules, besides DNA, which are encapsulated in liposomes.

Animals↗
PubMed2001

Using active management of labor and vaginal birth after previous cesarean delivery to lower cesarean delivery rates: aA 10-year experience.

OBJECTIVE: Our objective was to analyze the statistics on cesarean delivery rates and the factors that have led to a reduction in these rates. STUDY DESIGN: A retrospective analysis was done of delivery statistics from a 10-year period, January 1, 1989, to December 31, 1998. We investigated the changes made in the methods of delivery during the study period. The data were divided into 1-year periods and analyzed by chi(2) tables. RESULTS: The overall cesarean delivery rate decreased from 16.59% to 10.92%; the primary cesarean delivery rate decreased from 9.22% to 7.11% and the repeated cesarean delivery rate from 7.37% to 3.81%. All these decreases were statistically significant. An increase in the rate of active management of labor by increasing oxytocin use and encouraging a trial of labor after previous cesarean delivery was also statistically significant. No changes in the outcome were observed in terms of neonatal morbidity and mortality rates. CONCLUSION: We found that our working plan for management of labor and delivery yielded and maintained a successful decline in the cesarean delivery rates without any negative effect on neonatal or maternal mortality rates. This low rate was maintained for a 10-year period.

Adult↗
PubMed2002

Delivery strategies for women with a previous classic cesarean delivery: a decision analysis.

OBJECTIVE: The purpose of this study was to compare four strategies for treating patients with a previous classic cesarean delivery by medical outcomes and quality-adjusted life years. STUDY DESIGN: A decision tree was designed that compared four strategies for a hypothetical cohort of 10,000 women with a previous classic cesarean delivery: (1) delivery at 39 weeks of gestation, (2) delivery at 36 weeks of gestation without amniocentesis, (3) amniocentesis at 36 weeks of gestation with delivery if the fetus was mature and antenatal corticosteroids if the fetus was immature, and (4) weekly amniocentesis starting at 36 weeks of gestation with delivery when mature. RESULTS: Strategy 2 provided the greatest maternal quality-adjusted life years. Comparing strategy 1 with strategy 2, it was determined that 27 cesarean deliveries must be performed at 36 weeks of gestation with one associated case of respiratory distress syndrome to prevent one case of uterine rupture. Sensitivity analysis revealed that the uterine rupture rate must be below 0.36% for any strategy to surpass strategy 2 (elective cesarean delivery at 36 weeks of gestation without amniocentesis). CONCLUSION: A 36-week delivery may be preferable because it provides a lower risk of severe adverse outcomes and higher maternal quality of life.

Adrenal Cortex Hormones↗
PubMed2006

Trial of labor or repeat cesarean delivery in women with morbid obesity and previous cesarean delivery.

OBJECTIVE: Assess effects of body mass index (BMI) on trial of labor after previous cesarean delivery and determine whether morbidly obese women have greater maternal and perinatal morbidity with trial of labor compared with elective repeat cesarean delivery. METHODS: Secondary analysis from a prospective observational study included all term singletons undergoing trial of labor after previous cesarean delivery. Body mass index groups were as follows: normal 18.5-24.9, overweight 25.0-29.9, obese 30.0-39.9, morbidly obese 40.0 kg/m2 or greater, and were compared for failure and maternal and neonatal morbidities. The morbidly obese trial of labor and elective repeat cesarean delivery were compared for maternal and neonatal morbidities. Multivariable logistic regression analysis controlled for confounding variables. RESULTS: There were 14,142 trial of labor participants and 14,304 elective repeat cesarean delivery participants. Increasing BMI was directly associated with failed trial of labor after previous cesarean delivery: from 15.2% in normal weight (1,344) to 39.3% in morbidly obese (1,638), with combined risk of rupture/dehiscence increasing from 0.9% to 2.1% in morbidly obese women. Among morbidly obese women, trial of labor carried greater than five-fold risk of uterine rupture/dehiscence (2.1% versus 0.4%), almost a two-fold increase in composite maternal morbidity (7.2% versus 3.8%) and five-fold risk of neonatal injury (1.1% versus 0.2%) (fractures, brachial plexus injuries, and lacerations), but no neonatal encephalopathy. Morbidly obese women failing a trial of labor had six-fold greater composite maternal morbidity than those undergoing a successful trial of labor (14.2% versus 2.6%). CONCLUSION: Body mass index correlates with outcomes in trial of labor after previous cesarean delivery. Morbidly obese women undergoing a trial of labor were at increased risk for failure. Increased BMI was associated with greater composite morbidity and neonatal injury compared with elective repeat cesarean delivery, but absolute morbidities were small. Increased risks should be considered before trial of labor after previous cesarean delivery. LEVEL OF EVIDENCE: II-2.

Adult↗
PubMed2000

Birth trauma: short and long term effects of forceps delivery compared with spontaneous delivery on various pelvic floor parameters.

OBJECTIVE: To compare the effects of forceps delivery and spontaneous delivery on pelvic floor functions in nulliparous women. DESIGN: A longitudinal prospective study with investigations during the first pregnancy, 10 weeks and 10 months after delivery. SETTING: Antenatal clinic in a teaching hospital. POPULATION: One hundred and seven patients aged 28 +/- 4 years, divided into those with forceps (n = 25) or spontaneous (n = 82) delivery. METHODS: Investigations with a questionnaire, clinical examination, assessment of bladder neck behaviour, urethral sphincter function, intra-vaginal/intra-anal pressures during pelvic floor contractions. RESULTS: The incidence of stress urinary incontinence was similar in both groups at 9 weeks (32% vs 21%, P = 0.3) and 10 months (20% vs 15%, P = 0.6) after delivery, as was the incidence of faecal incontinence (9 weeks: 8% vs 4%, P = 0.9; 10 months: 4% vs 5%, P = 1) and the decreased sexual response at 10 months (12% vs 18%, P = 0.6). Bladder neck behaviour, urethral sphincter function and intra-vaginal and intra-anal pressures were also similar in the two groups. However, 10 months after delivery, the incidence of a weak pelvic floor (20% vs 6%, P = 0.05) and the decrease in intra-anal pressure between the pre- and post-delivery values (-17 +/- 28 cm H2O vs 3 +/- 31 cm H2O, P = 0.04) were significantly greater in the forceps-delivered women. CONCLUSIONS: Forceps delivery is not responsible for a higher incidence of pelvic floor complaints or greater changes in bladder neck behaviour or urethral sphincter functions. However, patients with forceps delivery have a significantly greater decrease in intra-anal pressure and a greater incidence of a weak pelvic floor.

Adult↗
PubMed1999

Maternal intrapartum temperature elevation as a risk factor for cesarean delivery and assisted vaginal delivery.

OBJECTIVES: This study investigated the association of intrapartum temperature elevation with cesarean delivery and assisted vaginal delivery. METHODS: Participants were 1233 nulliparous women with singleton, term pregnancies in vertex presentations who had spontaneous labors and were afebrile (temperature: 99.5 degrees F [37.5 degrees C]) at admission for delivery. Rates of cesarean and assisted vaginal deliveries according to highest intrapartum temperature were examined by epidural status. RESULTS: Women with maximum intrapartum temperatures higher than 99.5 degrees F were 3 times as likely to experience cesarean (25.2% vs 7.2%) or assisted vaginal delivery (25.2% vs 8.5%). The association was present in epidural users and nonusers and persisted after birthweight, epidural use, and labor length had been controlled. In adjusted analyses, temperature elevation was associated with a doubling in the risk of cesarean delivery (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5, 3.4) and assisted vaginal delivery (OR = 2.1, 95% CI = 1.4, 3.1). CONCLUSIONS: Modest temperature elevation developing during labor was associated with higher rates of cesarean and assisted vaginal deliveries. More frequent temperature elevation among women with epidural analgesia may explain in part the higher rates of cesarean and assisted vaginal deliveries observed with epidural use.

Adult↗
PubMed2000

Elective delivery in diabetic pregnant women.

BACKGROUND: In pregnancies complicated by diabetes the major concerns during the third trimester are fetal distress and the potential for birth trauma associated with fetal macrosomia. OBJECTIVES: The objective of this review was to assess the effect of a policy of elective delivery, as compared to expectant management, in term diabetic pregnant women, on maternal and perinatal mortality and morbidity. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register (last searched July 1999). SELECTION CRITERIA: All available randomized controlled trials of elective delivery, either by induction of labour or by elective caesarean section, compared to expectant management in diabetic pregnant women at term. DATA COLLECTION AND ANALYSIS: The reports of the only available trial were analysed independently by the three co-reviewers to retrieve data on maternal and perinatal outcomes. Results are expressed as relative risks (RR) and 95% confidence intervals (CI). MAIN RESULTS: The participants in the one trial included in this review were 200 insulin-requiring diabetic women. Most had gestational diabetes, except 13 women with type 2 preexisting diabetes (class B). The trial compared a policy of active induction of labour at 38 completed weeks of pregnancy, to expectant management until 42 weeks. The risk of caesarean section was not statistically different between groups (RR 0.81, 95% CI 0.52 - 1.26). The risk of macrosomia was reduced in the active induction group (RR 0.56, 95%CI 0.32 - 0. 98) and 3 cases of mild shoulder dystocia were reported in the expectant management group. No other perinatal morbidity was reported. REVIEWER'S CONCLUSIONS: There is very little evidence to support either elective delivery or expectant management at term in pregnant women with insulin-requiring diabetes. Limited data from a single randomized controlled trial suggest that induction of labour in women with gestational diabetes treated with insulin reduces the risk of macrosomia. Although the small sample size does not permit one to draw conclusions, the risk of maternal or neonatal morbidity was not modified. Women's views on elective delivery and on prolonged surveillance and treatment with insulin should be assessed in future trials.

Cesarean Section↗
PubMed1995

Immediate maternal and neonatal effects of low-forceps delivery according to the new criteria of The American College of Obstetricians and Gynecologists compared with spontaneous vaginal delivery in term pregnancies.

OBJECTIVE: Our purpose was to investigate the maternal and neonatal effects of elective low-forceps delivery, as currently defined by the 1988 criteria of The American College of Obstetricians and Gynecologists. STUDY DESIGN: During a 6-month period we conducted a prospective study that included 50 nulliparous term parturients who were randomly allocated to spontaneous or elective low-forceps delivery. Patients with either maternal or fetal disorders that could affect the outcome were excluded. All deliveries were attended by three experienced obstetricians. RESULTS: Spontaneous and forceps delivery group were similar regarding maternal or gestational age, fetal scalp pH, antepartum maternal hemoglobin and hematocrit levels, maternal outcome, mean birth weight, and number of neonates with low Apgar scores or cord arterial pH < 7.20. In the spontaneous delivery group the time elapsed since randomization to delivery was significantly longer (18 vs 10.2 minutes, p < 0.001) and the mean cord arterial pH was significantly lower (7.23 vs 7.27, p = 0.01) than in the forceps delivery group. CONCLUSION: Elective low forceps delivery may be used to shorten the second stage of labor without immediate maternal or neonatal side effects.

Adult↗
PubMed1996

Outcomes of newborns with gastroschisis: the effects of mode of delivery, site of delivery, and interval from birth to surgery.

OBJECTIVE: Our purpose was to determine the impact of delivery site, delivery mode, and delivery-to-surgery interval on outcomes for neonates diagnosed with gastroschisis. STUDY DESIGN: Data were obtained retrospectively by chart review on 56 newborns diagnosed with gastroschisis. Outcome measures examined included primary closure, days to enteral feeding, days in intensive care, total length of stay, and hospital charges. RESULTS: Inborn infants experienced fewer days to enteral feeding (p < 0.01)., shorter total lengths of hospital stay (p < 0.01), and lower hospital charges (p < 0.01). Newborns delivered by cesarean section tended to have longer lengths of stay (p = 0.07), greater hospital charges (p = 0.06), and significantly longer lengths of stay in intensive care (p = 0.05). Shorter intervals from delivery to surgery were observed for inborn neonates (p < 0.01) and for those delivered by cesarean section (p < 0.05). No relationships between hours from delivery to surgery and neonatal outcomes were observed. CONCLUSIONS: Delivery at a regional center is associated with improved outcomes, whereas cesarean deliveries were associated with worse outcomes. We observed no salutary effect related to the interval between delivery and initial surgical repair.

Abdominal Muscles↗
PubMed2002

Severe preeclampsia and delivery outcomes: is immediate cesarean delivery beneficial?

OBJECTIVE: This study was designed to determine whether immediate cesarean delivery for patients with severe preeclampsia confers any benefit to the mother or neonate. STUDY DESIGN: This retrospective chart review included all deliveries complicated by severe preeclampsia between July 1, 1999, and June 30, 2000. Cesarean deliveries performed for malpresentation, previous classic incision, multiple gestation, placenta previa, and herpetic outbreak were not included. Demographic variables, maternal outcomes, and neonatal outcomes were collected. RESULTS: Of 114 patients, 93 had an option regarding route of delivery. Thirty-four had an immediate cesarean section and 59 had induction of labor. Thirty-seven of 59 were delivered vaginally and 22 of 59 underwent cesarean delivery. Pulmonary complications in the mother and neonate were more common in cesarean delivery (P <.05). No morbidity was decreased by cesarean delivery. Bishop score and gestational age did not affect the labor induction success rate. CONCLUSION: Immediate cesarean delivery confers no benefit to patients with severe preeclampsia.

Adult↗
PubMed2005

Term breech delivery in Sweden: mortality relative to fetal presentation and planned mode of delivery.

OBJECTIVES: To compare perinatal and infant mortality in breech and cephalic presentations and between planned vaginal and cesarean section (CS) breech deliveries in Sweden. METHODS: The study comprised two parts. Study A is a national cohort study for the period 1991-2001, including 22 549 breech presentations and 875 249 cephalic presentations born at > or =38 completed weeks. Study B is a case-control study, including all 164 breech deliveries with perinatal or 1-year infant death (during 1991-1999 in Sweden) and controls. RESULTS: Study A: Among non-malformed infants, the total mortality rate was 0.46% in breech and 0.28% in cephalic presentations [adjusted odds ratio (OR) 1.6; 95% confidence interval 1.3-1.9]. Non-malformed breech babies were at an increased risk of antenatal death (breech versus cephalic hazard ratio: 2.7, 2.1-3.6). The infant mortality among non-malformed breech deliveries was higher in vaginal birth than in delivery by CS before labor (OR 2.5, 1.2-5.3). The perinatal + infant mortality among non-malformed breech babies was higher at delivery after 39 completed weeks than at CS delivery at 38 weeks (0.53% versus 0.14%; OR 3.5, 1.9-6.4). The estimated needed number of CS to avoid one death was 400. Study B: In breech presentations without malformations, OR for perinatal or infant death was 3.1 (1.7-5.8) at planned vaginal delivery compared with planned CS delivery, and when breech presentations not diagnosed at 37 gestational weeks were excluded, OR was 3.7 (1.6-9.2). CONCLUSIONS: These large population-based and case-control studies both show a significant reduction of perinatal and infant mortality with planned CS in term breech pregnancy.

Adult↗
PubMed2004

Maternal plasma procalcitonin concentrations in patients with preterm labor and intact membranes--prediction of preterm delivery and admission-to-delivery interval.

The purpose of this study was to evaluate procalcitonin (PCT) plasma levels in pregnancy complicated by preterm labor and to determine their value in the prediction of preterm delivery and the length of the admission-to-delivery interval. The study population consisted of 53 patients with preterm labor and 31 healthy pregnants. The study patients were divided according to the delivery time and to the admission-to-delivery interval. Plasma PCT concentrations were higher in preterm labor than in healthy pregnants. Although at the onset of preterm labor plasma PCT concentrations in patients who delivered prematurely were higher than in patients who, after tocolytic treatment, delivered at term, the difference was not significant. Also in cases of preterm labor delivered within and after three and seven days of admission no differences were observed. The highest values in the prediction of preterm delivery and the length of admission-to-delivery interval corresponded to a PCT concentration of 1.7 ng/ml. These findings suggest that although preterm labor is associated with increased PCT concentrations in maternal plasma, there is no significant association either between plasma concentration of PCT at the moment of threat and preterm delivery, or the admission-to-delivery interval. The predictive value of plasma PCT determinations is unsatisfactory.

Adult↗
PubMed2000

The relationship between antenatal risk characteristics, place of delivery and adverse delivery outcome in rural Malawi.

OBJECTIVE: To describe and compare the frequency of antenatally identified maternal 'risk' characteristics, place of delivery and occurrence of delivery complications. METHODS: A prospective cohort study of 780 pregnant women completing antenatal follow-up at a rural health center in Malawi. RESULTS: Three-quarters of the subjects had at least one commonly accepted risk characteristic. Only 30% of these women, and 22% of those with no risk characteristics, delivered in a modern health facility. Four women died, 127 experienced other delivery complications and there were 52 perinatal deaths. The 'at-risk' classification had over 80% sensitivity but less than 30% specificity to predict delivery complications or perinatal deaths. The positive predictive values were as low as 20% for delivery complications and 7% for perinatal mortality. Most individual 'risk' characteristics were not associated with adverse delivery outcomes, even when adjusted for the place of delivery. CONCLUSIONS: Antenatal risk identification failed to promote safe deliveries because of a poor predictive value of the 'risk' variables and the failure of the identified 'at-risk' individuals to deliver in modern health facilities.

Adult↗
PubMed2002

Targeted gene delivery to skin cells in vivo: a comparative study of liposomes and polymers as delivery vehicles.

Liposomes are microscopic lipid membrane vesicles that provide a current strategy for topical, dermal delivery of biologically active molecules. They have been successfully used for the delivery of various low and high molecular weight molecules into the skin, and as an alternative to virus-mediated delivery systems, have opened the field of dermal gene therapy. The present study was undertaken on 6-day-old rat pups to determine in vivo the efficacy of several liposome and nonliposome formulations, including phospholipid liposomes and their cationic or pegylated variants, nonionic liposomes and their cationic variant, PINC polymer (Protective, Interactive, Noncondensing polymers), and a propylene glycol:alcohol:water mixture (delivery vehicle for minoxidil) in delivering beta-galactosidase and luciferase reporter genes into skin cells. Based upon our observations of the expression of beta-galactosidase and luciferase reporter genes in skin cells, we report here that nonionic liposomes are the most efficient vehicle for transdermal delivery followed by nonionic/cationic and phospholipid (pegylated) liposomes. The propylene glycol:ethanol:water mixture and the PINC polymer were relatively inefficient in the delivery of beta-galactosidase or luciferase DNAs. This simple, noninvasive technique of using nonionic liposomes to deliver biomolecules provides an efficient delivery strategy for gene therapy and drug delivery to the dermal organ site.

Administration, Topical↗
PubMed1996

Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery.

OBJECTIVE: Our purpose was to establish a new animal model for human preterm delivery for assessment of the protective effect of drugs against preterm delivery. STUDY DESIGN: C3H/HeN, C3H/HeN, and BALB/c female mice impregnated by C3H/HeN, B6D2F1, and B6D2F1 male mice, respectively, were treated intraperitoneally with Escherichia coli lipopolysaccharide (0 to 100 microgram/kg, single dose or repeated doses at 1- to 6-hour intervals) on days 12 through 17 of pregnancy. On day 15 of pregnancy, the C3H/HeN females that had been impregnated by B6D2F1 males and administered lipopolysaccharide were treated intraperitoneally with indomethacin (1000 microgram/kg), ritodrine hydrochloride (1000 microgram/kg), urinary trypsin inhibitor (25 x 10(4) units/kg), or gabexate mesylate (100 mg/kg); preterm or term delivery was recorded for these mice. RESULTS: C3H/HeN females impregnated by B6D2F1 males revealed the highest (100%) incidence of preterm delivery when the females were treated with 50 microgram/kg lipopolysaccharide twice at a 3-hour interval on day 15 or 17 of pregnancy. Indomethacin and urinary trypsin inhibitor used separately significantly decreased the incidence of preterm delivery, but only urinary trypsin inhibitor, and not any of the other drugs, significantly increased the incidence of term delivery in the mice. CONCLUSION: A new animal model for investigation of preterm delivery was established, and its usefulness for assessment of the protective effect of drugs against preterm delivery was demonstrated.

Animals↗
PubMed1999

[Relation between calcaneal bone mass and lifestyles in young adult women. Influence of experience of delivery and months post delivery].

The aim of this study was to clarify the cross-sectional relation between calcaneal bone mass and lifestyles in healthy pre-menopausal young adult women classified by the experience of pregnancy and the months after delivery. The 457 healthy Japanese women aged 20-39 years living in an urban community underwent a health check up for osteoporosis. Calcaneal bone was measured by ultrasound using the Lunar Achilles, and stiffness was used as an index of bone mass. The information on pregnancy, delivery and lactation, and lifestyles including past and current exercise and frequency of food consumption were collected by a questionnaire. In addition, two-day dietary records were obtained to assess the nutrient intake, and seven-day walking records as an index of physical activities. These subjects were divided into 3 groups according to the experience of pregnancy, and the time after delivery (subgroups of no experience of pregnancy, 12-35 months post-delivery and 36 months or more post-delivery), and the relation between stiffness index and lifestyle factors was examined in the 3 groups. 1) Stiffness correlated significantly with experience of pregnancy, age at menarche, current exercise and frequency of intake of dairy products. 2) In the group without experience of pregnancy, stiffness in women with current exercise habit was significantly higher than women without the habit. Those with past exercise habit, current milk consumption and current calcium intake showed relatively greater stiffness. 3) In the 12-35 months post-delivery group, there was no relation of past and current physical activity to stiffness. For women whose frequency of milk consumption or daily calcium intake were high, the stiffness was significantly greater. In addition, past milk consumption and current frequency of dairy products consumption tended to show higher stiffness. 4) In 36 months or more post-delivery group, women with current exercise habit exhibited significantly higher stiffness than women without the habit. Low calcium intake tended to show low stiffness. These results indicated that the effects of lifestyle on calcaneal bone mass were different depending on the experience of pregnancy and the months after delivery in pre-menopausal young adult women.

Adult↗
PubMed1997

Local urokinase delivery with the Channel balloon: device safety, pharmacokinetics of intracoronary drug delivery, and efficacy of thrombolysis.

The Channel balloon is a new local drug-delivery catheter that has the dual capability of high-pressure lesion dilation and low-pressure drug infusion. The purpose of this study was to assess the safety and efficacy of this device in the local delivery of urokinase in the porcine model. Three in vivo protocols were performed in 57 anesthetized swine to assess the safety of Channel balloon use in the coronary vasculature, the pharmacokinetics of local urokinase delivery, and the ability of the catheter to lyse intraluminal thrombus. First, safety studies were performed in 18 coronary vessels in 13 pigs to compare angiographic and histologic changes following use of the Channel balloon with conventional balloon angioplasty. Second, intramural deposition of 123I-labeled urokinase was measured in 24 coronary arteries in 20 pigs to assess the efficiency and technical determinants of urokinase delivery and the time course of intramural drug retention. Finally, an in vivo thrombus model was used in 24 pigs to compare the thrombolytic capacity of local urokinase delivery with the Channel balloon in comparison with conventional urokinase infusion techniques. All balloon inflations and drug infusions with the Channel balloon were well tolerated in all animals without adverse angiographic, hemodynamic, or electrical sequelae. Comparative histologic studies with the Channel balloon demonstrated no additional vessel trauma beyond that seen with conventional balloon angioplasty. Between 0.09 and 0.35% of infused urokinase was intramurally deposited, with intracoronary persistence for at least 5 h. Drug infusion pressure did not significantly affect drug deposition, although larger amounts of urokinase were deposited with larger balloon:artery ratios and higher urokinase concentrations. In comparison to conventional systemic and guiding catheter infusions, local delivery of urokinase with the Channel balloon resulted in higher levels of clot dissolution. These studies have demonstrated safe intracoronary use of the Channel balloon in the porcine model. Local infusion of urokinase with this device results in significant intramural drug deposition that persists for at least 5 h. In comparison with conventional thrombolytic techniques, local urokinase delivery with the Channel balloon may result in enhanced intravascular thrombolysis.

Angioplasty, Balloon, Coronary↗
PubMedDate not supplied

A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 1. Synthesis and characterization.

Nonviral gene delivery systems are amenable to forming colloidal particles with a wide range of physicochemical properties that include size, surface charge, and density and type of ligand presented. However, it is not known how to best design these particles without having a set of physicochemical design constraints that have been optimized for the intended gene delivery application. Here, a nanoparticle-based model delivery system is developed that can mimic the surface properties of nonviral gene delivery particles, and this model system is used to define design constraints that should be applied to next generation gene delivery particles. As a test case, a well-defined nanoparticle-based system is developed to guide the rational design of gene delivery to hepatocytes in the liver. The synthetic scheme utilizes monodisperse polystyrene particles and provides for variation of mean particle size and particle size distribution through variation in reaction conditions. The nanoparticles are PEGylated to provide stability in serum and also incorporate targeting ligands, e.g., galactose, at tunable densities. Four nanoparticles are synthesized from uniformly sized polystyrene beads specifically for the purpose of identifying design constraints to guide next generation gene delivery to the liver. These four nanoparticles are Gal-50 and Gal-140, that are galactosylated 50 and 140 nm nanoparticles, and MeO-50 and MeO-140, that are methoxy-terminated 50 and 140 nm nanoparticles. All four particles have the same surface charge, and Gal-50 and Gal-140 have the same surface galactose density. The availability of galactose ligands to receptor binding is demonstrated here by agglutination with RCA120.

Animals↗