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PubMed2007

Use of a straight, side-hole delivery sheath for improved delivery of Amplatzer ASD occluder.

The Amplatzer ASD occluder may be difficult to position in some patients with a large atrial septal defect (ASD) or deficiency of one or more atrial septal rims. We developed a method to modify a Mullins transseptal sheath to enhance delivery. The resulting sheath is straight and has an exit orifice essential in the side of the distal portion of the sheath-a straight, side-hole (SSH) delivery sheath. We have used this modified delivery sheath in 140 successive patients with excellent results. The techniques of sheath modification and delivery of the device using the modified sheath are described.

Balloon Occlusion↗

PubMed1990

Drug delivery systems: 3A. Role of polymers in drug delivery.

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion-controlled systems; chemically controlled systems; solvent-activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin-releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.

Animals↗

PubMed1990

Drug delivery systems. 4. Implants in drug delivery.

In comparison with many of the other drug delivery systems, implantable pumps and implants for variable rate delivery are at a crude stage of development. Although exceptions exist, the typical implantable pump consists of an electromechanically complex mechanism to regulate drug delivery from a percutaneous refillable reservoir, while power to drive the system comes from a transcutaneous energy transmission system. The potential for electrical or mechanical failure is high, and the systems are not yet sufficiently convenient or easy to use to recommend in a routine therapy. Problems with refilling of an apparently well designed implanted reservoir have been observed while, at the same time, cutaneous energy transmission systems are not well established. In most instances, the development of an elementary osmotic pump system dosage form follows a well defined path of physical-chemical formulation and clinical testing. The benefits most often provided by the dosage form are expected to be (1) increase in selectivity of drug action achieved by the system's zero-order release rate, and (2) decrease in frequency of administration. The success in achieving these values is quantifiable from the pharmacology of the drug substance and its pharmacokinetics. Osmotic and other technical approaches to producing economical, rate-controlled dosage forms will make it possible for all new pharmaecutical products to carry kinetic specification of rate as well as static specification of content. This review considers the characteristics of the ideal implantable pump, the clinical situations which require pumps, the limitations of portable pumps, and the detailed characteristics of existing implantable pumps and implants. Most of the review, however, focuses on insulin delivery because of the importance of this subject.

Chlorofluorocarbons, Methane↗

PubMed1999

A comparison of two controlled-release delivery systems for the delivery of amiloride to control angiogenesis.

The diuretic amiloride has been reported to inhibit both Na+-H+ antiport and the urokinase-type plasminogen activator. As a consequence of these inhibitions, neovascularization may also be inhibited. We hypothesized that if amiloride could be effectively delivered in a site-specific manner, a system might be developed that could inhibit localized angiogenesis. In order to evaluate this possibility we conducted a study that compared two different controlled-release systems into which amiloride had been incorporated. The effectiveness of amiloride release from each delivery system was determined by quantitating angiogenic patterns in a chick chorioallantoic membrane (CAM) system using a fractal analysis software program. The two delivery systems compared were sucrose acetate isobutyrate (SAIB) and calcium alginate. Initial HPLC laboratory tests confirmed that amiloride could be released from both SAIB and calcium alginate in vitro in a sustained manner for 72 h. The CAM studies confirmed that neither SAIB nor calcium alginate alone promoted or inhibited angiogenesis when compared to nontreated controls. The release of amiloride from each delivery vehicle resulted in a significant (P < 0.05) inhibition of angiogenesis following both 24 and 48 h of release compared to controls. There was no difference in inhibition of angiogenesis, however, when comparing SAIB + amiloride treated CAMs with calcium alginate + amiloride treated CAMs. These data suggest that both SAIB and calcium alginate may be useful delivery vehicles for the localized application of amiloride to control angiogenesis. Such a system could potentially control tumor angiogenesis without systemic effects.

Alginates↗

PubMed2014

A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression.

This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n = 24 rats), retention of dye was evaluated 10 min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52 ± 4] % and LVIC-OCCL [58 ± 3] % groups p < 0.05 compared with IM [31 ± 8] % and LVIC [35 ± 4] %. In the second (n = 16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6 weeks post-delivery, a similar trend was found with liquid jet [54 ± 5] % and LVIC-OCCL [60 ± 8] % featuring more LV expression as compared with IM [30 ± 9] % and LVIC [23 ± 9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery.

Animals↗

PubMed2006

Liquid crystalline phases of monoolein and water for topical delivery of cyclosporin A: characterization and study of in vitro and in vivo delivery.

Reverse cubic and hexagonal phases of monoolein have been studied as drug delivery systems. The present study was aimed at investigating whether these systems enhance the cutaneous penetration of cyclosporin A (CysA) in vitro (using porcine ear skin) and in vivo (using hairless mice). Different mesophases were obtained depending on CysA concentration. CysA at 4% allowed the formation of reverse cubic and hexagonal phases in a temperature range of 25-40 degrees C. At 8%, CysA induced the formation of other phases, which might be due to an interaction between the polar groups of the peptide and monoolein. In vitro, the cubic phase increased the penetration of CysA in the stratum corneum (SC) and epidermis plus dermis ([E+D]) at 12 h post-application. The reverse hexagonal phase increased CysA penetration in [E+D] at 6 h and percutaneous delivery at 7.5 h post-application. In vivo, both liquid crystalline phases increased CysA skin penetration. Topical application of these systems, though, induced skin irritation after a 3-day exposure. These results demonstrate that liquid crystalline systems of monoolein are effective in optimizing the delivery of peptides to the skin. The skin irritation observed after topical application of cubic and hexagonal phases should be minimized for their safe use as topical delivery systems.

Animals↗

PubMed2006

In vitro susceptibility to the pro-apoptotic effects of TIMP-3 gene delivery translates to greater in vivo efficacy versus gene delivery for TIMPs-1 or -2.

Matrix metalloproteinases (MMPs) are essential for extracellular matrix (ECM) breakdown and repair, and have been implicated in the development of metastases. TIMP-3 was initially identified as a potent inhibitor of MMPs, however it also has several properties that are unique and not related to its ability to abrogate MMPs. We studied the effects of overexpression of tissue inhibitor of metalloproteinases-3 (TIMP-3) on lung cancer cells and explored the mechanisms involved in apoptosis-induction in susceptible cells and subsequently, the therapeutic effect in vivo. Overexpression of TIMP-3 resulted in apoptosis of A549 lung cancer cells and AdCMVTIMP3 up-regulated the expression of p53, Fas ligand, TNFR1 and TNFR2 on these cells. Adenoviral delivery of TIMP-3 gene inhibited the growth of pre-established A549 tumours in Balb/c nude mice, and was associated with a greater therapeutic effect than either TIMP-1 or -2 gene delivery. There was no evidence of increased hepatic toxicity following the delivery of TIMP-3 either from intra-tumoural or intravenous injection. Thus, at least in cells showing in vitro susceptibility, TIMP-3 gene therapy offers a therapeutic advantage over TIMPs 1 and 2. These findings establish the potential of adenoviral gene delivery of TIMP3 as a therapeutic agent for selected lung cancers.

Adenoviridae↗

PubMed1996

Portal insulin delivery is superior to peripheral delivery in handling of portally delivered glucose.

It is still controversial as to whether physiological portal insulin delivery has metabolic advantages over peripheral insulin delivery. To clarify this issue, glycemic regulation during intravenous (IVGTT) and oral (OGTT) glucose tolerance tests and hyperglycemic clamp studies with either peripheral or portal glucose infusion was investigated in left-segmentally pancreatectomized dogs with portal ([PPx] n = 7) or systemic ([Tx] n = 7) venous drainage of the remaining pancreas. In Tx dogs, systemic diversion of pancreatic venous effluent was accomplished by gastroduodenal-caval shunt. Data obtained were compared with those in normal control dogs ([NC] n = 7). The loss of pancreatic beta-cell mass in PPx dogs decreased insulin responses to peripheral and portal glucose loads. In contrast, Tx dogs showed insulin responses comparable to those of NC dogs to glucose loads via both routes. Against peripheral glucose loads (IVGTT and hyperglycemic clamp with peripheral glucose infusion), PPx and Tx dogs showed deteriorated glucose handling. Against portal glucose loads (OGTT and hyperglycemic clamp with portal glucose infusion), deteriorated glucose handling was observed in Tx dogs, but not in PPx dogs. Deterioration in glycemic regulation against portal glucose loads in left-segmentally pancreatectomized dogs with peripheral insulin delivery but not in pancreatectomized dogs with portal delivery indicates that intraportal hyperglycemia and hyperinsulinemia are essential for promoting hepatic glucose handling.

Animals↗

PubMed1997

Correlation between maximum cervical dilatation at cesarean delivery and subsequent vaginal birth after cesarean delivery.

OBJECTIVE: To determine whether the extent of cervical dilatation at cesarean delivery affects the subsequent vaginal birth after cesarean (VBAC) rate. METHODS: Relevant records of the index pregnancy (group I) were reviewed for cervical dilatation at cesarean delivery, oxytocin use, indication, neonatal weight, and epidural use. The records of the subsequent pregnancy (group II) were reviewed for successful VBAC rates, neonatal weight, oxytocin, and epidural use. RESULTS: There were 1917 patients in the study. The indications for cesarean in group I were malpresentation (5.1%), fetal distress (14.9%), and arrest disorders (80%). In group II, the VBAC success rates were 73% for previous malpresentation and 68% for previous fetal distress. In those with previous cesarean deliveries for arrest disorders with cervical dilatation at 5 cm or less, the VBAC success rate was 67%. It was 73% for 6-9 cm dilatation and 13% for the fully dilated group (P < .05). CONCLUSIONS: Patients who attempt a VBAC may be counseled that a cesarean delivery at full dilatation is associated with a reduced chance of a subsequent successful VBAC.

Cervix Uteri↗

PubMed2001

Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression.

BACKGROUND: There is now evidence that the availability of plasma tryptophan is decreased during pregnancy and the puerperium and also in patients with major depression and inflammation. The aims of the present study were to examine: (i) the effects of pregnancy and delivery on plasma tryptophan and the amino acids known to compete for the same cerebral uptake mechanism (CAAs), valine, leucine, tyrosine, phenylalanine and isoleucine; (ii) the relationships between the availability of plasma tryptophan and postpartum depression or anxiety; and (iii) the relationships between the availability of plasma tryptophan to the brain and inflammatory markers, such as serum interleukin-6 (IL-6), interleukin-1 receptor-antagonist (IL-1RA) and the leukaemia inhibitory factor receptor (LIF-R). METHODS: The above variables were measured in 13 healthy non-pregnant and in 98 pregnant women 3 to 6 days before delivery and 1 and 3 days after delivery. On each occasion the parturient women completed the state version of Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS). RESULTS: Plasma tryptophan and the tryptophan/CAA ratio were significantly lower at the end of term and after delivery than in the plasma of non-pregnant, healthy women. The tryptophan/CAA ratio was significantly lower in the early puerperium than at the end of term. There were no significant relationships between the availability of plasma tryptophan and either post-partum depression or changes in the STAI or ZDS scores in the early puerperium. The changes in the tryptophan/CAA ratio from the end of term to the early puerperium were significantly and inversely related to serum IL-6, IL-IRA and LIF-R. CONCLUSIONS: The results show that the reduction in the availability of plasma tryptophan from the end of term to the early puerperium is related to immune activation; and that the lowered availability of plasma tryptophan is not related either to depressive or anxiety symptoms in the early puerperium or to post-partum depression ensuing some months later.

Adult↗

PubMed2000

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression.

We have developed a method for stabilisation of polyelectrolyte gene delivery vectors by crosslinking their surfaces with biodegradable multivalent copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA). The resulting nanoparticulate vectors resist attack by serum proteins and can be modified for cell-specific delivery by incorporation of targeting ligands onto the polymer coating. Here we show that vascular endothelial growth factor (VEGF), transferrin and basic fibroblast growth factor (bFGF) can each be linked to polyHPMA-coated poly(L-lysine)/DNA complexes. All ligand-targeted complexes demonstrated increased uptake into receptor-positive cells (measured using plasmids containing 32P-dCTP), that could be antagonised with excess free ligand. Targeted complexes also showed increased transfection, resistant to inhibition by serum, suggesting the possibility of effective application in vivo. Analysis using fluorescence microscopy confirmed enhanced uptake of ligand-targeted complexes (using Texas Red-labelled plasmid DNA), although VEGF- and transferrin-targeted complexes were restricted to cytoplasmic or perinuclear distributions. In contrast, bFGF-targeted complexes showed efficient delivery into the nucleus, with accumulation of more than 100000 plasmids per cell within distinct intranuclear compartments. This method permits versatile targeting of genes to selected cells and may also permit manipulation of intracellular trafficking. It should find several important applications in gene delivery systems both in vitro and in vivo.

Cell Nucleus↗

PubMed2004

Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial 'delivery-efficacy' mismatch.

The aim of this study was to determine the effects of direct intramyocardial pVEGF165 gene transfer on regional myocardial blood flow in a porcine model of chronic myocardial ischaemia. Pigs underwent placement of an ameroid constrictor around the left circumflex coronary artery. After 3 weeks, animals received direct intramyocardial injections of pVEGF165 (20 x 50 microl at 1 microg/microl, n=11) or a plasmid vector encoding chloramphenicol acetyltransferase (20 x 50 microl at 1 microg/microl, n=11) into a specified target area (TA) of the left lateral wall. At 3 weeks after gene transfer, animals underwent final evaluation including a systematic assessment of regional myocardial blood flow (MBF) under resting and stress conditions. In all, 20 animals (10 per group) reached final studies. There was no change in mean arterial blood pressure or Rentrop collateral score from gene delivery to final studies in either group, nor were there differences between study groups. MBF was significantly higher in the areas adjacent to the TA in the VEGF group under resting (P<0.001) and stress conditions (P<0.05). In addition, pVEGF165 gene transfer abolished flow differences between the adjacent areas and the septum. MBF was not different between study groups in the TA, the anterior wall, or the septum. In conclusion, direct intramyocardial pVEGF165 gene transfer significantly improves myocardial blood flow. However, this effect is limited to the myocardial segments adjacent to the area of gene delivery. These data, therefore, demonstrate a spatial 'delivery-efficacy' mismatch with implications for myocardial gene delivery sites and detection of treatment effects in vivo.

Animals↗

PubMed2003

Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications.

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally.

Administration, Inhalation↗

PubMed2006

Rationale for the selection of an aerosol delivery system for gene delivery.

Genetic therapeutics show great promise toward the treatment of illnesses associated with the lungs; however, current methods of delivery such as jet and ultrasonic nebulization decrease the activity and effectiveness of these treatments. Extremely low transfection rates exhibited by non-complexed plasmid DNA in these nebulizers have been primarily attributed to poor translocation and loss of molecular integrity as a consequence of shear-induced degradation. Current research focusing on methods to increase transfection rates via the pulmonary delivery route has largely concentrated on the incorporation of carbon dioxide in the air stream to increase breath depth as well as the addition of cationic agents that condense DNA into compact, ordered complexes. The purpose of this study was to examine the impact of several classic as well as the latest atomization devices on the structure of non-complexed DNA. Various sizes of plasmid and cosmid DNA were processed through an electrostatic spray, ultrasonic nebulizer, vibrating mesh nebulizer, and jet nebulizer. Results varied dramatically based upon atomization device as well as DNA size. This may explain the inefficiency experienced by genetic therapeutics during pulmonary delivery. More importantly, this suggests that the selection of an atomization device should consider DNA size in order to achieve optimal gene delivery to the lungs.

Administration, Inhalation↗

PubMed1999

Local gene delivery within the media of rabbit iliac arteries by using the infiltrator intramural delivery device.

Percutaneous transluminal angioplasty continues to be limited by restenosis. Prevention of restenosis is now focusing on local delivery of therapeutic agents, such as proliferation-inhibiting genes, directly to the site of arterial injury. We evaluated use of the Infiltrator catheter (IVT, San Diego, CA. U.S.A.) for gene delivery within the arterial media. The goals of our study were to evaluate the histologic effects of the injection and the suitability of the Infiltrator catheter for local delivery of viral therapy. We injected the femoral arteries of 21 New Zealand White rabbits. Six animals were used for an evaluation of the intramural distribution of dextran/rhodamine injected via the Infiltrator catheter. In seven animals, injection site histology and in vitro vasoreactivity were studied after an injection of saline. In the remaining eight animals, a replication-deficient adenovirus encoding for the firefly luciferase gene (Ad RSVLuc) was injected, and luciferase activity was quantified 3 and 8 days later. After injection via the Infiltrator catheter, the fluorescent tracer was distributed throughout the entire circumference and width of the arteries. Histologic examination showed minimal damage with partial endothelial abrasion and disruption of the internal elastic lamina confined to the penetration sites. In vitro endothelium-dependent vasodilation was present at a reduced level after injection via the Infiltrator (maximal endothelium-dependent acetylcholine-induced relaxation, 51.5 +/- 7.4% vs. 23.8 +/- 14.6%; p < 0.05). Significant luciferase expression was found in all the arteries, with a significant increase from day 3 to day 8 (5,392.5 +/- 2,300 vs. 2,012 +/- 471 cpm/mg; p < 0.05). These data obtained in a rabbit iliac artery model show that the Infiltrator catheter is an efficient and safe local intramural delivery device that provides significant transgene expression in the arterial wall without causing significant structural damage.

Adenoviridae↗

PubMed1978

Risk of pre-term delivery in patients with previous pre-term delivery and/or abortion.

Patients with a history of two or more pregnancies which ended spontaneously before 37 weeks gestation had an increased risk of spontaneous pre-term labour and delivery in future pregnancies. This increased risk related mainly to previous second trimester abortions and not to previous first trimester abortions. Patients with one previous spontaneous pre-term labour and delivery had a 37 per cent risk, and those with two or more pre-term deliveries a 70 per cent risk of again delivering pre-term. There appeared to be no beneficial effect of cervical suture on the incidence of pre-term delivery in these patients.

Abortion, Habitual↗

PubMed2002

Incorporation of realistic delivery limitations into dynamic MLC treatment delivery.

The clinical implementation of IMRT involves the use of a number of complex software-based systems, typically including an inverse planning system, a leaf sequencer, and a computer-controlled treatment delivery system. The inverse planning system determines the desired fluence patterns, the leaf sequencer translates those fluence maps into leaf trajectories, and the control system delivers those trajectories. While verification of intensity-modulated treatment fields has focused primarily on the dosimetric aspects of delivery, accurate delivery of the intended fluence distribution is dependent upon both the leaf sequencer and delivery control systems. Leaf sequencing algorithms typically do not incorporate many control system limitations, and this can lead to discrepancies between planned and delivered sequences. In this work, simple and complex fields were sequenced for the dynamic sliding window technique using different leaf speeds and tolerance settings to identify various limitations of the accelerator control system. This work was conducted on a Varian 2100 EX equipped with a Millennium 120 leaf MLC. The identified limitations were then incorporated into the sequencing algorithm using a limiting leaf velocity (less than the maximum leaf velocity), the leaf position tolerance, and the communications delay in the control system. Collision avoidance in leaf pairs was found to depend on a control system-enforced minimum gap between leaves and led to acceleration effects. By incorporating these effects into the leaf sequencing algorithm, dynamic sliding-window leaf sequences were produced which did not require beam interruptions or dose rate modulations for the parameter values used in calculating the sequence (dose rate, tolerance, leaf speed, and total monitor units). Incorporation of control system limitations into the leaf sequencing algorithm results in IMRT fields that are delivered with the prescribed constant dose rate, require less time to deliver, and have well-defined, calculable transmission dose characteristics.

Acceleration↗

PubMed2000

[The influence of computer supervision of deliveries on the medical procedures during labor and neonatal post-delivery status].

OBJECTIVES: The aim of the study was estimation of the influence of computer supervision of delivery on the way of medical management during partus. MATERIALS AND METHODS: Authors analyzed 10,983 labours which took place in years 1990-1999 in University Clinic of Reproduction and Obstetrics of Medical Academy in Wrocław. Cases of labours without computer monitoring was the first analyzed group, and the cases of computer monitoring deliveries was the second group. In both groups, the count of cesarean sections performed because of first symptoms of fetal asphyxia, and Apgar score gained by newborns, were taken into consideration. RESULTS AND CONCLUSIONS: The frequency of cesarean sections and neonatal Apgar score gained by newborns were compared in two characterized group in order to evaluation the influence of computer monitoring deliveries on the neonatal status. No impact of computer supervision on the way of delivery procedures, quality of work and neonatals state was observed.

Apgar Score↗