Treatment of achalasia by injection of sclerosant substances: a long-term report.

BACKGROUND: Endoscopic sclerotherapy (EST) with ethanolamine oleate (EO) was proposed as a treatment for achalasia, based on the well-known necrotizing effect against the esophageal muscle layers. The aim of this study is to evaluate long-term efficacy of EST. METHODS: Four consecutive series of patients with achalasia were treated according to different schedules over a period of 20 years, by using EO or polidocanol (PD). The primary outcome was dysphagia relief. Secondary outcomes were lower esophageal sphincter pressure, esophagogram, gastroesophageal reflux and endoscopic ultrasonography (EUS). Patients not responding to EST were treated with 30 mm dilation. RESULTS: A total of 103 patients completed the treatment. On medium-term evaluation, 75 patients who completed the treatment reached a clinical response labeled as "good," 23 were assessed as "fair," and 5 were assessed as failures. EUS has become a very informative tool to guide the treatment. The overall follow-up lasted for 87.9 ± 66.7 months. Twelve patients experienced a late failure. The cumulative expectancy of being free of recurrence was 90 % at 50 months with EO, but it was only 65 % with PD. Those patients who responded to rescue measures remained in good or fair clinical condition during the remaining follow-up. Young age, PD, and the so-called fusiform pattern on esophagogram proved to be significant predictors of poor prognosis. CONCLUSION: EST with EO is a promising alternative to classic therapies for achalasia. In contrast, PD-treated patients showed an important trend to fibrosis and clinical recurrence. Dilation seems particularly effective after EST, when this technique has failed.

Compared to Aluminum Hydroxide Adjuvant, Montanide ISA 206 VG Induces a Higher and More Durable Neutralizing Antibody Response against FMDV in Goats.

Foot-and-mouth disease (FMD) has a high prevalence in cloven-hoofed animals. It is also highly contagious and remains a serious threat to livestock worldwide. Despite the widespread vaccination program in Iran, outbreaks of FMD continue to occur. Vaccination is one of the most effective methods of preventing FMD. The vaccines used in Iran are of the inactivated type and contain several serotypes. Since inactivated vaccines without adjuvants do not induce a high and durable antibody response, it is necessary to use adjuvants. Montanide ISA 206 VG is a mineral oil-based adjuvant that produces a water-in-oil-in-water (w:o:w) emulsion in vaccine preparations. However, a large number of manufacturers in Iran and around the world still use alum adjuvant (with or without saponin) to produce the FMD vaccine. This study used Montanide ISA 206 and alum adjuvants to administer the O2010 serotype of the FMD virus to goats. A total of six goats were divided randomly into three groups. Vaccines were administered subcutaneously twice, at a one-month interval. Blood sampling was done at different times, and the micro-neutralization method was used to measure the neutralizing antibody titer in each serum. Seven days after the second vaccination, the alum group's antibody titer was higher but not statistically significant. However, from the 28th day after the second injection until the end of the study, the Montanide ISA 206 group's antibody titer was significantly higher than that of the alum group. Six months after the second injection, the antibody titer in the ISA 206 group remained at the peak level, while in the alum group, it decreased and reached the minimum protective level. Nine months after the second injection, the antibody titer remained at its peak level in the ISA 206 group, whereas it dropped significantly in the alum group. Based on the findings, ISA 206 VG is capable of generating long-term humoral immunity in goats against the FMD serotype O2010 and could replace aluminum hydroxide adjuvants in FMD vaccine preparations.

Anatomic features and retrograde transvenous obliteration of duodenal varices associated with mesocaval collateral pathway.

PURPOSE: To evaluate techniques and efficacy of retrograde transvenous obliteration for the treatment of duodenal varices associated with mesocaval collateral pathway. MATERIALS AND METHODS: Six consecutive cases of large/growing or ruptured duodenal varices treated by retrograde transvenous obliteration were retrospectively reviewed. Selective balloon-occluded retrograde transvenous obliteration (B-RTO) with 5% ethanolamine oleate (EO) was performed in all cases. When EO could not be sufficiently stagnated in the varices, additional/alternative techniques were performed, including coil embolization of afferent vein or intravariceal injection of n-butyl-2-cyanoacrylate (NBCA). Clinical findings, anatomic features of duodenal varices, obliteration techniques, complications, posttherapeutic computed tomography (CT) findings, and follow-up endoscopic findings were investigated. RESULTS: All duodenal varices were located at the second/third junction of the duodenum and were fed by single (n = 1) or multiple (n = 5) pancreaticoduodenal veins. One varix fed by a single afferent vein was successfully treated by simple selective B-RTO technique alone. The other five cases required coil embolization of afferent vein (n = 1) or intravariceal injection of NBCA (n = 4) because sclerosant was not sufficiently stagnated in the varices. CT 1 week after the procedure showed complete occlusion of the varices in all cases. A duodenal ulcer at the variceal site developed in one patient and was successfully treated by medication. Follow-up endoscopy showed disappearance of varices in all cases, and no recurrence was observed during follow-up. CONCLUSIONS: Retrograde transvenous obliteration is an effective technique for the treatment of duodenal varices. However, additional/alternative techniques are required for successful treatment because of the complex anatomic features of duodenal varices.

Extravascular injection of sclerotic agents does not affect vessels in the rat: experimental implications for percutaneous sclerotherapy of arteriovenous malformations.

OBJECTIVES: Sclerotherapy is useful for the treatment of arteriovenous vascular malformations. However, intravascular administration of sclerotic agents into small arteriovenous niduses is often difficult. Extravascular administration of sclerotic agents causes reduction of vascular flow on Doppler echo during clinical sclerotherapy. Therefore, we aimed to investigate whether the extravascular injection of sclerotic agents affects tiny vessels. DESIGN: Animal study. MATERIALS: The effect of extravascular injection of sclerotic agents on vessels was investigated using rat femoral and superficial inferior epigastric vessels. METHODS: After surgical exposure of vessels, absolute ethanol, 5% ethanolamine oleate and 3% polidocanol were injected into perivascular surrounding tissues, and their effect on vessels was evaluated after 14 days using histology and coloured silicone rubber injection. RESULTS: The integrity of the vascular lumen, endothelial cells and vascular patency were not affected by injection of sclerotic agents. CONCLUSIONS: Attenuation of vascular flow of an arteriovenous shunt after extravascular injection of sclerotic agents is transient and/or trivial and does not cause disruption of vessels. Therefore, sclerotic agents should be delivered to obtain sufficient destruction of arteriovenous malformation lesions and blood flow.

Balloon-occluded retrograde transvenous obliteration of gastric varices.

OBJECTIVE: The purpose of this review is to describe the clinical factors related to balloon-occluded retrograde transvenous obliteration, including the preparation needed, the technique and challenges, and the outcomes. CONCLUSION: Although the procedure can be performed when transjugular intrahepatic portosystemic shunt is contraindicated or when endoscopic management fails, balloon-occluded retrograde transvenous obliteration is successful as a first-line or second-line therapy. Gastric variceal rebleeding rates are low and serious complications are rare. Randomized controlled trials are required to evaluate the superiority of this procedure over other methods of treating gastric varices and to determine which sclerosant should be used. In the near future, this procedure may play a larger role in emergency care and in the management of nongastric varices.

Nanostructured lipid carriers as delivery system for the phopholipase A2 inhibitors PX-18 and PX-13 for dermal application.

PX-18 and PX-13 are secretory phospholipase A2-IIA (sPLA2-IIA) inhibitors. An increased expression of sPLA2 in psoriatic skin has been reported. The selective inhibition of this enzyme is a new therapeutic approach. For dermal application PX-18 and PX-13 have been loaded to Nanostructured lipid carriers (NLC). The PX-18-loaded and PX-13-loaded NLC possessed an average particles size of about 250 nm, a narrow particle size distribution (PI < 0.2), a high entrapment efficiency as well as a good physical stability, as already indicated by their high zeta potential. Both NLC formulations have been incorporated into a hydroxyethyl cellulose gel and an o/w cream. In the gel and in the o/w cream PX-18-loaded and PX-13-loaded NLC showed a good physical stability. Neither aggregation nor dissolution of NLC took place.

Sclerotherapy followed by surgery for the treatment of oral hemangioma: a report of two cases.

Hemangiomas, vascular malformations, and varices are common benign vascular lesions in the head and neck region. They can occur in the mouth and primarily affect the lips, tongue, buccal mucosa, and palate. The main types of treatments are surgery and intralesional injection of sclerosant agents. However, other therapies have been considered, such as systemic corticosteroids, laser therapy, interferon a, and cryotherapy. Currently, sclerotherapy is employed largely because of its efficiency and ability to conserve the surrounded tissues. Surgery can be used exclusively or associated with sclerotherapy in lesions that do not show complete resolution. This article describes the cases of two patients with oral hemangiomas that were submitted to sclerotherapy with ethanolamine oleate. Although an important decrease was detected after seven applications in both cases, surgical resection of the residual lesion was performed to achieve optimal results.

Immune induction by adjuvanted Leishmania donovani vaccines against the visceral leishmaniasis in BALB/c mice.

Visceral leishmaniasis (VL) is a neglected tropical disease caused by Leishmania donovani or Leishmania infantum. Currently, the patients are treated with chemotherapeutic drugs; however, their toxicity limits their use. It would be desirable to develop a vaccine against this infection. In this study, we assessed the efficacy of different vaccine formulations at variable time points. Heat-killed (HK) antigen of Leishmania donovani was adjuvanted with two adjuvants (AddaVax and Montanide ISA 201) and three immunizations at a gap of 2 weeks (wk) were given to BALB/c mice. After 2 weeks of the last booster, mice were given challenge infection and sacrificed before challenge and after 4wk, 8wk, and 12 wk post-challenge. Significant protective immunity was observed in all the immunized animals and it was indicated by the notable rise in delayed-type hypersensitivity (DTH) response, remarkably declined parasite burden, a significant increase in the levels of interferon-gamma (IFN-γ), interleukin-12, interleukin-17 (Th1 cytokines), and IgG2a in contrast to infected control mice. Montanide ISA 201 with HK antigen provided maximum protection followed by AddaVax with HK and then HK alone. These findings elaborate on the importance of the tested adjuvants in the vaccine formulations against murine visceral leishmaniasis.

N-oleoylethanolamine - phosphatidylcholine complex loaded, DSPE-PEG integrated liposomes for efficient stroke.

Causing more and more deaths, stroke has been a leading cause of death worldwide. However, success in clinical stroke trials has remained elusive. N-oleoylethanolamine (OEA) was an endogenous highly hydrophobic molecule with outstanding neuroprotective effect. In this article, hydrogen bonds were successfully formed between OEA and soybean phosphatidylcholine (SPC). The synthetic OEA-SPC complex and DSPE-PEG were self-assembled into liposomes (OEA NPs), with OEA-SPC loaded in the core and PEG formed a hydrophilic shell. Hence, highly hydrophobic OEA was loaded into liposomes as amorphous state with a drug loading of 8.21 ± 0.18 wt%. With fairly uniform size and well-distributed character, the OEA NPs were systemically assessed as an intravenous formulation for stroke therapy. The results indicated that the administration of OEA NPs could significantly improve the survival rate and the Garcia score of the MCAO rats compared with free OEA. The TTC-stained brain slices declared that the cerebral infarct volume and the edema degree induced by MCAO could be decreased to an extremely low level via the administration of OEA NPs. The Morris water maze (MWM) test suggested that the spatial learning and memory of the MCAO rats could also be ameliorated by OEA NPs. The immunofluorescence assay stated that the apoptosis of the neurons and the inflammation within the brain were greatly inhibited. The results suggest that the OEA NPs have a great chance to develop OEA as a potential anti-stroke formulation for clinic application.

Nanoencapsulation of sophorolipids in PEGylated poly(lactide-co-glycolide) as a novel approach to target colon carcinoma in the murine model.

Poly(lactic-co-glycolic acid) nanocapsules containing amphiphilic biosurfactant sophorolipids were formulated using a dispersion-based procedure. Di-block copolymers were used to vary peripheral poly(ethylene glycol) density, and variation in the oil core was used to achieve efficient encapsulation of the sophorolipid payload. Particulate size, zeta potential, encapsulation efficiency, release and stability were characterised. A glyceryl monocaprate core composition had the lowest particulate size, maximum encapsulation efficiency and optimum shelf-life stability compared to other formulations. This core composition was used to deliver sophorolipid to both in vitro and in vivo model tumour cell lines (CT26 murine colon carcinoma) and the effect of peripheral hydrophilicity was evaluated. Formulations with 10% poly(ethylene glycol) density achieved more than 80% reduction in cancer cell viability after 72 h and enhanced cellular uptake in CT26 cells. These formulations exhibited higher tumour accumulation and a longer blood circulation profile when compared to the non-poly(ethylene glycol)-containing nanocapsules. Animals treated with sophorolipid-loaded nanocapsules showed a tumour growth inhibition of 57% when compared to controls. An assessment of tumour mass within the same study cohort showed the biggest reduction when compared control and free drug-treated cohorts. This study shows that hydrophilic poly(lactic-co-glycolic acid) nanocapsules loaded with sophorolipids can address the poor intracellular delivery associated with these biosurfactants and is a promising approach for the treatment of colon neoplasia. Graphical abstract.

Treatment of patients with gastric variceal hemorrhage: endoscopic N-butyl-2-cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration.

BACKGROUND AND AIM: Our study aimed to evaluate the therapeutic results of endoscopic N-butyl-2-cyanoacrylate injection (EBC) and balloon-occluded retrograde transvenous obliteration (BRTO) in patients with gastric variceal hemorrhage (GVH) and/or high-risk gastric varices (GV). METHODS: Twenty-seven patients with GVH and/or high-risk GV (>or= 5 mm in diameter, those with red spots, and a Child-Pugh grading of B or C liver cirrhosis) who were treated with either EBC or BRTO from April 2005 to December 2007 were included in our study. RESULTS: EBC or BRTO was initially used for the treatment of GVH in 14 and 13 patients, respectively. Technical success was achieved in all 14 patients (100%) initially treated with EBC, and 10 of 13 patients (76.9%) initially treated with BRTO. Significant rebleeding occurred in 10 patients (71.4%) of the EBC group, and two patients (15.4%) of BRTO group (P < 0.01). Five of six patients (83.3%) treated with rescue BRTO due to rebleeding after initial EBC achieved technical success, and all six patients who were treated with rescue BRTO had no rebleeding during the median follow up of 17 (range: 2-37) months. The cumulative survival rate of the EBC with the BRTO rescue group/BRTO group was significantly higher than the EBC group. CONCLUSION: The therapeutic efficacies of EBC and BRTO for the treatment of active GVH and/or high-risk GV appeared to be similar. However, EBC might be associated with a higher rebleeding rate than BRTO. BRTO could be an effective rescue treatment for patients with GVH after initial treatment of EBC.

Analysis of prognostic factors in patients with gastric varices after endoscopic treatment.

BACKGROUND: The prognostic factors, including gastric variceal bleeding itself, in patients with gastric varices (GV) after endoscopic treatment remain unclear. The aim of this study was to analyze prognostic factors in patients with GV after endoscopic treatment as well as to evaluate safety and efficacy of our endoscopic treatment. PATIENTS AND METHODS: This study enrolled 115 patients who underwent endoscopic treatment for GV between October 1988 and December 2003 using cyanoacrylate and 5% ethanolamine oleate. Successful hemostasis, recurrence rates, rebleeding rates, survival rates, complications and prognostic factors after the treatment were retrospectively reviewed. RESULTS: Treatment sessions for GV were performed 3.4 +/- 2.5 times. All cases, including 14 emergency cases, were treated successfully. The cumulative recurrence rates at 1, 3 and 5 years after the treatment were 7.0%, 15.6% and 20.0%, respectively, and the cumulative rebleeding rates at 1, 3 and 5 years were 3.5%, 8.7% and 14.8%, respectively. The overall survival rates were 78.3%, 63.7% and 51.5% at 1, 3 and 5 years, respectively. Grade B or C in Child-Pugh classification, emergency or elective cases, and association with hepatocellular carcinoma were identified as significant negative prognostic factors after endoscopic treatment by multivariate analysis. Although several complications were observed, there was no mortality. CONCLUSIONS: Grade B or C in Child-Pugh classification, emergency or elective situation, and association with hepatocellular carcinoma are negative prognostic factors after endoscopic treatment.

Intralesional sclerotherapy for subcutaneous venous malformations in children.

BACKGROUND: Venous malformations (VMs) involve multiple anatomical spaces and encase critical neuromuscular structures, making surgical treatment difficult. Recently sclerotherapy has been suggested as the primary treatment for VMs instead of surgical intervention. This report represents eight cases of children with VMs treated with direct percutaneous injections of sclerosing agents, such as ethanol, polidocanol or ethanolamine oleate. METHODS: All eight patients had large lesions (>3 cm) located on the head, foot, neck and face. Sclerotherapy was performed in an angiographic suite under general anesthesia. Prior to sclerotherapy, percutaneous phlebography was performed in order to visualize the dynamic situation inside the lesion and the draining flow into the adjacent venous vascular system. A 2-15 ml of sclerosing agent was injected into VM lesions under fluoroscopy. RESULTS AND CONCLUSIONS: An evaluation by MRI examination showed that 6 out of 8 patients had remission, and alleviation of their symptoms without major complications, furthermore one of the lesions apparently disappeared. Intralesional sclerotherapy provides a simple, safe and effective treatment for VMs in the subcutaneous lesions in children.

Sclerotherapy as an esthetic indication in oral vascular malformations: a case series.

BACKGROUND: The use of monoethanolamine oleate 5% is effective for the treatment of vascular malformations with low blood flow. OBJECTIVES: To report a case series of vascular malformations in the mouth and oral cavity treated with monoethanolamine oleate 5%. METHODS: A retrospective descriptive study was performed in electronic patient charts covering seven years. Patient demographics, diagnostic resources, lesion site, size, and number of applications of monoethanolamine oleate 5% were collected. RESULTS: A total of 21 vascular malformations were recorded, located mostly on the lower lip (52.3%) and resolved in a single application in 14 patients. The authors found 19 patients treated with sclerotherapy. Thirteen were women and six were men, with a mean age of 61 years. STUDY LIMITATION: Small sample size. CONCLUSIONS: Sclerotherapy is an effective treatment for vascular malformations of the lips and oral cavity, with resolution after only one or two applications (n=16).

Antiproliferative and proapoptotic effects of DODAC/synthetic phosphoethanolamine on hepatocellular carcinoma cells.

BACKGROUND: Current studies have demonstrated that DODAC/PHO-S (Dioctadecyldimethylammonium Chloride/Synthetic phosphoethanolamine) liposomes induces cytotoxicity in Hepa1c1c7 and B16F10 murine tumor cells, with a higher proportion than PHO-S. Therefore, our aim was to evaluate the potential of DODAC/PHO-S to elucidate the mechanism of cell death whereby the liposomes induces cytotoxicity in hepatocellular carcinoma Hepa1c1c7, compared to the PHO-S alone. METHODS: Liposomes (DODAC/PHO-S) were prepared by ultrasonication. The cell cycle phases, protein expression and types of cell's death on Hepa1c1c7 were analyzed by flow cytometry. The internalisation of liposomes, mitochondrial electrical potential and lysosomal stability were also evaluated by confocal laser scanning microscopy. RESULTS: After treatment with liposomes (DODAC/PHO-S), we observed a significant increase in the population of Hepa1c1c7 cells experiencing cell cycle arrest in the S and G2/M phases, and this treatment was significantly more effective to promote cell death by apoptosis. There also was a decrease in the mitochondrial electrical potential; changes in the lysosomes; nuclear fragmentation and catastrophic changes in Hepa1c1c7 cells. The liposomes additionally promoted increases in the expression of DR4 receptor, caspases 3 and 8, cytochrome c, p53, p21, p27 and Bax. There was also a decrease in the expression of Bcl-2, cyclin D1, CD90 and CD44 proteins. CONCLUSION: The overall results showed that DODAC/PHO-S liposomes were more effective than PHO-S alone, in promoting cytotoxicity Hepa1c1c7 tumor cells, activating the intrinsic and extrinsic pathways of programmed cell death.

Lipid excipients Peceol and Gelucire 44/14 decrease P-glycoprotein mediated efflux of rhodamine 123 partially due to modifying P-glycoprotein protein expression within Caco-2 cells.

PURPOSE: The objective of this study was to determine the influence of two lipid excipients, Peceol(c) and Gelucire(c) 44/14 on P-glycoprotein (Pgp) activity and protein expression in human colon adenocarcinoma cells (Caco-2). Lipid excipients are increasingly used as drug delivery systems for hydrophobic drugs to increase their bioavailability by overcoming the barrier of low absorption. This study will probe a novel mechanism by which lipid excipients reduce Pgp-mediated efflux and thereby increase bioavailability of orally administered therapeutics. METHODS: Non-cytotoxic concentrations of Peceol(c) and Gelucire(c) 44/14 were determined for 24-hour treatments of Caco-2 cells using integrity of the cell membranes and mitochondrial respiration as markers. Pgp activity after treatment with non-cytotoxic concentrations of Peceol(c) and Gelucire(c) 44/14 was measured with a fluorescent Pgp substrate, rhodamine 123 (Rh123). The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123 using the Transwell(c) semi-permeable cell culture support system. To assess the effect of Peceol(c) and Gelucire(c) 44/14 on Pgp protein expression, Western blotting with a specific Pgp antibody was performed. RESULTS. The two assays for cytotoxicity were in agreement and showed that concentrations of less than 0.5% (v/v) Peceol(c) and less than 0.02% (w/v) Gelucire(c) 44/14 were not toxic to Caco-2 cells. Rh123 accumulation was increased up to 3-fold in cells treated with sub-toxic concentrations of the excipients. The flux of Rh123 across the cell monolayer was unaffected by treatment in the absorptive (apical to basolateral) direction but the efflux transport was reduced after treatment with Peceol(c), Gelucire(c) 44/14 or the positive control , 100microM verapamil. Some of the reduction in Pgp efflux activity can be explained by the reduction in protein expression after treatment with the lipid excipients; treatment with 0.25% (v/v) and 0.5% (v/v) Peceol(c) reduced Pgp protein levels to 62.4% and 68.4% of the control respectively while Gelucire(c) 44/14 treatments of 0.01% (w/v) and 0.02% (w/v) reduced Pgp to 64.5% and 51.8% respectively. CONCLUSION: In this study we utilized established methodologies to assess the inhibitory effect of the excipients on the Pgp-mediated efflux of the probe, Rh123 and tested the hypothesis that long-term treatment of Caco-2 cells with the lipid excipients, Peceol(c) and Gelucire(c) 44/14, decreased Pgp protein expression. The results suggest a new mechanism which may contribute to the improved bioavailability seen for drugs formulated with lipid-based excipients.

Cytotoxicity of diphtheria toxin A fragment to toxin-resistant murine cells delivered by pH-sensitive immunoliposomes.

pH-sensitive immunoliposomes composed of dioleoylphosphatidylethanolamine and oleic acid (8:2 molar ratio) mediated the delivery of the cytotoxic fragment A of diphtheria toxin to the cytoplasm of target L-929 cells. Free fragment A, fragment A encapsulated in antibody-free liposomes, or fragment A encapsulated in pH-insensitive immunoliposomes was not effective in the inhibition of the cellular protein synthesis. pH-sensitive immunoliposomes containing diphtheria fragment A were not toxic to nontarget diphtheria-resistant A31 cells or to nontarget diphtheria-sensitive Vero cells. Pretreatment of target L-929 cells with the weak bases NH4Cl or chloroquine, agents which raise the endosome/lysosome pH, blocked the cytotoxic effect of the pH-sensitive immunoliposomes containing fragment A. Excess free antibody or excess empty pH-sensitive immunoliposomes also blocked the cytotoxic effect. Since it is known that fragment A alone cannot cross lipid membranes, the results of this study indicate that pH-sensitive immunoliposomes are able to release the toxin into the cytoplasm, probably by fusing with the endosome membrane following a receptor-mediated endocytosis of the immunoliposome.

Biodistribution of pH-sensitive immunoliposomes.

Liposomes composed of either dioleoylphosphatidylethanolamine and oleic acid (pH-sensitive) or dioleoylphosphatidylcholine and oleic acid (pH-insensitive) were injected into C3H and Balb/c mice in order to determine the tissue distribution of both the lipid and the aqueous content. The lipid component was monitored by use of [3H]cholestanyl ether and the aqueous content was monitored by use of encapsulated 125I-tyraminyl-inulin. The pH-insensitive liposomes injected into both types of mice were rapidly cleared from the blood stream followed by accumulation primarily in the liver, followed by the spleen. The presence of a monoclonal antibody on the liposome surface caused a slight acceleration in liver accumulation, though generally gave the same profile as the antibody-free liposomes. pH-sensitive liposomes were leaky upon exposure to the mouse plasma following injection. The lipid component, though, displayed a large amount (e.g., 50-70% in C3H mice) of accumulation in the lung for up to 6 h, followed by a subsequent appearance in the liver and spleen. The presence of monoclonal antibody had no effect on the tissue distribution profile. These results indicate that the pH-sensitive liposomes, although ineffective as an aqueous drug delivery agent, may be effective as a means of delivering lipophilic drugs to the lung.

Deposition of Particles in Human Mouth-Throat Replicas and a USP Induction Port.

BACKGROUND: Oral inhalation is the common route of drug delivery to pulmonary airways. In general, deposition in the oropharyngeal airways from a drug-delivery device makes up a substantial portion of the emitted dose, which affects the dose delivered to the lung. Studies with airway replicas made from cadaver or magnetic resonance imaging scans show that for micrometer-sized particles, impaction is the dominant deposition mechanism. Several deposition studies in oropharyngeal replicas found that the deposition efficiency can be correlated with the mouth inlet velocity and inlet mouthpiece diameter. Other studies show that the deposition efficiency is best correlated with the mean diameter of internal geometry and the mean velocity based on the mean diameter. METHOD: We investigated the mouth inlet diameter, as well as internal airway dimensions and their influence on oropharyngeal deposition based on experimental data from this study. Several human oropharyngeal replicas with different mouth inlet diameters and the USP induction port were used. RESULTS: We found that the aerosol deposition increased with decreasing mouth inlet diameter. Several mathematical expressions were tried to correlate the deposition efficiency with the Stokes number calculated based on (1) mouth inlet diameter and inlet velocity, (2) mean diameter of internal geometry and mean velocity, (3) mouth inlet velocity and mean diameter, and (4) mouth inlet velocity and minimum diameter in the oropharyngeal replica. The best correlation was obtained in case 4. CONCLUSIONS: This correlation could explain the intra-subject variation when deposition was found to vary with mouth inlet diameter, such as in some aerosol drug-delivery devices. It could also explain the intersubject variability in oropharyngeal deposition when human volunteers with different airway geometries and mouth openings were studied.