Ruptured Intracranial Aneurysms Treated with the Pipeline Embolization Device: A Systematic Review and Pooled Analysis of Individual Patient Data.

BACKGROUND: The Pipeline Embolization Device (PED) is a flow-diverting stent for the treatment of intracranial aneurysms and is used off-label for a subset of ruptured aneurysms not amenable to traditional treatment. PURPOSE: Our aim was to evaluate the safety and efficacy of the PED for treatment of ruptured intracranial aneurysms. DATA SOURCES: A systematic review of the MEDLINE, EMBASE, and Scopus data bases from January 2011 to March 2020 was performed for articles reporting treatment of ruptured intracranial aneurysms with the PED. STUDY SELECTION: A total of 12 studies comprising 145 patients with 145 treated aneurysms were included for analysis. DATA ANALYSIS: Individual patient data were collected. Nonparametric tests were used to compare differences among patients. Logistic regression was used to determine an association with outcome variables. DATA SYNTHESIS: Mean aneurysm size was 5.9 mm, and most were blister (51.0%) or dissecting (26.9%) in morphology. Three (2.1%) aneurysms reruptured following PED placement. Univariate logistic regression identified larger aneurysm size as a significant predictor of aneurysm rerupture (P = .008). Of patients with radiographic follow-up, 87.5% had complete aneurysm occlusion. Symptomatic neurologic complications occurred in 16.5%. LIMITATIONS: Analysis was limited by the quality of the included data, most of which were from small case series representing class III medical evidence. No study assessed outcome in a blinded or independently adjudicated manner. CONCLUSIONS: Most ruptured aneurysms treated with the PED were blister or dissecting aneurysms. Treatment was associated with a rerupture rate of 2.1% and a complete occlusion rate of 87.5%.

Risk of Branch Occlusion and Ischemic Complications with the Pipeline Embolization Device in the Treatment of Posterior Circulation Aneurysms.

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device is increasingly used for endovascular treatment of intracranial aneurysms due to high reported obliteration rates and low associated morbidity. While obliteration of covered branches in the anterior circulation is generally asymptomatic, this has not been studied within the posterior circulation. The aim of this study was to evaluate the association between branch coverage and occlusion, as well as associated ischemic events in a cohort of patients with posterior circulation aneurysms treated with the Pipeline Embolization Device. MATERIALS AND METHODS: A retrospective review of prospectively maintained databases at 8 academic institutions from 2009 to 2016 was performed to identify patients with posterior circulation aneurysms treated with the Pipeline Embolization Device. Branch coverage following placement was evaluated, including the posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery, and posterior cerebral artery. If the Pipeline Embolization Device crossed the ostia of the contralateral vertebral artery, its long-term patency was assessed as well. RESULTS: A cohort of 129 consecutive patients underwent treatment of 131 posterior circulation aneurysms with the Pipeline Embolization Device. Adjunctive coiling was used in 40 (31.0%) procedures. One or more branches were covered in 103 (79.8%) procedures. At a median follow-up of 11 months, 11% were occluded, most frequently the vertebral artery (34.8%). Branch obliteration was most common among asymptomatic aneurysms (P < .001). Ischemic complications occurred in 29 (22.5%) procedures. On multivariable analysis, there was no significant difference in ischemic complications in cases in which a branch was covered (P = .24) or occluded (P = .16). CONCLUSIONS: There was a low occlusion incidence in end arteries following branch coverage at last follow-up. The incidence was higher in the posterior cerebral artery and vertebral artery where collateral supply is high. Branch occlusion was not associated with a significant increase in ischemic complications.

Predictors of Incomplete Occlusion following Pipeline Embolization of Intracranial Aneurysms: Is It Less Effective in Older Patients?

BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device (PED) for the treatment of intracranial aneurysms is associated with a high rate of aneurysm occlusion. However, clinical and radiographic predictors of incomplete aneurysm occlusion are poorly defined. In this study, predictors of incomplete occlusion at last angiographic follow-up after PED treatment were assessed. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the PED between 2009 and 2016, at 3 academic institutions in the United States, was performed. Cases with angiographic follow-up were selected to evaluate factors predictive of incomplete aneurysm occlusion at last follow-up. RESULTS: We identified 465 aneurysms treated with the PED; 380 (81.7%) aneurysms (329 procedures; median age, 58 years; female/male ratio, 4.8:1) had angiographic follow-up, and were included. Complete occlusion (100%) was achieved in 78.2% of aneurysms. Near-complete (90%-99%) and partial (<90%) occlusion were collectively achieved in 21.8% of aneurysms and defined as incomplete occlusion. Of aneurysms followed for at least 12 months (211 of 380), complete occlusion was achieved in 83.9%. Older age (older than 70 years), nonsmoking status, aneurysm location within the posterior communicating artery or posterior circulation, greater aneurysm maximal diameter (≥21 mm), and shorter follow-up time (<12 months) were significantly associated with incomplete aneurysm occlusion at last angiographic follow-up on univariable analysis. However, on multivariable logistic regression, only age, smoking status, and duration of follow-up were independently associated with occlusion status. CONCLUSIONS: Complete occlusion following PED treatment of intracranial aneurysms can be influenced by several factors related to the patient, aneurysm, and treatment. Of these factors, older age (older than 70 years) and nonsmoking status were independent predictors of incomplete occlusion. While the physiologic explanation for these findings remains unknown, identification of factors predictive of incomplete aneurysm occlusion following PED placement can assist in patient selection and counseling and might provide insight into the biologic factors affecting endothelialization.

Treatment of Tandem Internal Carotid Artery Aneurysms Using a Single Pipeline Embolization Device: Evaluation of Safety and Efficacy.

BACKGROUND AND PURPOSE: Tandem aneurysms are defined as multiple aneurysms located in close proximity on the same parent vessel. Endovascular treatment of these aneurysms has rarely been reported. Our aim was to evaluate the safety and efficacy of a single Pipeline Embolization Device for the treatment of tandem aneurysms of the internal carotid artery. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the Pipeline Embolization Device between 2009 and 2016 at 3 institutions in the United States was performed. Cases included aneurysms of the ICA treated with a single Pipeline Embolization Device, and they were divided into tandem versus solitary. Angiographic and clinical outcomes were compared. RESULTS: The solitary group (median age, 58 years) underwent 184 Pipeline Embolization Device procedures for 184 aneurysms. The tandem group (median age, 50.5 years) underwent 34 procedures for 78 aneurysms. Aneurysms were primarily located along the paraophthalmic segment of the ICA in both the single and tandem groups (72.3% versus 78.2%, respectively, P = .53). The median maximal diameters in the solitary and tandem groups were 6.2 and 6.7 mm, respectively. Complete occlusion on the last angiographic follow-up was achieved in 75.1% of aneurysms in the single compared with 88.6%% in the tandem group (P = .06). Symptomatic thromboembolic complications were encountered in 2.7% and 8.8% of procedures in the single and tandem groups, respectively (P = .08). CONCLUSIONS: Tandem aneurysms of the ICA can be treated with a single Pipeline Embolization Device with high rates of complete occlusion. While there appeared to be a trend toward higher thromboembolic complication rates, this did not reach statistical significance.

Observed changes in the alertness and communicative involvement of students with multiple and severe disability following in-class mentor modelling for staff in segregated and general education classrooms.

BACKGROUND: The improvement of engagement and involvement in communicative and socially centred exchanges for individuals with multiple and severe disability (MSD) presents complex and urgent challenges to educators. This paper reports the findings of an intervention study designed to enhance the interactive skills of students with MSD using an in-class mentor model of staff development to improve the skills and strategies of their communication partners in two distinct educational settings. METHODS: Observational data were collected on eight students with MSD and their 16 teachers and teachers' aides (paraprofessionals), using a multiple baseline across students design, replicated across special and general school setting types. RESULTS: Results indicated variable improvements in student alertness and increased communicative interactions. In some cases significant differences in communicative involvement and awake-active-alert activity were observed. CONCLUSIONS: These findings underline the complexity of variables involved in delivering educational and communicative interventions for staff working with this population. Implications for further research and application to daily practices in classrooms are discussed.

Spinal cord stimulation paresthesia and activity of primary afferents.

A patient with failed back surgery syndrome reported paresthesia in his hands and arms during a spinal cord stimulation (SCS) screening trial with a low thoracic electrode. The patient's severe thoracic stenosis necessitated general anesthesia for simultaneous decompressive laminectomy and SCS implantation for chronic use. Use of general anesthesia gave the authors the opportunity to characterize the patient's unusual distribution of paresthesia. During SCS implantation, they recorded SCS-evoked antidromic potentials at physiologically relevant amplitudes in the legs to guide electrode placement and in the arms as controls. Stimulation of the dorsal columns at T-8 evoked potentials in the legs (common peroneal nerves) and at similar thresholds, consistent with the sensation of paresthesia in the arms, in the right ulnar nerve. The authors' electrophysiological observations support observations by neuroanatomical specialists that primary afferents can descend several (in this case, at least 8) vertebral segments in the spinal cord before synapsing or ascending. This report thus confirms a physiological basis for unusual paresthesia distribution associated with thoracic SCS.

Effect on the nasal bioavailability of co-processing drug and bioadhesive carrier via spray-drying.

A mucoadhesive combination of a maize starch (Amioca, mainly consisting of amylopectine) and a cross-linked acrylic acid-based polymer (Carbopol 974P) was spray-dried with metoprolol tartrate (used as model molecule) in order to develop a powder suitable for nasal drug delivery via a one-step manufacturing process. The bioavailability of metoprolol tartrate after nasal administration of this powder to rabbits was compared with powders manufactured via other procedures: (a) freeze-drying of a dispersion prepared using the co-spray-dried powder, (b) freeze-drying of a dispersion prepared using a physical mixture of drug and mucoadhesive polymers. After co-processing via spray-drying a low bioavailability (BA 10.8+/-2.3%) was obtained, whereas manufacturing procedures based on freeze-drying yielded a higher BA: 37.9+/-12.8% using the co-processed powder and 73.6+/-24.9% using the physical mixture. The higher bioavailability was due to the deprotonation of poly(acrylic acid) during neutralisation of the dispersion prior to freeze-drying. This induced repulsion of the ionised carboxyl groups and a lower interaction between poly(acrylic acid) and starch, creating a less compact matrix upon hydration of the polymer and allowing an easier escape of metoprolol tartrate from the matrix. This study showed that co-processing of a mucoadhesive Amioca/Carbopol 974P formulation with metoprolol tartrate via co-spray-drying did not provide any added value towards the bioavailability of the drug after nasal administration of the mucoadhesive powder.

Influence of heat treatment on spray-dried mixtures of Amioca starch and Carbopol 974P used as carriers for nasal drug delivery.

A mucoadhesive spray-dried starch/poly(acrylic acid) powder underwent different heat treatments in order to induce cross-linking between the functional groups of starch (Amioca) and poly(acrylic acid) (Carbopol 974P). After heat treatment the water-absorbing capacity, viscosity and elasticity of the mucoadhesive powder increased. NMR analysis in combination with FT-IR indicated that heat treatment induced a low degree of cross-linking between the polymers. Nasal administration of Amioca/Carbopol 974P powders without heat treatment resulted in an absolute bioavailability in rabbits of 8.2+/-3.0% for insulin. Due to the difference in water-absorbing capacity (which opened the tight junctions of the nasal mucosa), elasticity and plasticity (which reduced mucociliairy clearance and prolonged residence time) heat treatment at 120 degrees C improved the bioavailability: 26.4+/-21.9, 36.5+/-11.0 and 19.3+/-17.3% after heat treatment during 30 min, 1 h and 4 h, respectively. Heat treatment at 60 degrees C was less efficient. This study demonstrated that the nasal insulin absorption improved via heat treatment of the Amioca/Carbopol 974P powder (prior to the addition of insulin). The bioavailability-enhancing effect of a 1 h heat treatment at 120 degrees C was confirmed using the same polymer matrix in combination with different drugs (salmon calcitonin, human growth hormone and metoprolol tartrate).

Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine.

Mucosal vaccination has several advantages over parenteral vaccination. In this study, viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen were investigated. Powder formulations based on spray-dried mixtures of starch (Amioca)/poly(acrylic acid) (Carbopol 974P) in different ratios were used as carriers of the viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR192G adjuvant was made in vivo in a rabbit model. Individual rabbit sera were tested for seroconversion against hemagglutinin (HA), the major surface antigen of influenza. The powder vaccine formulations were able to induce systemic anti-HA IgG responses. The presence of Carbopol 974P improved the kinetics of the immune responses and the level of IgG titers in a dose-dependent way which was correlated with moderately irritating capacities of the formulation. In contrast, mucosal IgA responses were not detected. In conclusion, it was demonstrated that the use of bioadhesive carriers based on Amioca starch and poly(acrylic acid) facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.

The addition of calcium ions to starch/Carbopol mixtures enhances the nasal bioavailability of insulin.

To evaluate the influence of calcium poly(acrylates) on the nasal absorption of insulin in rabbits, starch/poly(acrylic acid) (ratio 25/75) (SD 25/75) was neutralised with NaOH and/or Ca(OH)(2). After neutralisation, a mixture of sodium and/or calcium carboxylate was formed depending on the Ca(OH)(2) concentration in the formulation. IR spectroscopy confirmed that most of the calcium molecules in the formulation interacted with acid groups of the acrylic acid polymer. Addition of Ca(OH)(2) to aqueous dispersions containing starch/poly(acrylic acid) yielded powders with an enhanced absorption of insulin after nasal delivery to rabbits in comparison with the equivalent powder without Ca(OH)(2). A mixture of SD 25/75 and Ca(OH)(2) at a ratio of 90/10 neutralised to pH 7.4 with NaOH induced the highest absorption of insulin, obtaining a bioavailability of +/-29% (vs. 19% for an equivalent formulation without Ca(OH)(2)). This increase in nasal delivery was possibly due to a higher elasticity after dispersing this formulation in nasal fluid and to a higher water absorbing capacity. Furthermore, after nasal delivery of (SD 25/75)/Ca(OH)(2) 90/10, a decrease in t(max) was observed, possibly due to a progressive dissociation of Ca(2+)-ions after hydration of the powder resulting in the closing of the tight junctions.

Focal occipital seizures with cerebral polyopia.

Polyopia is the visual perception of multiple images of a single visual stimulus. Cerebral polyopia has previously been described as an ictal phenomenon associated with temporal lobe seizures. We report the case of a man with multiple cavernous angiomas and occipital lobe seizures manifesting as cerebral polyopia.

Influence of deposition and spray pattern of nasal powders on insulin bioavailability.

The influence of the deposition pattern and spray characteristics of nasal powder formulations on the insulin bioavailability was investigated in rabbits. The formulations were prepared by freeze drying a dispersion containing a physical mixture of drum dried waxy maize starch (DDWM)/Carbopol 974P (90/10, w/w) or a spray-dried mixture of Amioca starch/Carbopol 974P (25/75, w/w). The deposition in the nasal cavity of rabbits and in a silicone human nose model after actuation of three nasal delivery devices (Monopowder, Pfeiffer and experimental system) was compared and related to the insulin bioavailability. Posterior deposition of the powder formulation in the nasal cavity lowered the insulin bioavailability. To study the spray pattern, the shape and cross-section of the emitted powder cloud were analysed. It was concluded that the powder bulk density of the formulation influenced the spray pattern. Consequently, powders of different bulk density were prepared by changing the solid fraction of the freeze dried dispersion and by changing the freezing rate during freeze drying. After nasal delivery of these powder formulations no influence of the powder bulk density and of the spray pattern on the insulin bioavailability was observed.

Characterization and in vivo evaluation of ocular minitablets prepared with different bioadhesive Carbopol-starch components.

The purpose of this study was to evaluate different bioadhesive ocular formulations based on drum dried waxy maize starch (DDWM), Amioca starch and Carbopol 974P. The concentrations of Carbopol 974P in the mixtures varied between 5 and 25% (w/w). The rheological properties of the non-sterilized and gamma-irradiated physical blends of Carbopol 974P with either DDWM or Amioca were compared to those of the corresponding co-spray dried Amioca starch/Carbopol powders. Higher viscosity or consistency values were measured for sterilized co-spray dried powder mixtures containing an amount of Carbopol 974P equal or above 15% (w/w) compared to the physical blends. Sustained release minitablets (2 mm, 6 mg), consisting of sodium fluorescein as model drug and the bioadhesive powders, were manufactured at a compression force of 1.25 kN. Afterwards, the tablets were sterilized with gamma-irradiation. The amount of Carbopol in the co-spray dried powder mixtures on the one hand and gamma-irradiation on the other hand had no significant influence on the crushing strength and friability of the minitablets evaluated. However, these two factors affected the in vitro release properties of the minitablets. The slowest release was obtained with tablets containing 25% Carbopol 974P, which unfortunately possess mucosal irritating properties. By using co-spray dried Amioca with 15% (w/w) Carbopol 974P, a slower release can be achieved compared to the physical mixtures of DDWM or Amioca starch with Carbopol 974P. Moreover, this ocular formulation is very promising and is preferred, as it did not cause any mucosal irritation and released the model drug for at least 12 h, after application in the fornix.

Spray-dried Amioca starch/Carbopol 974P mixtures as buccal bioadhesive carriers.

In the present study, spray-dried Amioca starch/Carbopol 974P mixtures were evaluated as potential buccal bioadhesive tablets. Carbopol (C 974P) concentrations from 5 to 75% were tested. All spray-dried mixtures showed a comparable or better bioadhesive capacity compared to a reference formulation (DDWM/C 974P 95/5). The bioadhesive capacities of Amioca/Carbopol 974P mixtures were improved by spray-drying. All spray-dried mixtures showed significantly higher work of adhesion values compared to their equivalent physical mixtures. The influence of Carbopol concentration on the in vivo adhesion time of placebo tablets and in vitro miconazole nitrate release was tested. The ratio Amioca/C 974P 70/30 showed the longest in vivo adhesion time (24.5+/-8.5 h). Lower and higher C 974P concentrations had a shorter in vivo adhesion time. The mixtures containing between 15 and 30% C 974P could all sustain the in vitro miconazole nitrate release over 20 h. Again, lower and higher C 974P concentrations showed a faster in vitro miconazole release. The drug loading capacity of a spray-dried mixture containing 20% C 974P was investigated in vivo in dogs using testosterone as model drug. The spray-dried mixture could be loaded with 60% drug without loosing its in vivo bioadhesive and pharmacokinetic properties.

Starch/Carbopol spray-dried mixtures as excipients for oral sustained drug delivery.

The present study evaluated if mixtures prepared by spray-drying an aqueous dispersion of Amioca starch and Carbopol 974P could be used as matrix for oral sustained drug delivery. The influence of the Amioca/Carbopol 974P ratio (0/100, 25/75, 50/50, 60/40, 85/15, 90/10, 95/5 and 100/0) and the pH and ionic strength (mu) of the dissolution medium on the drug release was investigated. The matrices composed of the spray-dried mixtures with 10% or 15% Carbopol 974P sustained the drug release over the longest time period. At this Carbopol concentration, shear viscosity measurements indicated the formation of an optimal network between the polymer chains of Amioca starch and Carbopol 974P, forming a rigid gel layer offering resistance to erosion during the dissolution experiments.

Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons.

Mcl1 is a Bcl2-related antiapoptotic protein originally isolated from human myeloid leukemia cells. Unlike Bcl2, expression has not been reported in CNS neurons. We isolated Mcl1 in a direct screen for candidate modifier genes of neuronal vulnerability by differential display of mRNAs upregulated following prolonged seizures in two mouse strains with contrasting levels of hippocampal cell death. Mcl1 is widely expressed in neurons, and transcription is rapidly induced in both strains. In resistant C57Bl/6J mice, Mcl1 protein levels remain persistently elevated in hippocampal pyramidal neurons after seizures, but fall rapidly in C3H/HeJ hippocampus, coinciding with extensive neuronal apoptosis. DNA damage and caspase-mediated cell death were strikingly increased in Mcl1-deficient mice when compared to +/+ littermates after similar seizures. We identify Mcl1 as a neuronal gene responsive to excitotoxic insult in the brain, and link relative levels of Mcl1 expression to inherited differences in neuronal thresholds for apoptosis.

Characterization of the protein processing and secretion pathways in a comprehensive set of expressed sequence tags from Trichoderma reesei.

Trichoderma reesei is a filamentous fungus widely used as an efficient protein producer and known to secrete large quantities of biomass degrading enzymes. Much work has been done aimed at improving the secretion efficiency of this fungus. It is generally accepted that the major bottlenecks in secretion are protein folding and ornamentation steps in this pathway. In an attempt to identify genes involved in these steps, the 5' ends of 21888 cDNA clones were sequenced from which a unique set of over 5000 were also 3' sequenced. Using annotation tools Gene Ontology terms were assigned to 2732 of the sequences. Homologs to the majority of Aspergillus niger's Srg genes as well as a number of homologs to genes involved in protein folding and ornamentation pathways were identified.

Rheological study on mucoadhesivity of some nasal powder formulations.

Various powder mixtures were used to administer insulin via the nasal route: a co-spray dried mixture of Amioca starch and Carbopol 974 P (1/3), drum dried waxy maize starch and Carbopol 974 P (9/1), maltodextrin DE38/Carbopol 974 P (9/1) and pure drum dried waxy maize starch. Oscillatory rheology is performed to study and compare the viscosity, elasticity and mucoadhesivity of these powder formulations. There was no rheological synergism detectable with the co-spray dried mixture of Amioca starch and Carbopol 974 P (1/3), drum dried waxy maize starch and Carbopol 974 P (9/1) and maltodextrin DE38/Carbopol 974 P (9/1). Interaction due to entanglements was seen with drum dried waxy maize starch (100%). The differences in nasal bioavailability between the different carriers could be explained by differences in G' (storage modulus, elasticity) and G" (loss modulus, viscosity) values. The formulation giving the highest bioavailability, provided also the highest G' and G" values.

Evaluation of the mucosal irritation potency of co-spray dried Amioca/poly(acrylic acid) and Amioca/Carbopol 974P mixtures.

The purpose of this study was to evaluate the biocompatibility of different Amioca/poly(acrylic acid) and Amioca/Carbopol 974P co-spray dried mixtures with an alternative mucosal irritation test using slugs. The irritation potential of the mixtures was measured by the amount of mucus produced during a repeated 30-min contact period. Additionally, membrane damage was assessed by measuring the protein and enzyme release from the body wall of slugs after treatment. All the Amioca/poly(acrylic acid) co-spray dried mixtures (50:50 and 25:75 ratios) induced slight irritation of the mucosal tissue as was demonstrated by the significantly increased mucus production however no increased protein and enzyme release was detected. Co-spray dried Amioca/Carbopol 974P mixtures containing 40% and more Carbopol 974P demonstrated a significantly higher mucus production and release of cytosolic LDH, indicating membrane damage. The total mucus production of the slugs treated with the co-spray dried mixtures containing up to 20% Carbopol 974P was significantly higher compared to the blank slugs. However, these mixtures induced no membrane damage since no additional effect on the protein release and no enzyme release was detected. By co-spray drying up to 20% Carbopol 974P could be incorporated without showing a distinct sign of irritation. These mixtures can be considered as potentially safe bioadhesive carriers.

Ex vivo bioadhesion and in vivo testosterone bioavailability study of different bioadhesive formulations based on starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures.

Starch-g-poly(acrylic acid) copolymers or grafted starches synthesized by 60Co irradiation or chemical modification and co-freeze-dried starch/poly(acrylic acid) mixtures were evaluated on their ex vivo bioadhesion capacity. The buccal absorption of testosterone from a bioadhesive tablet formulated with the grafted starches or starch/poly(acrylic acid) mixtures was investigated. The results were compared to a reference formulation (physical mixture of 5% Carbopol 974P and 95% Drum Dried Waxy Maize). Rice starch-based irradiated grafted starches showed the best bioadhesion results. Partial neutralization of the acrylic acid with Ca(2+) ions resulted in significantly higher bioadhesion values compared to the reference. Ca(2+) and Mg(2+) partially neutralized maltodextrin-based irradiated grafted starches showed significantly higher bioadhesion values compared to the reference formulation. The chemically modified grafted starches showed significantly higher adhesion force values than for the reference tablet. None of the co-freeze-dried starch/poly(acrylic acid) mixtures showed significantly higher bioadhesion results than the reference (Bonferroni test, P<0.05). A chemically modified grafted starch could sustain the 3 ng/ml plasma testosterone target concentration during +/- 8 h (T(>3 ng/ml)). By lyophilization of a partially neutralized irradiated grafted starch, the in vivo adhesion time (22.0 +/- 7.2 h) and the T(>3 ng/ml) (13.5 +/- 1.3 h) could be increased. The absolute bioavailability of the lyophilized formulation approached the reference formulation. Some of the grafted starches showed to be promising buccal bioadhesive drug carriers for systemic delivery.