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PubMed2001

The insert region of Rac1 is essential for membrane ruffling but not cellular transformation.

The Rho family of Ras-related proteins, which includes Rac1, RhoA, and Cdc42, is distinguished from other members of the Ras superfamily of small GTPases in that its members possess additional sequences positioned between beta-strand 5 and alpha-helix 4, designated the insert region. Previous studies have established the importance of an intact insert region for the transforming, but not actin cytoskeletal reorganization, activities of Cdc42 and RhoA. Similarly, the insert region was determined to be essential for Rac1-mediated mitogenesis. Additionally, an intact insert region was also determined to be required for the antiapoptotic activity of Rac1 as well as for Rac1 activation of reactive oxygen species and the NF-kappaB transcription factor. However, it has not been determined whether the insert region is important for Rac1-mediated growth transformation. In this study, we assessed the requirement for the insert region in Rac1 transformation and signaling in NIH 3T3 cells. Unexpectedly, we found that a mutant of constitutively activated Rac1 that lacked the insert region retained potent transforming activity. The insert region of Rac1 was dispensable for Rac1 stimulation of transcription from the cyclin D1 promoter and for activation of the c-Jun, NF-kappaB, and E2F-1 transcription factors but was essential for Rac1 induction of serum response factor activity. While an intact insert region was dispensable for inducing reactive oxygen species production in vivo, it was required for Rac1 induction of lamellipodia. When taken together, these results show that the insert region of Rac1 serves roles in regulating actin organization and cell growth that are distinct from those of the analogous regions of Cdc42 and RhoA and support its involvement in regulating specific downstream effector interactions.

3T3 Cells↗

PubMed1985

Bombyx mori 28S ribosomal genes contain insertion elements similar to the Type I and II elements of Drosophila melanogaster.

We have examined the 28S ribosomal genes of the silkmoth, Bombyx mori, for the presence of insertion sequences. Two types of insertion sequences were found, each approximately 5 kb in length, which do not share sequence homology. Comparison of the nucleotide sequences of the junction regions with the uninserted gene reveals that one type of insertion has resulted in a 14 bp duplication of the 28S coding region at the insertion site. The location of this insertion and the 14 bp duplication are identical to that found in the Type I ribosomal insertion element of Drosophila melanogaster. The second type of insertion element is located at a site corresponding to approximately 75 bp upstream of the first type. The location of this insertion, the variability detected at its 5' junction, and a short region of sequence homology at its 3' junction suggest that it is related to the Type II element of D. melanogaster. This is the first example of a Type II-like rDNA insertion outside of sibling species of D. melanogaster, and the first example of a Type I-like rDNA insertion outside of the higher Diptera.

Animals↗

PubMed1990

Package inserts for antihypertensive drugs: use by the patients and impact on adverse drug reactions.

In Belgium, all dispensed drugs are provided with package inserts. Traditional physician-orientated inserts are gradually being replaced by patient package inserts (PPIs). The present survey is focused on the use of inserts for antihypertensive drugs and their impact on the reported occurrence and attribution of adverse drug reactions (ADRs). A group of 28 general practitioners (GPs) from the Flemish part of Belgium collected data from 702 hypertensive patients. Each participating GP submitted a consecutive sample of his patients to an interview in the Spring 1989, when 25% of the antihypertensive specialties carried a PPI-version. 1049 prescriptions for antihypertensive drugs had been dispensed. Two thirds of the patients, mostly those with a higher educational level, had read the package inserts. PPIs accounted for 16% of the inserts, and they had not been read significantly more than the traditional inserts. Reporting by the patients of possible drug-related health problems (spontaneously + after having heard the items on a check-list) was not affected by reading the insert or by the type of insert. However, the PPI did bring about spontaneous reporting, especially by patients with a low educational level. Attribution of at least one health problem to the medication was not affected by reading in itself but by the type of insert. Attribution was higher when the patient had received a PPI, except in the case of highly educated patients. Spontaneous reporting and attribution of health problems to the medications prescribed was found more frequently among patients with higher education, who did not seem to need a PPI to recognize problems as being drug-related.

Antihypertensive Agents↗

PubMed1987

Insertion of an intermediate repetitive sequence into a sea urchin histone-gene spacer.

A common polymorphism of the early embryonic histone-gene repeat of Strongylocentrotus purpuratus is a 195-bp insertion within the H4-H2B spacer. The sequence, found as an insert in histone-gene repeats of 6 of 22 individuals screened, is also found at approximately 50 sites elsewhere in the genome of every individual. We compare the sequences of the histone-gene spacers that do and do not contain the insert. The insert is found not to have transposon-like features, and no sequence in the original spacer has been duplicated to flank the insert. There is, however, a hexanucleotide sequence that is repeated three times at one end of the insert, and the element has inserted between direct repeats of 5 bp that were present in the original spacer. One of the copies found outside the histone gene cluster was cloned and sequenced and is compared with the insert. Again, no transposon-like features are evident. Regions flanking the homologous sequence in this clone were used as hybridization probes in whole-genome blots. Results indicate that the 195-bp sequence insert is itself embedded within a larger element that is repeated within the genome. Therefore, only a portion of a larger repetitive sequence has integrated into the histone-gene spacer. The sequence features of the insert, although not typical of mobile elements, may be representative of other illegitimate recombination events.

Animals↗

PubMed1999

Is skin puncture beneficial prior to arterial catheter insertion?

PURPOSE: To compare the insertion time and incidence of catheter damage between skin puncture (SP) and no skin puncture (NP) techniques prior to arterial catheter insertion in patients undergoing neurosurgery. METHODS: Patients undergoing surgery for intracranial tumours or cervical spine lesions were randomized to receive either SP or NP prior to arterial catheter insertion. The total insertion time, number of passes made, number of catheters used, method of insertion (direct or transfixation) and whether catheter was inserted with patients awake or anesthetised were recorded. After removal, catheters were examined microscopically for damage. RESULTS: Eighty-two patients, 36 in SP group and 46 in NP group were recruited. Microscopic damage was seen in 36.5% of catheters and there was no difference between the two groups. The mean/median insertion time were 180/62 sec and 205/77 sec for SP and NP respectively (P:NS). The insertion time was shorter for the direct than for the transfixation technique with median of 42 vs 174 sec (P = 0.001). CONCLUSION: There are no differences in insertion time or catheter damage between skin puncture and no skin puncture techniques prior to arterial catheter insertion. The practice of skin puncture may be abandoned resulting in decreased risk of needlestick injury.

Anesthesia, General↗

PubMed2005

Intraoperative insertion torque of lumbar pedicle screw and postoperative radiographic evaluation: short-term observation.

The correlation between the insertion torque of a lumbar pedicle screw and the mechanical stability of the screw in the bone has been mentioned in in vitro studies. The purpose of this study was to confirm the factors affecting the insertion torque of such screws in vivo. Also, the contribution of insertion torque to the initial stability of the fusion area was to be analyzed in vivo. A series of 23 cases representing 50 lumbar vertebrae were included in this study, in which we examined bone mineral density using quantitative computed tomography (CT) prior to operation. Two screw shapes were utilized, with the insertion torque for each screw measured at two points in time. The correlation between insertion torque and mineral density was investigated. Screw positions were confirmed on postoperative CT scans, and the effect of the screw thread cutting into the cortex bone was investigated. Radiographic changes at three points during a period of 3 months were also measured, and we then evaluated the interrelations between these changes and insertion torque. Furthermore, the relation between insertion torque and instability at 3 months was investigated. Correlations of insertion torque and bone mineral density depended on screw shape. There was no correlation found with mineral density in the case of cylindrical screws. Insertion torque was not affected by the screw thread cutting into the cortex of bone. As for postoperative alignment changes, no definitive trends could be ascertained, and no interrelations with torque and alignment changes were observed. There is a possibility that insertion torque was related to early-stage stability, but no statistical relation could be determined.

Aged↗

PubMed1979

Nature of the regions involved in the insertion of newly synthesized protein into the outer membrane of Escherichia coli.

Outer membrane proteins are synthesized by cytoplasmic membrane-bound polysomes, and inserted at insertion sites which cover about 10% of the total outer membrane when cells grow with a generation time of 1 h. A membrane fraction enriched in outer membrane insertion regions was isolated and partly characterized. The rat at which newly inserted proteins are transferred from such insertion regions into the rest of the outer membrane was found to be very fast; the new protein content of insertion regions and that of the remaining outer membrane equilibrate completely within about 20 s at 25 degrees C. Given the rather rigid structure of the outer membrane and the multiple interactions between outer membrane components and the murein layer, lateral diffusion of newly inserted proteins from insertion sites to the remaining outer membrane is not likely to explain this rapid equilibration. Instead, the data support a model in which insertion regions move along the cell surface, leaving behind stationary, newly inserted outer membrane proteins.

Bacterial Proteins↗

PubMed1980

Translocation specificity of the Tn3 element: characterization of sites of multiple insertions.

247 independent events involving insertion of the TN3 transposable element into a 4 kb constructed plasmid (pTU4) of partially known DNA sequence were studied by restriction endonuclease mapping, and 65 of these insertion sites were examined further by DNA sequence analysis. Our results show that the previously proposed regional specificity for Tn3 insertion is associated with a strong preference for AT-rich segments as insertion sites. Moreover, multiple insertions of the Tn3 occurred at certain AT-rich nucleotide positions, and 23 of 26 independent insertion events at a single nucleotide position were found to be in the same orientation. A region of the recipient plasmid showing major homology with the terminal 18 bp of Tn3 was identified in the vicinity of an 11 nucleotide segment that included three insertional hot spots and 36 independent insertions. Our results indicate that the site and orientation of insertion of Tn3 are at least partly determined by the primary nucleotide sequence of the recipient genome, and suggest that insertional hot spots may result from the combined effects of AT richness plus homology of the recipient genome with the terminal sequences of Tn3.

Adenine↗

PubMed1995

Laryngeal mask airway: a more successful method of insertion.

STUDY OBJECTIVE: To compare the ease of insertion of the laryngeal mask airway (LMA) by two methods. DESIGN: Prospective, randomized study. SETTING: Operating room of a university-affiliated teaching hospital. PATIENTS: 350 ASA I, II, and III patients undergoing general anesthesia, in whom use of the LMA was not contraindicated. INTERVENTIONS: With all routine monitors in place and after the induction of anesthesia with propofol, we compared the ease of insertion of the LMA in the two groups of 175 patients each. The timing of insertion was made on clinical grounds. In one group, the LMA was inserted with the cuff fully deflated, in the other group, the cuff was partially inflated (i.e., filled with half the recommended air in the cuff). When correct placement of the mask was not successful by one method, the other method was tried and the insertion graded in the same manner. MEASUREMENTS AND MAIN RESULTS: The ease of insertion of the LMA was graded by the user on a scale of 1-4. Insertion of the LMA with the cuff partially inflated was significantly more successful (97.7%) than when the cuff was fully deflated (92%) (p < 0.05). When correct placement of the mask was not possible with the cuff fully deflated, partial inflation resulted in correct placement. CONCLUSIONS: Inserting the LMA with the cuff partially inflated is likely to be more successful than with the cuff fully deflated. When it is not possible to insert the LMA with the cuff fully deflated, partial inflation before insertion may result in correct placement.

Anesthesia↗

PubMed2003

Enabling bone formation in the aged skeleton via rest-inserted mechanical loading.

The mild and moderate physical activity most successfully implemented in the elderly has proven ineffective in augmenting bone mass. We have recently reported that inserting 10 s of unloaded rest between load cycles transformed low-magnitude loading into a potent osteogenic regimen for both adolescent and adult animals. Here, we extended our observations and hypothesized that inserting rest between load cycles will initiate and enhance bone formation in the aged skeleton. Aged female C57BL/6 mice (21.5 months) were subject to 2-week mechanical loading protocols utilizing the noninvasive murine tibia loading device. We tested our hypothesis by examining whether (a) inserting 10 s of rest between low-magnitude load cycles can initiate bone formation in aged mice and (b) whether bone formation response in aged animals can be further enhanced by doubling strain magnitudes, inserting rest between these load cycles, and increasing the number of high-magnitude rest-inserted load cycles. We found that 50 cycles/day of low-magnitude cyclic loading (1200 microepsilon peak strain) did not influence bone formation rates in aged animals. In contrast, inserting 10 s of rest between each of these low-magnitude load cycles was sufficient to initiate and significantly increase periosteal bone formation (fivefold versus intact controls and twofold versus low-magnitude loading). However, otherwise potent strategies of doubling induced strain magnitude (to 2400 microepsilon) and inserting rest (10 s, 20 s) and, lastly, utilizing fivefold the number of high-magnitude rest-inserted load cycles (2400 microepsilon, 250 cycles/day) were not effective in enhancing bone formation beyond that initiated via low-magnitude rest-inserted loading. We conclude that while rest-inserted loading was significantly more osteogenic in aged animals than the corresponding low-magnitude cyclic loading regimen, age-related osteoblastic deficits most likely diminished the ability to optimize this stimulus.

Age Factors↗

PubMed2004

Investigation of the validity of modeling the Achilles tendon as having a single insertion site.

OBJECTIVE: To assess the propriety of modeling the Achilles tendon insertion on the calcaneus as a single point when musculoskeletal models are used to predict subtalar joint moment arms. DESIGN: The sensitivity of model-predicted subtalar joint moment arms to insertion site position was investigated and measurements of Achilles tendon function were made in cadaver specimens. BACKGROUND: The insertion site of the Achilles tendon is typically modeled as having a single-point insertion. A more sophisticated representation may be required, however, when subtalar joint function is considered. METHODS: Achilles tendon moment arms about the subtalar joint axis were assessed using a computer model in which a single-point insertion was systematically displaced. The effective insertion site was located at three positions in three cadaver specimens using a six-degree-of-freedom load cell. RESULTS: Model-predicted moment arms of the Achilles tendon about the subtalar joint axis were substantially affected by medial-lateral displacement of the insertion site. The medial-lateral location of the effective insertion site varied linearly with subtalar joint angle in cadaver specimens, shifting medially when the foot was everted and laterally when the foot was inverted. CONCLUSIONS: More sophisticated representations of the Achilles tendon are needed when the subtalar joint is of interest. A single-segment tendon with an insertion that is fixed throughout subtalar joint motion may not permit accurate predictions of moment arms about the subtalar joint. RELEVANCE: Accurate prediction of the large moments produced by the triceps surae when simulating movement or investigating the effects of orthopaedic surgeries requires a realistic representation of the Achilles tendon insertion.

Achilles Tendon↗

PubMed2005

Ease of insertion, contraceptive efficacy and safety of new T-shaped levonorgestrel-releasing intrauterine systems.

OBJECTIVE: The objective of the study was to evaluate ease of insertion, contraceptive performance and safety, in parous and nulliparous women, of two new T-shaped levonorgestrel (LNG)-releasing intrauterine systems (LNG-IUS), Femilistrade mark (parous women) and Femilis Slim (nulliparous women), releasing 20 mug of LNG per day. An ancillary objective was to evaluate expulsion and user continuation. DESIGN AND METHODS: An open, prospective, noncomparative study (interim analysis). Two hundred thirty-five insertions were performed in fertile women seeking contraception. Of these, 143 (60.8%) parous women were fitted with Femilis and 92 (39.2%) nulliparous women were fitted with Femilis Slim. The LNG-IUS was inserted using a simplified push-in technique (without folding the cross-arms in the insertion tube). RESULTS: This paper is the first report with the Femilis LNG-IUS. The push-in technique of insertion was considered simple and safe. Insertion was reported "easy" in virtually all women (97.9%). Pain at insertion was absent in 24.7% and "mild" in 67.7% of women. With respect to pain, there were no statistical differences between the parous and nulliparous group. At the time of study analysis, the total number of women-months of use was 1769.7. Seventy-six women had the Femilis IUS in place for periods in excess of 1 year. The study was well followed up with lost to follow-up of only two women. No pregnancies were observed. There was one expulsion in the nulliparous and one in the parous group. Ten removals were performed for medical reasons (mainly bleeding and pain). One pelvic infection occurred in a nulliparous woman caused by Chlamydia trachomatis, which was resolved without removing the IUS. There were no other serious adverse events reported. Both Femilis and Femilis Slim were well tolerated, which resulted in a high continuation rate (94.04%). CONCLUSION: The Femilis LNG-IUS is an effective contraceptive and is easily inserted. The simple and safe insertion procedure could be an advantage for use by nonspecialist providers such as nurses, midwives, general practitioners, and for those not inserting intrauterine devices regularly. Femilis Slim could be an attractive long-term contraceptive option in young and adolescent women.

Adolescent↗

PubMed2005

A temporal bone study of insertion trauma and intracochlear position of cochlear implant electrodes. II: Comparison of Spiral Clarion and HiFocus II electrodes.

In recent years, several new designs of cochlear implant electrodes have been introduced clinically with the goal of optimizing perimodiolar placement of stimulation sites. Previous studies suggest that perimodiolar electrodes may increase both the efficiency and performance of a cochlear implant. This is the second of two studies designed to examine the positioning of electrodes and the occurrence of insertion-related injury with these newer designs and to directly compare two perimodiolar electrodes to their predecessors. In our previous report we compared the Nucleus banded electrode with the Nucleus Contour perimodiolar electrode. In the present study, using the same protocol, we examine the Spiral Clarion electrode and its successor, the HiFocus II electrode with attached positioner. Eight Spiral Clarion arrays and 20 HiFocus II electrodes with positioners were inserted into human cadaver temporal bones. Following insertion, the specimens were embedded in acrylic resin, cut in quarters with a diamond saw and polished. Insertion depth, proximity to the modiolus and trauma were evaluated in X-ray images and light microscopy. The newer electrode was consistently positioned closer to the modiolus than the previous device whereas the angular depth of insertion measured for the two electrodes was similar. The incidence of trauma was minimal when either electrode was inserted to a depth of less than 400 degrees . However, severe trauma was observed in every case in which the HiFocus II with positioner was inserted beyond 400 degrees and in some cases in which the Spiral Clarion was inserted beyond 400 degrees . To evaluate the possible role of electrode size in the trauma observed we modeled both devices relative to the dimensions of the scala tympani. We found that the fully inserted HiFocus II electrode with positioner was larger than the scala tympani in approximately 70% of temporal bones measured. The results suggest that both the Clarion spiral and HiFocus II with positioner can be inserted with minimal trauma, but in many cases not to the maximum depth allowed by the design.

Cadaver↗

PubMed1996

Mechanism of alamethicin insertion into lipid bilayers.

Alamethicin adsorbs on the membrane surface at low peptide concentrations. However, above a critical peptide-to-lipid ratio (P/L), a fraction of the peptide molecules insert in the membrane. This critical ratio is lipid dependent. For diphytanoyl phosphatidylcholine it is about 1/40. At even higher concentrations P/L > or = 1/15, all of the alamethicin inserts into the membrane and forms well-defined pores as detected by neutron in-plane scattering. A previous x-ray diffraction measurement showed that alamethicin adsorbed on the surface has the effect of thinning the bilayer in proportion to the peptide concentration. A theoretical study showed that the energy cost of membrane thinning can indeed lead to peptide insertion. This paper extends the previous studies to the high-concentration region P/L > 1/40. X-ray diffraction shows that the bilayer thickness increases with the peptide concentration for P/L > 1/23 as the insertion approaches 100%. The thickness change with the percentage of insertion is consistent with the assumption that the hydrocarbon region of the bilayer matches the hydrophobic region of the inserted peptide. The elastic energy of a lipid bilayer including both adsorption and insertion of peptide is discussed. The Gibbs free energy is calculated as a function of P/L and the percentage of insertion phi in a simplified one-dimensional model. The model exhibits an insertion phase transition in qualitative agreement with the data. We conclude that the membrane deformation energy is the major driving force for the alamethicin insertion transition.

Adsorption↗

PubMed2003

Uterine perforation on intrauterine device insertion: is the incidence higher than previously reported?

The objective of the study was to determine the rate of uterine perforation associated with insertion of Multiload Cu375 in 'real-life' clinical use. It was a prospective observational cohort study using Prescription Event Monitoring methodology. There were 17,469 Multiload Cu375 insertions in 16,159 women between 1991 and 2001. The insertions were performed by 1,699 different doctors (mostly general practitioners) in surgeries, clinics, and hospitals throughout New Zealand. The results found 28 reports suggesting complete or partial uterine perforation, giving an incidence of 1.6 per 1000 insertions. Most perforations (86%) were not diagnosed at the time of insertion, with some remaining undiagnosed for several years. Doctors who reported inserting fewer than 10 Multiload Cu375 devices in the study period reported significantly more perforations than doctors who reported inserting between 10 and 100 devices did. In conclusion, we found the perforation rate in this study is higher than in clinical trials of Multiload Cu375. This might be because of inclusion of partial perforations in this study, a longer follow-up period, the large number of insertions studied, or because the majority of inserting doctors were less experienced than inserters in other studies.

Adolescent↗

PubMed2004

[A study of pupil dilation using the Mydriasert ophthalmic insert].

PURPOSE: To evaluate the tolerance and efficiency of the Mydriasert(R) ophthalmic insert on pupil dilation. METHOD: Two pharmaceutical forms of a combination of tropicamide and phenylephrine (HCl) were compared on both eyes of 80 patients. For each patient, one Mydriasert insert (Ioltech) was placed in the lower conjunctival sac of the eye. Dilation of the control eye was obtained using 0.5% tropicamide eye drops and 10% phenylephrine eye drops (Novartis Ophthalmics), which were instilled with three frequency regimens (5, 10 or 15 min). The pupil diameter was regularly measured until the maximal mydriasis had occurred. RESULTS: Both subjective and objective tolerance of the insert was excellent. The size of the maximal mydriasis obtained when using the insert was significantly greater than that obtained when using the eye drops, regardless of the frequency of the instillation (p < 0.04). The difference in maximal pupil diameter ranged from +0.16 mm to +0.38 mm. Mydriasis kinetics was slower with the insert. The time necessary to obtain a maximal mydriasis was 47.3 min when the insert was used, whereas it was in the range of 31.4 to 38.5 minutes with the eye drops (p < 0.001). As far as pupil diameter is concerned, the superiority of the insert compared to the eye drops became observable only about 45 min after the insert had been placed in the eye. The relative efficacy of the insert compared to the eye drops did not correlate with patient features (p > or = 0.06). CONCLUSION: Despite the small quantity of drug delivered by the insert, Mydriasert allows a much greater mydriasis compared to that usually obtained when the eye drops were used. However, a longer time lapse is necessary for this to occur.

Adolescent↗

PubMed1997

The influence of a small insert, in the footbed of a shoe, upon plantar pressure distribution.

INTRODUCTION:: A recent development in plantar pressure distribution research, has been the study of the effects of sensory input on pressure distribution. It has been suggested that proprioceptive and exteroceptive information received from the plantar surface of the foot plays an important role in adapting to high pressures in shoes. Robbins and Gouw (1991) suggested that surface irregularities should be added to the insoles of running shoes to gain correct sensory input. Hayda et al. (1994) found that placing a pad proximal to the metatarsal heads produced significant reductions in forefoot plantar pressures around the first and second metatarsal heads. A development by Villeneuve (1993), 'La Posteropodle', utilized a small insert to maintain postural equilibrium, by stimulating the mechanoreceptors in the plantar surface of the foot. The aim of this study was to measure changes in plantar pressure distribution using a small circular insert. METHODS:: Ten non-pathological male subjects were tested whilst walking, after one day of wearing a pair of oxfords (hard) and running shoes (soft), containing an insert of 4 mm in height placed on a 0.8 mm EVA insole. The foot was split into five sections: (1) midfoot, (2) first metatarsal head, (3) 2nd and 3rd metatarsal heads, (4) 4th and 5th metatarsal heads, (5) the phalanges. A PEDAR system (Novel GmbH) was used to collect in-shoe plantar pressure data, with data collections at the beginning and end of a working day. Subjects were tested under two conditions: (1) the insert 5 mm proximal to the metatarsal heads, between the 2nd and 3rd heads, (2) a control, with no insert. RESULTS:: Preliminary results indicate that whilst wearing a hard shoe the insert had the effect of shifting peak pressures from the first metatarsal head, to the area of the second and third metatarsal heads. Peak pressures were found to be lower with the insert present. This has not yet been tested for significance. With the running shoe there appeared to be no significant differences between conditions with and without the insert. There were also no differences between the beginning and end of the day, for both shoe types. DISCUSSION:: From the results it appears that the insert is successful in both shifting peak pressures from the medial to the lateral forefoot, whilst reducing peak pressures simultaneously. This was only evident in the hard shoe condition however, suggesting that the footbed of the running shoe was perhaps too soft to allow the insert to influence sensory input sufficiently. These findings indicate that there may be implications for the use of small orthotics. Further study is required, however, to fully substantiate this hypothesis.

Journal Article↗

PubMed2001

Gel-forming erodible inserts for ocular controlled delivery of ofloxacin.

A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.

Animals↗