Test-retest reliability of the two-point discrimination test on the sole of the foot in people with multiple sclerosis.

BACKGROUND: Two-point discrimination (TPD) is an assessment of tactile acuity. People with multiple sclerosis (MS) can have reduced foot sole tactile acuity, which has been linked to impaired balance. OBJECTIVE: To quantify the test-retest reliability of TPD on the sole of the foot in people with MS. APPROACH: 41 participants (32 females), with mean (SD) age of 60 (9) years, and Expanded Disability Status Scale of <7.5, had their TPD measured at the head of the first metatarsal and the heel on two occasions, 2-14 d apart. Mean systematic change, within-subjects SD, limits of agreement (LOA), coefficient of variation and the intraclass correlation coefficient (ICC) were quantified as point estimates (95% CI). MAIN RESULTS: Systematic learning effects were evident. The within-subjects SD at the metatarsal and the heel was 6.7 mm (5.5-8.6) and 8.3 mm (6.7-10.8), and the LOAs were 18.6 mm (15.2-24.) and 23.7 mm (18.7-30.1), respectively. ICCs for metatarsal and heel was 0.87 (0.76-0.93) and 0.90 (0.80-0.95), respectively, but these were likely inflated by sample heterogeneity. SIGNIFICANCE: In people with MS, TPD on the sole of the foot has an adequate test-retest reliability for research purposes, but there is substantial measurement variability for individual patients.

The Avon patellofemoral joint arthroplasty: two- to 18-year results of a large single-centre cohort.

Aims: This study reports on the medium- to long-term implant survivorship and patient-reported outcomes for the Avon patellofemoral joint (PFJ) arthroplasty. Patients and Methods: A total of 558 Avon PFJ arthroplasties in 431 patients, with minimum two-year follow-up, were identified from a prospective database. Patient-reported outcomes and implant survivorship were analyzed, with follow-up of up to 18 years. Results: Outcomes were recorded for 483 implants (368 patients), representing an 86% follow-up rate. The median postoperative Oxford Knee Score (0 to 48 scale) was 35 (interquartile range (IQR) 25.5 to 43) and the median Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, 0 to 100 scale) was 35 (IQR 25 to 53) at two years. There were 105 revisions, 61 (58%) for progression of osteoarthritis. All documented revisions were to primary knee systems without augmentation. The implant survival rate was 77.3% (95% confidence interval (CI) 72.4 to 81.7, number at risk 204) at ten years and 67.4% (95% CI 72.4 to 81.7 number at risk 45) at 15 years. Regression analysis of explanatory data variable showed that cases performed in the last nine years had improved survival compared with the first nine years of the cohort, but the individual operating surgeon had the strongest effect on survivorship. Conclusion: Satisfactory long-term results can be obtained with the Avon PFJ arthroplasty, with maintenance of patient-reported outcome measures (PROMs), satisfactory survival, and low rates of loosening and wear. Cite this article: Bone Joint J 2018;100-B:1162-7.

Survivorship and clinical outcome of the minimally invasive Uniglide medial fixed bearing, all-polyethylene tibia, unicompartmental knee arthroplasty at a mean follow-up of 7.3years.

BACKGROUND: Medial UKA performed in England and Wales represents seven to 11% of all knee arthroplasty procedures, and is most commonly performed using mobile-bearing designs. Fixed bearing eliminates the risk of bearing dislocation, however some studies have shown higher revision rates for all-polyethylene tibial components compared to those that utilize metal-backed implants. The aim of the study is to analyse survivorship and maximum eight-year clinical outcome of medial fixed bearing, Uniglide unicompartmental knee arthroplasty performed using an all-polyethylene tibial component with a minimal invasive approach. METHODS: Between 2002 and 2009, 270 medial fixed UKAs were performed in our unit. Patients were reviewed pre-operatively, five and eight years post-operatively. Clinical and radiographic reviews were carried out. Patients' outcome scores (Oxford, WOMAC and American Knee Score) were documented in our database and analysed. RESULTS: Survival and clinical outcome data of 236 knees with a mean of 7.3years follow-up are reported. Every patient with less than 4.93years of follow-up underwent a revision. The patients' average age at the time of surgery was 69.5years. The American Knee Society Pain and Function scores, the Oxford Knee Score and the WOMAC score all improved significantly. The five-year survival rate was 94.1% with implant revision surgery as an end point. The estimated 10years of survival rate is 91.3%. Fourteen patients were revised before the five-year follow-up. CONCLUSION: Fixed bearing Uniglide UKA with an all-polyethylene tibial component is a valuable tool in the management of a medial compartment osteoarthritis, affording good short-term survivorship. Level of evidence IV.

Dropped Gallstones Causing a Perihepatic Abscess and Empyema.

Iatrogenic perforation of the gallbladder during laparoscopic cholecystectomy is a well-known occurrence; however, the consequences of spillage of gallstones in the peritoneum and particularly intrathoracic complications are less defined. We describe the delayed development of a perihepatic abscess and empyema in a patient five years following laparoscopic cholecystectomy secondary to dropped gallstones. A 53-year-old man with medical history significant for a laparoscopic cholecystectomy five years prior to acute cholecystitis presented with purulent cough, hemoptysis, night sweats, and right-upper quadrant (RUQ) pain. Computed tomography (CT) scan revealed 5.4 cm right-sided subpulmonic and 5.9 cm perihepatic fluid collections with an 8 mm focal radiopaque density within the perihepatic fluid collection. Open intra-abdominal exploration resulted in retrieval of a 1 cm intraperitoneal gallstone. Laparoscopic cholecystectomy is a common surgical operation during which gallstone spillage can occur, causing both intra-abdominal and intrathoracic complications, presenting even years after surgery. This necessitates an attempt to retrieve all free intra-abdominal gallstones during the initial operation.

Bristol index of patellar width to thickness (BIPWiT): a reproducible measure of patellar thickness from adult MRI.

BACKGROUND: The restoration of an adequate patellar thickness is a key to the successful outcome of knee arthroplasty. This study investigated the relationship between the thickness of the native patellar and medial-lateral patellar width using magnetic resonance imaging (MRI). METHODS: 75 MRI scans of young adults, with an average age of 27 (range 16-40) were studied. Exclusion criteria included a diagnosis of degenerative joint disease, patello-femoral pathology or age under 16/over 40 (170 patients). The bony thickness of the patellar, the chondral thickness and patellar width were measured, as was the location of maximal patellar thickness. Inter/intraobserver variability was calculated and correlation analysis was performed. RESULTS: We found a strong correlation between patellar width and thickness (bone plus cartilage) (Pearson 0.75, P<0.001). The mean width to thickness ratio was 1.8:1 (standard deviation 0.1, 95% confidence interval 1.78-1.83). Without cartilage the ratio was 2.16:1 (SD 0.15, 95% CI 2.11-2.21), correlation was moderate (Pearson 0.59, P<0.001). The average maximal patellar cartilage thickness was 4.1mm (SD 1.3). CONCLUSION: The strong correlation and narrow confidence intervals for the ratio of patellar width to thickness, suggest that patellar width might be used as a guide for accurate restoration of patellar thickness during total knee or patello-femoral replacement. After removing osteophytes we would recommend a ratio of 1.8:1. Further work is required to establish whether there is a relationship between anterior knee pain post total knee arthroplasty and an abnormal patellar width:thickness ratio. LEVEL OF EVIDENCE: Level III.

Do long leg supine CT scanograms correlate with weight-bearing full-length radiographs to measure lower limb coronal alignment?

INTRODUCTION: The gold standard for measuring knee alignment is the lower limb mechanical axis (MA) using weight-bearing lower limb full-length x-ray (FLX). However, CT scanograms (CTS) are becoming increasingly popular in view of lower radiation exposure, speed of data acquisition and supine positioning. We compared the correlation and degree of agreement of knee joint coronal alignment using these two imaging modalities. METHOD: From our series of complex primary and revision knee arthroplasty patients, we selected those with both FLX and CTS recorded onto digital PACS. The coronal alignments were assessed in 24 knees and the valgus/varus angles relative to the MA were measured. Results were analysed statistically using the paired samples t-test, Pearson's correlation coefficient, intra-class correlation coefficient, Cohen's kappa and Passing and Bablok regression to assess potential equality of methods. RESULTS: The mean MA was 180.5° (165°-200°) for the CTS and 181° (164°-202°) for the FLX. The CTS MA angle data between the assessors were highly correlated (r=0.971, p <0.001) as were FLX MA angle measurements (r=0.988, p <0.001). 41.7% of the CTS and 37.5% of the FLX were in varus alignment, while 50% of the CTS and 43.8% of the FLX were in valgus alignment. Malalignment >5° was revealed by 18.8% of the CTS and 35.4% of the FLX. CONCLUSION: Overall, good agreement was observed in MA angle data between the two imaging modalities, but reproducibility may be problematic. In the malaligned limb, weight-bearing FLX still remains a vital imaging modality. CTS should be used with caution in view of the under-detection of malalignment.

Early failure of a mobile-bearing unicompartmental knee replacement.

Concerned by a perceived high revision rate, we retrospectively reviewed the survivorship of a series of 43 cemented, medial, mobile-bearing Preservation unicompartmental knee replacements implanted during a 2-year period at a single institution. The initial post-operative AP and lateral radiographs were independently assessed to test the hypothesis that suboptimal implantation of the prosthesis was responsible for early failure. An X-ray scoring system based on the criteria for assessing the Oxford mobile-bearing unicompartmental knee replacement was devised. The components of this score included assessment of prosthesis alignment, sizing and cementation. Nine (21%) LCS Preservation mobile-bearings prostheses had required revision at a mean of 22 months post-implantation. The commonest causes for failure were pain (44%) and tibial component loosening (33%). Analysis of post-operative radiographs showed no difference (n.s.) between the compound error scores for the revised and the surviving prostheses. No particular surgical error was identifiable leading to subsequent need for revision. The high failure rates shown in this study have led us to cease using this implant. The clinical relevance of this study is that the captive running track of the LCS mobile-bearing prosthesis may over constrain the meniscal component leading to early failure.

Cotton harvest at 40% versus 75% boll-splitting on yield and economic return under standard and proactive boll weevil (Coleoptera: Curculionidae) spray regimes.

The standard practice of two or three preemptive insecticide applications at the start of pinhead (1-2-mm-diameter) squaring followed by threshold-triggered (when 10% of randomly selected squares have oviposition punctures) insecticide applications for boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), control does not provide reliable protection of cotton, Gossypium hirsutum L., lint production. This study, conducted during 2004 and 2005, showed that three to six fewer spray applications in a "proactive" approach, in which spraying began at the start of large (5.5-8-mm-diameter) square formation and continued at approximately 7-d intervals while large squares were abundant, resulted in fewer infested squares and 1.4- to 1.7-fold more lint than the standard treatment. Fewer sprays and increased yield made proactive spraying significantly more profitable than the standard approach, which resulted in relatively low or negative economic returns. Harvest at 75% boll-split in the proactive spray regime of 2005 resulted in four-fold greater economic return than cotton harvested at 40% boll-split because of improved protection of large squares and the elimination of late-season sprays inherent to standard spray regime despite the cost of an extra irrigation in the 75% boll-split treatments. The earlier, 40% harvest trigger does not avoid high late-season boll weevil pressure, which exerts less impact on bolls, the predominant form of fruiting body at that time, than on squares. Proactive spraying and harvest timing are based on an important relationship between nutrition, boll weevil reproduction, and economic inputs; therefore, the tactic of combining proaction with harvest at 75% boll-split is applicable where boll weevils are problematic regardless of climate or region, or whether an eradication program is ongoing.

Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems.

This study was designed to combine the mucoadhesive property of Noveon and the thermosensitive property of Pluronic F-127 into one gel system. A rheological study of Pluronic aqueous sols (10-35%), Noveon gels (0.5-2%) and of mixed gels containing Pluronic (10-17.5%) and polycarbophil (0.5-2.5%) was conducted at different temperatures (15-35 degrees C). The viscosity of Pluronic sols increased with an increase in temperature and the mixed gels had thermoreversible property. The viscosity of mixed gels was higher than that of the Pluronic sols containing only Pluronic because of the increase in total polymer concentration. No interaction was found between -COOH groups of Noveon and Pluronic molecules at the studied concentrations of polymers; the viscosity of mixed gels containing un-neutralized Noveon was lower than that of the neutralized mixed gels. The effect of Pluronic F-127 on the mucoadhesive property of Noveon was investigated. The mucoadhesive properties of Pluronic and Noveon gels were compared by a force of detachment test. It was found that Pluronic and Noveon gels showed approximately the same mucoadhesive strength. However, there were significant differences in the viscosity of Noveon and Pluronic gels. The adhesive force of the mixed gel was almost same as that of the Noveon gel. The Pluronic did not affect the adhesive power of Noveon and the increased viscosity did not affect the bioadhesive force of the mixed gels. In spite of increasing viscosity of the gel, the percentage of released model material (mannitol) increased with increasing temperature. This is based on the previously reported observation that the interaction between the Pluronic molecules squeezed mannitol molecules out of the polymer chains. The mannitol release obeyed zero-order kinetics and the flux values of mixed gels at 15 and 35 degrees C were very similar. The Noveon chains among Pluronic chains probably hindered the diffusion of mannitol molecules and the release was thus controlled by Noveon. The combination of a thermosensitive polymer like Pluronic and a bioadhesive polymer like Noveon appears promising from a pharmaceutical viewpoint. These gel systems may find use in the development of bioadhesive, thermosensitive and controlled release formulations.

Effects of planting dates on boll weevils (Coleoptera: Curculionidae) and cotton fruit in the subtropics.

The effects of planting dates 2-3-wk apart on boll weevil, Anthonomus grandis grandis Boheman (Coleoptera: Curculionidae), field-level populations, and feeding and oviposition damage to cotton, Gossypium hirsutum L., squares and bolls, were studied during 2002 and 2003 in the Lower Rio Grande Valley of Texas. Squares were 44-56% more abundant in some later planted treatments than in the earlier planted treatments, but mean cumulative numbers of oviposition- and feeding-damaged squares were 2.7 - 4.8-fold greater in some later planted treatments than in earlier treatments. Increased square production in later planted cotton was offset by boll weevil infestations that occurred when squares are most vulnerable and contribute most toward the pest's reproduction. Early planting avoided boll weevil population buildups in the field when large squares were abundant. Lint yields in 2002 did not differ significantly between the planting date treatments, but in 2003, mean yield in the middle treatment was 23% greater than in the early and late-planted treatments. Insecticide sprays in the earliest planted treatment of each year, based on the 10% damaged squares threshold, were >33% and >43% fewer than in the corresponding middle and latest planting treatments, respectively. Delayed planting, relative to the onset of favorable cotton-growing weather, at the field level, even when not applied uniformly on an areawide scale, is more cost-effective than planting too early or too late.

The posteromedial corner revisited. An anatomical description of the passive restraining structures of the medial aspect of the human knee.

We have reviewed the literature on the anatomy of the posteromedial peripheral ligamentous structures of the knee and found differing descriptions. Our aim was to clarify the differing descriptions with a simplified interpretation of the anatomy and its contribution to the stability of the knee. We dissected 20 fresh-frozen cadaver knees and the anatomy was recorded using video and still digital photography. The anatomy was described by dividing the medial collateral ligament (MCL) complex into thirds, from anterior to posterior and into superficial and deep layers. The main passive restraining structures of the posteromedial aspect of the knee were found to be superficial MCL (parallel, longitudinal fibres), the deep MCL and the posteromedial capsule (PMC). In the posterior third, the superficial and deep layers blend. Although there are oblique fibres (capsular condensations) running posterodistally from femur to tibia, no discrete ligament was seen. In extension, the PMC appears to be an important functional unit in restraining tibial internal rotation and valgus. Our aim was to clarify and possibly simplify the anatomy of the posteromedial structures. The information would serve as the basis for future biomechanical studies to investigate the contribution of the posteromedial structures to joint stability.

Biomechanics of the PCL and related structures: posterolateral, posteromedial and meniscofemoral ligaments.

This paper reviews and updates our knowledge of the anatomy and biomechanics of the posterior cruciate ligament, and of the posterolateral, posteromedial and meniscofemoral ligaments of the knee. The posterior cruciate ligament is shown to have two functional fibre bundles that are tight at different angles of knee flexion. It is the primary restraint to tibial posterior draw at all angles of knee flexion apart from near full extension. In contrast, the posterolateral and posteromedial structures are shown to tighten as the knee extends, and to be well-aligned to resist tibial posterior draw. These structures also act as primary restraints against other tibial displacements. Tibial internal rotation is restrained by the medial and posteromedial structures, while tibial external rotation is restrained by the lateral and posterolateral structures. They are also the primary restraints against tibial abduction-adduction rotations. The meniscofemoral ligaments are shown, for the first time, to contribute significantly to resisting tibial posterior draw, and to have a strength of approximately 300 N. Taken together, this evidence shows how the posterolateral and posteromedial structures are responsible for posterior knee stability near extension, and this, along with the action of the meniscofemoral ligaments, may explain why an isolated rupture of the posterior cruciate ligament does not often lead to knee instability

Problem-solving abilities among mothers of infants with failure to thrive.

OBJECTIVE: Maternal problem-solving abilities, as they related to specific child-rearing situations, were examined and compared among mothers of infants with failure to thrive (FTT) and a matched group of comparison mothers. METHODS: Participants were 37 mothers of children diagnosed with FTT and 37 mothers with normally growing children matched on three child variables and five maternal variables. Participants were administered a means-ends problem-solving measure specific to parents of young children and measures of language ability, depression, negative affect, and stressful life events. RESULTS: Multivariate analysis of covariance results supported our main study hypotheses that mothers of infants with FTT would generate fewer problem-solving strategies that would be judged of poorer quality (i.e., less likely to result in positive outcomes) than mothers of healthy, normally growing infants. There were no significant associations obtained among problem-solving variables and individual difference variables (e.g., depression, negative affect, and stressful life events). CONCLUSIONS: Limited maternal problem-solving abilities may contribute to FTT by interfering directly with the quality of nurturance, feeling, and caloric intake the child receives. Recommendations are made for future research and interventions with mothers of children with FTT.

Drug delivery to the posterior segment of the eye: some insights on the penetration pathways after subconjunctival injection.

The aim of this study is to gain an understanding of the penetration pathways for a drug to enter the posterior segment of the eye after subconjunctival injection. 14C-mannitol was injected subconjunctivally, and 14C-mannitol and 14C-inulin were injected intracamerally. The aqueous and vitreous levels were determined at selected time points. The results of subconjunctival injection and intracameral injection were compared. The vitreous level of the dosed eye is much higher than that of the corresponding contralateral eye after subconjunctival injection so that the recirculation pathway is not a dominant penetration pathway. In addition, the results also showed that it is unlikely for significant amounts of drug to move from the aqueous to the vitreous chamber after subconjunctival injection. Therefore, direct penetration is the dominant pathway for a subconjunctivally injected compound to enter the vitreous chamber.

Feeding problems, sleep disturbances, and negative behaviors in a toddler.

Tiffany, a 3-year-old girl, was referred to the developmental and behavioral pediatrics service for evaluation of significant and persistent negative behaviors associated with refusal to eat at meal time and constant snacking during the past 3 months. She lost 2 pounds, but her weight for her height was at the 50th percentile. Her mother indicated that Tiffany had frequent night awakenings (>10) and late sleep onset (between 12:00 and 1:00 a.m.). Her mother described her as being "easily frustrated," getting upset and angry very quickly. Tiffany was identified at an early intervention program as having mild to moderate developmental delays in pragmatic speech, gross and fine motor skills, and social interaction skills. Tiffany was born at 33 weeks gestation and was hospitalized for 10 days without significant perinatal problems. She was readmitted at 2 months of age when she was diagnosed with gastroesophageal reflux, lactose intolerance, sleep apnea, and bradycardia. She was discharged with an apnea monitor. A seizure disorder was diagnosed at 1 year of age and reactive airway disease at 2 years of age. At the time of the referral to the developmental and behavioral pediatrics service, Tiffany was followed by multiple services, including cardiology, neurology, gastroenterology, psychology, and pulmonary. Pharmacologic therapies included albuterol and cromalyn inhalers, phenobarbital, valproic acid, levocarnitine, ranitidine, and an inhaled steroid. She continued to use the apnea monitor each night, although three sleep studies demonstrated a normal sleep pattern with no evidence of apnea or bradycardia. A recent electroencephalogram was normal. Tiffany lives with her mother and maternal grandparents. Her mother is morbidly obese with a history of asthma and depression. She was infertile for a 10-year period, which she attributed to the stress associated with living with an abusive man. Tiffany was the result of a subsequent, brief relationship with another man; she has not had contact with her father. Her mother is a licensed practical nurse who has not worked as a nurse since Tiffany's birth. An interdisciplinary treatment approach to Tiffany's multiple biological and behavioral problems was implemented by admitting her to a collaborative care unit at a children's hospital.

Improvement in function after valgus bracing of the knee. An analysis of gait symmetry.

The use of a valgus brace can effectively relieve the symptoms of unicompartmental osteoarthritis of the knee. This study provides an objective measurement of function by analysis of gait symmetry. This was measured in 30 patients on four separate occasions: immediately before and after initial fitting and then again at three months with the brace on and off. All patients reported immediate symptomatic improvement with less pain on walking. After fitting the brace, symmetry indices of stance and the swing phase of gait showed a consistent and immediate improvement at 0 and 3 months, respectively, of 3.92% (p = 0.030) and 3.40% (p = 0.025) in the stance phase and 11.78% (p = 0.020) and 9.58% (p = 0.005) in the swing phase. This was confirmed by a significant improvement at three months in the mean Hospital for Special Surgery (HSS) knee score from 69.9 to 82.0 (p < 0.001). Thus, wearing a valgus brace gives a significant and immediate improvement in the function of patients with unicompartmental osteoarthritis of the knee, as measured by analysis of gait symmetry.

Microbial populations, fermentation end-products, and aerobic stability of corn silage treated with ammonia or a propionic acid-based preservative.

We studied the effects of ammonia treatment on microbial populations during the fermentation of corn silage. We also compared the effects of ammonia to a preservative containing buffered propionic acid and other antifungal compounds on the fermentation and aerobic stability of corn silage. In the first experiment, whole-plant corn was ensiled without treatment or treated with ammonia-N to supply an additional 0.3% N (fresh-forage basis). The addition of ammonia immediately increased silage pH and had no effect on numbers of lactic acid bacteria, but delayed their growth compared with untreated silage. Numbers of enterobacteria declined more slowly, but numbers of yeasts and molds declined more quickly in silage treated with ammonia. During the early stages of ensiling, lactic acid increased more rapidly in untreated than in treated silage. The reverse was true for acetic acid concentrations. When exposed to air, growth of yeasts and molds was delayed in ammonia-treated silage. In a second experiment, various levels (0.1 to 0.3%, fresh weight) of ammonium-N or a preservative with buffered propionic acid were added to whole-plant corn and allowed to ensile for 106 d. Silage treated with ammonia had a greater ratio of L- to D-lactic acid than did other silages. Untreated silage was aerobically stable for 32.3 h, whereas the low (42 h) and moderate (52.7 h) concentrations of both additives numerically improved aerobic stability. High concentrations of ammonia-N (0.3%) or a buffered propionic acid preservative (0.3%), markedly improved the aerobic stability of corn silage (82 and 69 h for ammonia and propionic acid-treated silage, respectively).

Bioadhesive-based dosage forms: the next generation.

Prolonged contact time of a drug with a body tissue, through the use of a bioadhesive polymer, can significantly improve the performance of many drugs. These improvements range from better treatment of local pathologies to improved drug bioavailability and controlled release to enhanced patient compliance. There are abundant examples in the literature over the past 15 years of these improvements using first generation or "off-the-shelf" bioadhesive polymers. The present mini-review will remind us of the success achieved with these first-generation polymers and focus on proposals for the next-generation polymers and attendant benefits likely to occur with these improved polymeric systems.

Carrier-enhanced human growth hormone absorption across isolated rabbit intestinal tissue.

Small molecular weight alpha acid derivatives are able to enhance the intestinal absorption of human growth hormone through isolated rabbit intestinal tissue. The enhancement is not through the usual tissue modification associated with traditional penetration enhancers nor is it through an active transport process. Rather these small molecules associate with human growth hormone in solution to make it more transportable through intestinal tissue. It is shown that the enhancer has specificity for a particular protein and the enhancer and human growth hormone must be in solution together to be effective, i.e. pretreating the tissue with enhancer and then adding the protein does not increase tissue permeability. Moreover, the enhancer does not increase the permeability of mannitol or progesterone, thus providing additional evidence of specificity and establishing that these agents are not classical penetration enhancers.

Transport of human growth hormone across Caco-2 cells with novel delivery agents: evidence for P-glycoprotein involvement.

Emisphere Technologies, Inc. has synthesized a series of small molecules which have been shown to improve protein absorption through mucosal tissue. This enhancement is specific between protein and a particular delivery agent. Despite the specificity of interaction, the mechanism of enhanced tissue penetration is still unclear. The purpose of this work is to understand the enhancement mechanism(s) of these delivery agents by using Caco-2 cells as a model membrane. It was found that the bidirectional transepithelial fluxes of human growth hormone (hGH) in the presence of these delivery agents across human intestinal epithelial Caco-2 cell line showed marked asymmetry. Average permeability coefficient values obtained in the apical (AP) to basolateral (BL) direction were lower than those of the reverse (BL to AP) direction. On the other hand, the fluxes for human growth hormone alone were symmetric. When P-glycoprotein inhibitors were included in the transport medium, the permeability coefficient values of BL to AP direction were significantly decreased while the transport was increased in the reverse direction in the presence of delivery agents. P-glycoprotein inhibitors had no effect on the transport of human growth hormone alone. This study shows that human growth hormone alone can be transported across Caco-2 cells in very limited quantities by passive diffusion, but in the presence of delivery agents, human growth hormone can be effluxed in a P-glycoprotein-mediated fashion. This also indirectly shows that the human growth hormone has become more lipophilic in the presence of delivery agents.