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PubMed1999

Saturation of the endoplasmic reticulum retention machinery reveals anterograde bulk flow

We have studied the possible mechanisms of endoplasmic reticulum (ER) export and retention by using natural residents of the plant ER. Under normal physiological conditions, calreticulin and the lumenal binding protein (BiP) are efficiently retained in the ER. When the ER retention signal is removed, truncated calreticulin is much more rapidly secreted than truncated BiP. Calreticulin carries two glycans of the typical ER high-mannose form. Both glycans are competent for Golgi-based modifications, as determined from treatment with brefeldin A or based on the deletion of the ER retention motif. In contrast to BiP, calreticulin accumulation is strongly dependent on its retention signal, thereby allowing us to test whether saturation of the retention mechanism is possible. Overexpression of calreticulin led to 100-fold higher levels in dilated globular ER cisternae as well as dilated nuclear envelopes and partial secretion of both BiP and calreticulin. This result shows that both molecules are competent for ER export and supports the concept that proteins are secreted by default. This result also supports previous data suggesting that truncated BiP devoid of its retention motif can be retained in the ER by association with calreticulin. Moreover, even under these saturating conditions, cellular calreticulin did not carry significant amounts of complex glycans, in contrast to secreted calreticulin. This result shows that calreticulin is rapidly secreted once complex glycans have been synthesized in the medial/trans Golgi apparatus and that the modified protein does not appear to recycle back to the ER.

Journal Article↗
PubMed1994

Evaluation of indocyanine green retention and aminopyrine breath tests in patients with malignant biliary obstruction.

Impaired hepatic function is a major contributory factor to the high incidence of postoperative morbidity and mortality in patients with malignant biliary obstruction. Dynamic hepatic function tests such as indocyanine green (ICG) retention and aminopyrine breath tests were evaluated in such patients to define whether they were clinically useful for prediction of postoperative morbidity and mortality. Forty-four patients with malignant biliary obstruction undergoing surgery for relief of obstructive jaundice were recruited into the study. Indocyanine green retention and aminopyrine breath tests were carried out in all patients pre-operatively and repeated in 36 patients postoperatively. The ICG retention was abnormal in all patients before surgery and there was significant improvement 2 weeks after surgery (32.8 +/- 2.5% vs 18.3 +/- 2.8%, P = 0.001). The change in ICG retention levels correlated with the serum bilirubin levels but the pre-operative ICG retention value could not predict postoperative morbidity and mortality. The aminopyrine breath test was abnormal in all but one patient. It correlated with pre-operative prothrombin time of the patients before surgery but it did not improve significantly after surgery and was not predictive of postoperative outcome. It is concluded that both ICG retention and aminopyrine breath tests have limited clinical value in the pre-operative evaluation of patients with malignant biliary obstruction.

Aged↗
PubMed2005

Post-training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo-oxygenase-2-specific inhibitor celecoxib in rats.

Recently, we demonstrated that intrahippocampal infusion of the cyclo-oxygenase (COX)-2-specific inhibitor celecoxib impaired spatial memory retention in the Morris water maze. In the present work, we investigated the effects of nicotine, infused in the rat dorsal hippocampus several minutes after infusion of celecoxib, on memory retention in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained four trials. Test trials were conducted 48 h after surgery. As expected, bilateral intrahippocampal infusion of celecoxib (19 microg/side; 0.1 m) increased escape latency and travel distance in rats, indicating significant impairment of spatial memory retention. We also examined the effects of bilateral infusion of nicotine (0.5, 1.0 and 2.0 microg/side) on memory retention. Infusion of 1 microg nicotine significantly decreased escape latency and travel distance but not swimming speed, compared with controls, suggesting memory retention enhancement by nicotine at this concentration. In separate experiments, bilateral infusion of nicotine, infused 5 min after 0.1 m (19 microg/side) celecoxib infusion, was associated with escape latency, travel distance and swimming speed profiles very similar to those in control animals. Brain tissue sections from several of these animals were subjected to immunohistochemical staining analysis with anti-COX-2 antibodies. Quantification analysis by optical density measurements showed that the celecoxib infusion reduced the immunoreactivity of COX-2-containing neurons in the CA1 area of the hippocampus compared with controls, although this reduction was not significant. However, infusion of a combination of celecoxib and nicotine significantly increased this immunoreactivity compared with levels in control and celecoxib-infused groups. These results suggest that nicotine prevented or reversed the adverse effects of celecoxib on spatial memory retention and protected or restored the immunostaining pattern of COX-2 neurons in the rat dorsal hippocampus.

Animals↗
PubMed2002

Maximizing retention in community-based clinical trials.

PURPOSE: To identify and discuss retention strategies and their effectiveness in community-based clinical trials in the last decade. METHODS: Online and hand searches for reports for the period 1990-1999. A total of 87 reports on 64 different trials were found; 21 of these published reports included a description of both retention strategies and outcomes. These studies, rank-ordered on participant retention, were compared. FINDINGS: Despite differences in study populations, interventions, and endpoints, community-based trials with the highest retention rates included a combination of retention strategies. CONCLUSIONS: As more funding agencies emphasize clinical trials, more investigators will be held accountable for credible and generalizable findings based on retaining the projected number of study participants. The small number of published reports for the decade that identified both retention strategies and outcomes substantiates the need to better document these factors in future research reports.

Clinical Trials as Topic↗
PubMed1981

Evaluation of the retention of two types of pit and fissure sealants.

The aim of this study was to statistically compare the retention of a chemically polymerized sealant (Delton, Johnson & Johnson Co., East Windsor, N.J.) with a widely tested UV-polymerized system (Nuva-Seal, L.D. Caulk Co., Milford, Del.) Two hundred children aged 5-16 years who resided in Fairfax County, Virginia (a fluoridated community) and who had one or more pairs of homologous permanent posterior teeth free of decay or fillings were admitted to the study. Posterior teeth on one side of the mouth of each subject were randomly assigned to receive Nuva-Seal; teeth on the other side were treated with Delton. Treated teeth were examined for sealant loss approximately every 6 months for a period of 2 years. Scores for complete retention of Nuva-Seal were 86% after 6 months and 78% at the end of 2 years. The corresponding values for Delton-treated teeth were 96% and 92%. For both sealants, scores of total retention were highest in mandibular first premolars and lowest in mandibular second molars. The greatest rate of sealant loss occurred within the first 6 months after placement. A comparison of overall retention scores (net gain) for Delton and Nuva-Seal revealed that Delton scores were significantly higher than Nuva-Seal at each semi-annual examination. The McNemar test was used to compare the retention of the two sealants for each tooth type. The test showed that the retention scores for Delton were significantly higher than those for Nuva-Seal only on maxillary and mandibular first molars.

Acrylates↗
PubMed2001

The influence of rinsing routines on fluoride retention after toothbrushing.

OBJECTIVE: An important determinant of the anticaries effect of brushing with a fluoride dentifrice is the retention of fluoride in the oral fluids. This study measured the influence of various post-brushing rinsing routines on fluoride retention. SETTING: The Faculty of Odontology, Göteborg University, Sweden. SUBJECTS: Twenty-one healthy dental students, aged 23 +/- 2 yr. DESIGN: A randomised, cross-over protocol, comparing various post-brushing rinsing procedures, with the following variables: volume of rinsing water (5 mL vs. 10 x 3 mL) and duration of rinsing (10 vs. 60 s). Samples of whole saliva, interdental fluid and interdental plaque were analysed for fluoride content. RESULTS: The duration of rinsing did not influence fluoride retention in whole saliva, interdental fluid or interdental plaque. Rinsing with a higher volume of water substantially decreased fluoride retention in all samples. CONCLUSION: Brushing with a fluoride dentifrice should be followed by rinsing procedures which enhance the retention of fluoride. Rinsing with large volumes of water decreases fluoride retention in the oral fluids, and should be discouraged.

Adult↗
PubMed2006

Rural Illinois hospital chief executive officers' perceptions of provider shortages and issues in rural recruitment and retention.

BACKGROUND: It is important to assess rural health professions workforce needs and identify variables in recruitment and retention of rural health professionals. PURPOSE: This study examined the perspectives of rural hospital chief executive officers (CEOs) regarding workforce needs and their views of factors in the recruitment and retention process. METHODS: A survey was mailed to CEOs of 28 Illinois rural hospitals, in towns ranging from 3,396 to 33,530 in population size. The survey addressed CEO perceptions of number of physicians needed by specialty, need for other health professionals, and variables important to recruitment and retention. FINDINGS: Twenty-two CEOs (79%) responded to the survey. Eighty-six percent indicated a physician shortage in the community, with 64% reporting the need for family physicians. CEOs also indicated the need for physicians in obstetrics-gynecology, general and orthopedic surgery, general internal medicine, cardiology, and psychiatry. In terms of needs for other health professionals, most often mentioned were registered nurses (91%), pharmacists (64%), and nurses' aides (46%). Related to recruitment and retention, most often mentioned by the CEOs was community attractiveness in general, followed by practice and physician career opportunities. CONCLUSIONS: CEOs offer 1 important perspective on health professions needs, recruitment, and retention in rural communities. While expressing a range of opinions, rural hospital CEOs clearly indicate the need for more primary care physicians, call for an increased capacity in nursing, and point to community development as a key factor in recruitment and retention.

Attitude of Health Personnel↗
PubMed2004

Twelve-month sealant retention in a school-based program using a self-etching primer/adhesive.

OBJECTIVES: Very little independent research has been done on the new self-etching primer/adhesives in dentistry. A recent clinical study compared two sealant application techniques involving self-etching primer adhesives and the traditional phosphoric acid etch. The purpose of this study was to compare these two techniques in an Iowa school-based sealant program. METHODS: Twelve-month sealant retention data on 208 students from the Des Moines, Iowa, school-based sealant program were analyzed retrospectively. RESULTS: Sealant retention reported at the person level showed that 60 percent of the students who received sealants at the five schools had to be recalled at one year to have one or more surfaces resealed. A logistic regression model at the person level demonstrated that the phosphoric acid technique was six times as likely to have retention of all the sealed tooth surfaces as those sealed with Prompt-L-Pop. CONCLUSIONS: In this study, many students had to be recalled to the chair 12 months after sealant application due to incomplete retention. Though sealants were retained in larger numbers with phosphoric acid, overall sealant retention at the tooth level was lower than previously published for clinical studies and school-based programs. Examining retention data at the person level, however, allows program administrators to plan resources more effectively and reevaluate sealant protocol to ensure as few children return for sealant reapplication.

Acid Etching, Dental↗
PubMed1997

The retention of pit and fissure sealants placed in primary school children by Dental Health Services, Victoria.

The benefit of a public sector sealant programme for children in Australia is yet to be established. This study evaluated sealants placed by therapists of the School Dental Service in Victoria, between 1989 and 1994, on permanent teeth of children in 15 primary schools in Melbourne. Seven hundred and seventy four children aged 6-12 years were examined in school dental clinics by six calibrated examiners. A total of 5363 sealants placed on 2875 permanent teeth (including 2616 first molars, 91 per cent of sample) up to four and a half years previously was examined. Values for complete and partial sealant retention were highest for premolars (86 per cent, 9 per cent respectively, total 95 per cent); similar for occlusal surfaces of maxillary and mandibular first molars (63 per cent, 30 per cent; 62 per cent, 32 per cent respectively) and buccal pits of mandibular molars (66 per cent); and low for pits/fissures of Carabelli's cusps of maxillary molars (44 per cent). Cross-sectional examination up to 24 months for both maxillary and mandibular first molars indicated average values of 67 per cent complete retention, 27 per cent partial retention, 6 per cent missing; thereafter complete retention decreased and partial retention increased. Sealant failures in the six months post-placement were attributed to technique failure. Regardless of sealant retention, caries experience was low under partially retained or missing sealants (4.5 per cent) and completely retained sealants (0.4 per cent). It is concluded that the SDS sealant programme is a sound preventive dental public health approach.

Bicuspid↗
PubMed1984

Increase in weight and water retention on overfeeding dogs.

Dogs, kept in metabolism cages, were weighed daily and the daily water intake, urine volume and evaporative loss of water measured or calculated. When the daily meal was doubled, the weight increased in two phases: during the first 4 d the increase in weight was more than could be accounted for by the deposition of protein, glycogen and fat so that water retention must have occurred; after the fourth day the increase in weight was slower and could have been due to the deposition of solids, without water retention. When carbohydrate was added to the meal either as starch or glucose, the increase in weight in the first 3 d was more than the weight of the added carbohydrate, showing water retention. After the third day the slower increase in weight could be explained by the deposition of solids. When the daily meal was supplemented with fat, increase in weight occurred uniformly throughout the period of overfeeding and was equal to or less than the added fat. There was thus no evidence for water retention. Addition of meat to the daily meal caused an increase in weight larger than the fat and protein of the extra meat. Meat therefore caused water retention. The results indicate that during overfeeding, deposition in the body of protein and glycogen, but not fat, determines water retention.

Animals↗
PubMed1981

Fibrinogen enhances complement-mediated augmentation of retention of polymorphonuclear leukocytes by nylon columns.

Retention of polymorphonuclear leukocytes (PMN) by nylon columns is significantly increased when PMN are suspended in zymosan-activated plasma. In zymosan-activated plasma, 25.8 +/- 4.9% of PMN were retrained as compared with 11.1 +/- 2.7% suspended in zymosan-activated serum (ZAS) (P = 0.001) and 7.9 +/- 3.2% in fresh serum (P = 0.0005). Addition of heated plasma (56 degrees C for 30 min) to ZAS restored optimal retention. These results suggested a role for a heat-stable factor(s) in plasma, which augmented complement-mediated enhancement of PMN adhesiveness. This study was designed to determine whether fibrinogen enhanced retention by nylon columns of PMN in the presence of activated complement. Addition of defibrinated plasma to ZAS failed to enhance adhesiveness to nylon. The retention of PMN suspended in ZAS was 11.1 +/- 2.7%, as compared with 10.5 +/- 3.7% in ZAS plus defibrinated plasma. Retention of PMN suspended in ZAS plus fibrinogen was 27.92 +/- 13.2% as opposed to 16.35 +/- 7.5% (P = 0.045) in ZAs. In contrast, retention of cells in serum was 12.96 +/- 7.5%. These results suggest that the process which enhances PMN adhesiveness involves the interaction of cells, activated complement, and fibrinogen.

Cell Adhesion↗
PubMed1990

The relationship between 'normal' fluid retention in women and idiopathic oedema.

A sample of women attending a gynaecological outpatient clinic were examined for symptoms and objective signs of fluid retention. Patients completed a questionnaire on symptoms suggesting fluid retention and recorded daily weight and abdominal girth variation. Daily weight variation varied from 0-9 pounds (mode 2 pounds) with no discernable difference between premenstrual and intermenstrual variation. Daily girth variation varied from 0-6 inches (mode 1 inch). Symptoms of breast swelling were more common premenstrually, finger/hand and ankle swelling intermenstrually and abdominal swelling occurred with equal frequency in both periods. No correlation between symptoms and weight variation was seen although abdominal swelling and girth variation were associated (P less than 0.04). The results indicate that symptoms of mild fluid retention and of diurnal weight and abdominal girth variation are part of the everyday experience of our study population. There is no clear-cut separation between 'normal' and 'abnormal' fluid retention (idiopathic oedema, periodic oedema, fluid retention syndrome); the latter may be an exaggeration of normal fluid-retaining mechanisms common to most women or may represent a pathological state. An approach which evaluates individual risk factors and the severity of fluid retention in each patient is recommended.

Adolescent↗
PubMed2005

Pharmacokinetic of rhein in healthy male volunteers following oral and retention enema administration of rhubarb extract: a single dose study.

Rhubarb is a common herb used in traditional Chinese medicine. However, few publications exist about its pharmacokinetic profiles in animals or healthy volunteers. Whether retention enema administration of rhubarb extract affects its pharmacokinetics as well as its tolerability is unknown. Therefore, we set out to compare the pharmacokinetic parameters of rhein administered by retention enemas with those of conventional oral dosing of rhubarb extract. Eight healthy male volunteers were enrolled in a prospective crossover study. All subjects received a single dose of rhubarb extract (50 mg.kg(-1)) on two separate occasions, once orally, once by a retention enema. Rhein plasma concentration was measured by HPLC. The C(max), AUC(0-infinity), AUMC were significantly higher in oral administration than those in retention enema administration (p < 0.05), while V(d) of rhein after oral administration of rhubarb extract was significantly lower (p < 0.05) than that after retention enema administration. However, no statistically significant differences between the two treatments were observed for any of the other pharmacokinetic parameters (T(max), t(1/2), MRT(0-infinity), CL). Dosage adjustment is advisable for retention enema administration of rhubarb extract in patients.

Administration, Oral↗
PubMed1993

Lung retention of phosphatidylcholine and cholesterol from liposomes: effects of oxygen exposure and fasting.

Antioxidants such as glutathione may play a role in prevention and treatment of several lung diseases. Liposomes can be used to deliver antioxidants to the lung and increase their retention. In addition, liposomes alone may protect against oxidant-induced damage. In addition, liposomes alone may protect against oxidant-induced damage. This study was designed to characterize the retention and distribution of liposomes in the lung under normal circumstances and during either fasting, exposure to 100% oxygen, or a combination of the two. Positively charged liposomes, consisting of phosphatidylcholine (PC), cholesterol, and stearylamine plus either [14C]cholesterol or [3H]PC, were instilled intratracheally. Five minutes to 5 days later the lungs were removed and the radioactivity determined. Both [14C]cholesterol and [3H]PC labels had prolonged and equal retention in the lung, but their distribution within lung compartments differed. The cholesterol label increased in lung tissue over time, comprising 78% of the remaining label after 5 days, whereas the PC label persisted at high levels in lavage fluid and became equally distributed between lung tissue and bronchoalveolar lavage fluid. Fasting had little effect on the retention of the labels and no effect on their distribution within the lung. Exposure to 100% oxygen increased lung retention of both radiolabels and altered their distribution such that [14C]cholesterol label decreased and [3H]PC label increased in lung tissue. These results demonstrate the prolonged retention of intratracheally administered liposomes or their components in the lung and the effects of two clinically relevant conditions, fasting and hyperoxic exposure. Furthermore, they provide a basis for designing future studies using liposomes.

Animals↗
PubMed1998

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space.

The fractional deposition of particles in boluses delivered to shallow lung depths and their subsequent retention in the airways may depend on the relative volume and size of an individual's airways. To evaluate the effect of variable anatomic dead space (ADS) on aerosol bolus delivery we had healthy subjects inhale radiolabeled, monodisperse aerosol (99mTc-iron oxide, 3.5 micron mean mondispersed aerosol diameter) boluses (40 ml) to a volumetric front depth of 70 ml into the lung at a lung volume of 70% total lung capacity end inhalation. By using filter techniques, aerosol photometry, and gamma camera analysis, we estimated the fraction of the inhaled boluses deposited in intrathoracic airways (IDF). ADS by single-breath N2 washout was also measured from 70% total lung capacity. Results showed that among all subjects IDF was variable (range = 0.04-0.43, coefficient of variation = 0.54) and increased with decreasing ADS (r = -0.76, P = 0.001, n = 16). We found significantly greater deposition in the left (L) vs. right (R) lungs; mean L/R (ratio of deposition in L lung to R lung, normalized to ratio of L-to-R lung volume) was 1.58 +/- 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 h was independent of ADS or IDF. There was significant retention of particles at 24 h postdeposition (0.27 +/- 0.05) and slow clearance of these particles continued through 48 h postdeposition. Finally, analysis of central-to-peripheral ratios of initial deposition and 24-h-retention gamma-camera images suggest significant retention of insoluble particles in large bronchial airways at 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 +/- 0. 44 and 1.82 +/- 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0). These data may prove useful for 1) designing aerosol delivery techniques to target bronchial airways and 2) understanding airway retention of inhaled particles.

Adult↗
PubMed2004

Radioiodination of rhenium cyclized alpha-melanocyte-stimulating hormone resulting in enhanced radioactivity localization and retention in melanoma.

Radiohalogenated alpha-melanocyte-stimulating hormone (alpha-MSH) analogs were proposed for melanoma imaging and potential radiotherapy because alpha-MSH receptors are overexpressed on both mouse and human melanoma cell lines. However, biodistribution studies in tumor-bearing mice with radiohalogenated alpha-MSH peptides showed very rapid tumor radioactivity wash out due to lysosomal degradation of the radiohalogenated complex after internalization, which decreased the therapeutic efficacy significantly (R. Stein et al., Cancer Res., 55: 3132-3139, 1995; P. K. Garg et al., Bioconjugate Chem., 6: 493-501, 1995.). The melanoma-targeting metallopeptide ReO[Cys(3,4,10),D-Phe(7)]alpha-MSH(3-13) (ReCCMSH) was shown to possess high tumor uptake and retention properties (J. Chen et al., Cancer Res., 60: 5649-5658, 2000). Therefore, three peptides, Ac-Lys-ReCCMSH(Arg(11)), Ac-D-Lys-ReCCMSH(Arg(11)), and [Nle(4),D-Phe(7)]alpha-MSH (NDP) (for comparison), labeled with N-succinimidyl 4-[(125)I]iodobenzoate ((125)I-PIB), were prepared and evaluated in vitro and in vivo to develop radiohalogenated alpha-MSH peptide analogs with high tumor uptake, retention, and favorable biodistribution characteristics. In vitro cell binding and internalization data showed that approximately 90% of radioiodinated peptides were internalized at 2 h in cultured B16/F1 melanoma cells. Cellular retention studies showed that the receptor-bound radioiodinated linear alpha-MSH analog NDP was released from the cells into the medium very quickly, whereas significant amounts of cell-associated radioactivity remained in the cells for Ac-Lys((125)I-3- or 4-iodobenzoate (IBA))-ReCCMSH(Arg(11)) and Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)). The in vitro data clearly demonstrate that rhenium cyclization significantly enhanced peptide trapping in the cells, as did D-amino acid incorporation. The combination of these two effects resulted in a 2.9-fold increase in the retention of radioactivity for Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) relative to (125)I-IBA-NDP at 4 h. In vivo studies also showed that Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) exhibited extremely high radioactivity accumulation and prolonged retention in the tumor. Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) and Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)) exhibited much higher tumor uptake at 24 h after injection compared with (125)I-IBA-NDP [7.18% injected dose/gram (ID/g), 4.92% ID/g, and 0.26% ID/g, respectively]. Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) also showed very fast whole body clearance and low nonspecific radioactivity accumulation in normal tissues compared with (125)I-IBA-NDP and Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)). A tumor:blood ratio of 34.3 was observed for Ac-D-Lys((125)I-IBA)-ReCCMSH(Arg(11)) at 24 h postinjection, whereas values of 4.3 and 2.0 were observed for Ac-Lys((125)I-IBA)-ReCCMSH(Arg(11)) and (125)I-IBA-NDP, respectively. The biodistribution data clearly demonstrate that both rhenium cyclization and D-Lys incorporation enhanced the tumor localization and retention of the radiolabel. Therefore Ac-D-Lys-ReCCMSH(Arg(11)) is an excellent candidate for additional therapeutic studies.

Animals↗
PubMed2004

VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein.

PURPOSE: The pipecolinate derivative VX-710 (biricodar; Incel) is a clinically applicable modulator of P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1); we studied its activity against the third multidrug resistance (MDR)-associated drug efflux protein, breast cancer resistance protein (BCRP). EXPERIMENTAL DESIGN: VX-710 modulation of uptake, retention, and cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, and SN38 was studied in cell lines overexpressing Pgp, MRP-1 and wild-type (BCRP(R482)) and mutant (BCRP(R482T)) BCRP. RESULTS: In 8226/Dox6 cells (Pgp), VX-710 increased mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased their retention by 100 and 60%, respectively, and increased their cytotoxicity 3.1- and 6.9-fold, respectively. In HL60/Adr cells (MRP-1), VX-710 increased mitoxantrone and daunorubicin uptake by 43 and 130%, increased their retention by 90 and 60%, and increased their cytotoxicity 2.4- and 3.3-fold. In 8226/MR20 cells (BCRP(R482)), VX-710 increased mitoxantrone uptake and retention by 60 and 40%, respectively, and increased cytotoxicity 2.4-fold. VX-710 increased daunorubicin uptake and retention by only 10% in 8226/MR20 cells, consistent with the fact that daunorubicin is not a substrate for BCRP(R482), but, nevertheless, it increased daunorubicin cytotoxicity 3.6-fold, and this increase was not associated with intracellular drug redistribution. VX-710 had little effect on uptake, retention, or cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, or SN38 in MCF7 AdVP3000 cells (BCRP(R482T)). CONCLUSIONS: VX-710 modulates Pgp, MRP-1, and BCRP(R482), and has potential as a clinical broad-spectrum MDR modulator in malignancies such as the acute leukemias in which these proteins are expressed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Essential metal balance and retention during the second half of pregnancy in the rat.

The daily copper, zinc, iron, magnesium, calcium, sodium and potassium retention from the diet in rats during the second half of pregnancy have been determined and compared with those of adult virgin male and female rats. Pregnant rats had higher mean magnesium and potassium daily retentions than virgin females. The retention of essential metals changed along the second half of pregnancy towards lower values for copper and magnesium and higher ones for potassium. The net absolute metal retention followed the same trends. All other metals studied showed little global differences versus controls without clearly identifiable trends. The results suggest that metal retention is an adaptative element in maintaining the pregnant rat's metal supply, as the considerable metal retention in the first half of pregnancy is modulated in the second half according to the actual needs of the maternofetal unit.

Animals↗