PubMed Health⌕ Search

Biomedical subjects

D Glass

Publications and source records attributed to D Glass.

At least 19 recordsLinked to original sources
PubMed2002

Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease.

APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer's disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies, we have shown that the synaptic organizing protein agrin can be found in neurons, and is a major component of the brain microvascular basement membrane. Here, we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area (micro(2)) of prefrontal cortical microvessels. An average of 10 capillaries was measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 micro(2))+/-6.2) than APOE3,3 homozygotes (26.9 micro(2)+/-6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer's disease.

Aged↗
PubMed2001

Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.

The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.

Adult↗
PubMed2000

The role of X-chromosome inactivation in female predisposition to autoimmunity.

We propose that the phenomenon of X-chromosome inactivation in females may constitute a risk factor for loss of T-cell tolerance; specifically that skewed X-chromosome inactivation in the thymus may lead to inadequate thymic deletion. Using a DNA methylation assay, we have examined the X-chromosome inactivation patterns in peripheral blood from normal females (n = 30), female patients with a variety of autoimmune diseases (n = 167). No differences between patients and controls were observed. However, locally skewed X-chromosome inactivation may exist in the thymus, and therefore the underlying hypothesis remains to be disproved.

Alleles↗
PubMed2000

Comparison of myocardial contrast echocardiography with NC100100 and (99m)Tc sestamibi SPECT for detection of resting myocardial perfusion abnormalities in patients with previous myocardial infarction.

OBJECTIVE: To determine whether myocardial contrast echocardiography (MCE) following intravenous injection of perfluorocarbon microbubbles permits identification of resting myocardial perfusion abnormalities in patients who have had a previous myocardial infarction. PATIENTS AND INTERVENTIONS: 22 patients (mean (SD) age 66 (11) years) underwent MCE after intravenous injection of NC100100, a novel perfluorocarbon containing contrast agent, and resting (99m)Tc sestamibi single photon emission computed tomography (SPECT). With both methods, myocardial perfusion was graded semiquantitatively as 1 = normal, 0.5 = mild defect, and 0 = severe defect. RESULTS: Among the 203 normally contracting segments, 151 (74%) were normally perfused by SPECT and 145 (71%) by MCE. With SPECT, abnormal tracer uptake was mainly found among normally contracting segments from the inferior wall. By contrast, with MCE poor myocardial opacification was noted essentially among the normally contracting segments from the anterior and lateral walls. Of the 142 dysfunctional segments, 87 (61%) showed perfusion defects by SPECT, and 94 (66%) by MCE. With both methods, perfusion abnormalities were seen more frequently among akinetic than hypokinetic segments. MCE correctly identified 81/139 segments that exhibited a perfusion defect by SPECT (58%), and 135/206 segments that were normally perfused by SPECT (66%). Exclusion of segments with attenuation artefacts (defined as abnormal myocardial opacification or sestamibi uptake but normal contraction) by either MCE or SPECT improved both the sensitivity (76%) and the specificity (83%) of the detection of SPECT perfusion defects by MCE. CONCLUSIONS: The data suggest that MCE allows identification of myocardial perfusion abnormalities in patients who have had a previous myocardial infarction, provided that regional wall motion is simultaneously taken into account.

Aged↗
PubMed1999

A placebo-controlled clinical trial to compare a gel containing a combination of isotretinoin (0.05%) and erythromycin (2%) with gels containing isotretinoin (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris.

PURPOSE: To compare the clinical benefit of isotretinoin (0.05%) and erythromycin (2%) gels alone and in combination (Isotrexintrade mark) in acne patients. PROCEDURE: The study was a randomised placebo-controlled trial in acne patients who should benefit from topical therapy. RESULTS: All treatment groups except placebo produced a time-related reduction in lesion counts, with the combined therapy producing the largest mean decrease. Between-group comparisons showed several significant differences. CONCLUSION: Isotrexin was significantly better than placebo at all time points for inflamed and total lesions, and was better than isotretinoin at week 4. Side-effects were minimal.

Acne Vulgaris↗
PubMed1997

Human papillomavirus type 11 neutralization in the athymic mouse xenograft system: correlation with virus-like particle IgG concentration.

Neutralization of virus is likely to be necessary for development of an effective prophylactic vaccine against genital human papillomavirus (HPV) infection. Two New Zealand white rabbits were immunized with purified HPV type 11 (HPV 11) virions in Freund's adjuvant. An enzyme linked immunoassay (ELISA) was used to determine the quantity of IgG which recognized the HPV 11 major capsid protein (L1 protein) virus-like particles (VLPs) in the two anti-HPV 11 sera (serum A and serum B). The concentration of HPV 11 L1 VLP-specific IgG in the A and B sera were determined to be 37 and 90 micrograms per ml, respectively. The A and B sera were used in neutralization experiments in the athymic mouse xenograft system with known quantities of purified HPV 11 virions. The concentration of HPV 11 L1 VLP-specific IgG required to neutralize HPV 11 was determined for each antiserum. This concentration of IgG was approximately 700 to 900 ng per ml. This study demonstrates a positive correlation between the level of HPV 11 L1 VLP-specific IgG in animals immunized with HPV 11 virions and neutralization of HPV 11 in the athymic mouse model. Further studies are needed 1) to determine if sera or genital secretions from other species are neutralizing in the athymic mouse xenograft system, and 2) to determine if the VLP ELISA can be used as a reliable substitute for more cumbersome neutralization assays.

Animals↗
PubMed1997

ECAT ART - a continuously rotating PET camera: performance characteristics, initial clinical studies, and installation considerations in a nuclear medicine department.

Advances in fully three-dimensional (3D) image reconstruction techniques have permitted the development of a commercial, rotating, partial ring, fully 3D positron emission tomographic (PET) scanner, the ECAT ART. The system has less than one-half the number of bismuth germanate detectors compared with a full ring scanner with the equivalent field of view, resulting in reduced capital cost. The performance characteristics, implications for installation in a nuclear medicine department, and clinical utility of the scanner are presented in this report. The sensitivity (20 cm diameterx20 cm long cylindrical phantom, no scatter correction) is 11400 cps.kBq-1.ml-1. This compares with 5800 and 40500 cps.kBq-1.ml-1 in 2D and 3D respectively for the equivalent full ring scanner (ECAT EXACT). With an energy window of 350-650 keV the maximum noise equivalent count (NEC) rate was 27 kcps at a radioactivity concentration of approximately 15 kBq.ml-1 in the cylinder. Spatial resolution is approximately 6 mm full width at half maximum on axis degrading to just under 8 mm at a distance of 20 cm off axis. Installation and use within the nuclear medicine department does not appreciably increase background levels of radiation on gamma cameras in adjacent rooms and the dose rate to an operator in the same room is 2 microSv. h-1 for a typical fluorine-18 fluorodeoxyglucose (18F-FDG) study with an initial injected activity of 370 MBq. The scanner has been used for clinical imaging with18F-FDG for neurological and oncological applications. Its novel use for imaging iron-52 transferrin for localising erythropoietic activity demonstrates its sensitivity and resolution advantages over a conventional dual-headed gamma camera. The ECAT ART provides a viable alternative to conventional full ring PET scanners without compromising the performance required for clinical PET imaging.

Equipment Design↗
PubMed1997

Efficiency and productivity of a sheathed fiberoptic sigmoidoscope compared with a conventional sigmoidoscope.

PURPOSE: The aim of this study was to measure and compare time and productivity between a new sheathed flexible sigmoidoscope and a traditional fiberoptic flexible sigmoidoscope relative to labor and cost analysis. METHODS: Two flexible sigmoidoscopes, the Vision Sciences sigmoidoscope using a protective sheath covering requiring removal and replacement between procedures and a conventional flexible sigmoidoscope requiring meticulous cleaning using a washer and high-level disinfection, were compared. Sigmoidoscope preparation was defined as the average time between the procedures (reprocessing, start to finish) and was measured by an independent nonmedical timekeeper JG). The parameter recorded was scope reprocessing time. RESULTS: Ten procedures were performed using the sheathed flexible sigmoidoscope system compared with nine using a conventional sigmoidoscope. Scope performance and endoscopic visualization for both systems were comparable. The average reprocessing time was 46.8 minutes for the conventional sigmoidoscope vs. 4.9 minutes for the sheathed sigmoidoscope (P < 0.0001). The average time saved was 9.5 times greater with the sheathed flexible sigmoidoscope system than with the conventional sigmoidoscope. CONCLUSION: The almost tenfold difference in the time saved using the sheathed flexible sigmoidoscope system represents increased productivity and potentially decreased overall labor cost. By reducing endoscope turnover time, this new sheathed system can reduce or even eliminate the need for backup endoscopes and endoscope washers and potentially allow better use of nursing staff.

Endoscopes↗
PubMed1996

Safety of long-term high-dose minocycline in the treatment of acne.

Minocycline is widely used as a second-line antimicrobial for acne vulgaris. Some patients require doses of up to 200 mg daily to control their acne. To assess the long-term safety of minocycline when used at higher doses, 700 patients treated with minocycline at doses of 100 mg daily, 100/200 mg on alternate days and 200 mg daily, were recruited. The mean duration of treatment was 10.5 months. Side-effects were monitored and full blood count, blood urea, electrolytes and liver function tests were carried out on 200 of the 700 patients. Side-effects were recorded in 13.6%, and included vestibular disturbance, candida infection, gastrointestinal disturbance, cutaneous symptoms (pigmentation, pruritus, photosensitive rash and urticaria) and benign intracranial hypertension. Pigmentation was the only side-effect found to be significantly increased in patients taking higher doses of minocycline, as compared with lower doses (P < 0.01). All patients with pigmentation had taken a total cumulative dose of over 70 g. No significant abnormalities were found in any of the haematological and biochemical profiles. We conclude that minocycline, at doses of up to 200 mg/day, is safe, long-term, for acne, when such doses are clinically necessary.

Acne Vulgaris↗
PubMed1995

Functional analysis of mutant neurotrophins deficient in low-affinity binding reveals a role for p75LNGFR in NT-4 signalling.

The neurotrophins mediate their effects through binding to two classes of receptors, a tyrosine kinase receptor, member of the Trk family, and the low-affinity neurotrophin receptor, p75LNGFR, of as yet undefined signalling capacity. The need for a two-component receptor system in neurotrophin signalling is still not understood. Using site-directed mutagenesis, we have identified positively charged surfaces in BDNF, NT-3 and NT-4 that mediate binding to p75LNGFR. Arg31 and His33 in NT-3, and Arg34 and Arg36 in NT-4, located in an exposed hairpin loop, were found to be essential for binding to p75LNGFR. In BDNF, however, positively charged residues critical for p75LNGFR binding (Lys95, Lys96 and Arg97) were found in a spatially close but distinct loop region. Models of each neurotrophin were built using the coordinates of NGF. Analysis of their respective electrostatic surface potentials revealed similar clusters of positively charged residues in each neurotrophin but with differences in their precise spatial locations. Disruption of this positively charged interface abolished binding to p75LNGFR but not activation of cognate Trk receptors or biological activity in Trk-expressing fibroblasts. Unexpectedly, loss of low-affinity binding in NT-4, but not in BDNF or NT-3, affected receptor activation and biological activity in neuronal cells co-expressing p75LNGFR and TrkB, suggesting a role for p75LNGFR in regulating biological responsiveness to NT-4. These findings reveal a possible mechanism of ligand discrimination by p75LNGFR and suggest this receptor may selectively modulate the biological actions of specific neurotrophin family members.

3T3 Cells↗
PubMed1995

Pan-neurotrophin 1: a genetically engineered neurotrophic factor displaying multiple specificities in peripheral neurons in vitro and in vivo.

Pan-neurotrophin 1 (PNT-1) is a synthetic trophic factor engineered by combining active domains of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3) into an NT-3 backbone. This molecule was produced in transiently transfected COS cells or in baculovirus-infected insect cells transfected COS cells or in baculovirus-infected insect cells and subsequently purified to homogeneity. Saturation binding in embryonic spinal sensory neurons demonstrated a greater number of high-affinity binding sites for PNT-1 than for its parental molecule NT-3. PNT-1 was shown to efficiently block the chemical crosslinking of NGF, BDNF, and NT-3 to their cognate Trk receptors and to the low-affintiy NGF receptor expressed on neuronal and nonneuronal cells. PNT-1 stimulated survival and proliferation of MG87 fibroblasts expressing either TrkA, TrkB, or TrkC. PNT-1 also promoted survival of a greater number of embryonic dorsal root ganglion neurons than any of the other neurotrophins alone, and its effects were equivalent to a combination of NGF, BDNF, and NT-3. Analysis of receptor-specific neurotrophic activities demonstrated that PNT-1 efficiently rescued TrkA mRNA-containing sympathetic neurons and TrkB and TrkC mRNA-containing sensory neurons from the dorsal root and nodose ganglia. Finally, PNT-1 showed robust retrograde transport to DRG neurons in vivo after injection into the sciatic nerve. Radiolabeled PNT-1 accumulated in small-, medium-, and large-sized neurons. Coinjection with different unlabeled neurotrophins inhibited PNT-1 transport in distinct subpopulations of neurons of different sizes, suggesting that this molecule affects sensory neurons of different modalities. These results indicate that PNT-1 is a potent and multispecific neurotrophic factor that may be useful in the treatment of peripheral neurophathies and nerve damage.

Animals↗
PubMed1995

4-(4-Guanidinobenzoyl)-2-imidazolones and related compounds: phosphodiesterase inhibitors and novel cardiotonics with combined histamine H2 receptor agonist and PDE III inhibitor activity.

A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H2 receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H2 agonism was incorporated by p-(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3-fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 microM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1-(4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)-carbonyl]phenyl)-N2 - [3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5-fold higher maximal response than the reference compound.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Technetium-99m and indium-111 double labelling of granulocytes for kinetic and clinical studies.

A new technique of labelling granulocytes with both technetium-99m hexamethylpropylene amine oxime (HMPAO) and indium-111 in a single protocol was developed in order to exploit the advantages of each radiolabel in clinical and investigative studies. Fourteen patients were included in this prospective study. Granulocytes were labelled with both 111In-tropolonate and 99mTc-HMPAO. In vitro shape change assay and in vivo distribution and recovery studies were performed to assess the activation of and damage to these cells due to the labelling procedure. The comparative kinetics of 111In and 99mTc in the blood, liver, spleen, and bone marrow were studied by blood sampling and dual radionuclide imaging early (1 h) and late (24 h) after injection. The functional integrity of the double-labelled granulocytes and the feasibility of the technique were investigated in 14 patients with a painful prosthetic hip due to causes other than infection. The efficiency of double labelling was 63% (SD 14%) for 111In and 39% (SD 12%) for 99mTc-HMPAO. In vitro granulocyte activation and ex vivo recovery values were comparable to those from single radionuclide labelling. No artefactual granulocyte sequestration was seen in the lungs or liver. The radioactivity was distributed between the liver, spleen and bone marrow and, to a lesser extent, the lung. Early 99mTc counts in the liver, spleen and bone marrow, in relation to background, were significantly higher than 111In counts while the reverse was seen in late images.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Prevalence and correlates of depressive syndromes among adults visiting an Indian Health Service primary care clinic.

Depression is common among patients visiting primary care clinics. In order to describe the prevalence of depressive syndromes in an American Indian primary care clinic population and to help define the clinical correlates of depressive syndromes in this setting, a clinic-based research study of depression was undertaken by the Indian Health Service (IHS). One hundred and six patients from an IHS primary care clinic were systematically enlisted for participation in the study. Participants completed the Inventory for Diagnosing Depression (IDD). Twenty-two (20.7%) responded with answers scoring positive for a depressive syndrome. Nine of these 22 (8.9% of the 106 participants) met IDD criteria for a major depressive syndrome. A diagnosis of depression, a past history of depression, use of mental health facilities, unexplained pains, and antidepressant medication use were associated with the presence of a depressive syndrome.

Adult↗
PubMed1994

Effect of smoking on serum nutrient concentrations in African-American women.

The relationship between current cigarette smoking and serum concentrations of vitamins C, E, and A, and of five carotenoids in human serum were examined in 91 low-income, African-American women. General linear models were used to adjust geometric mean serum concentrations of micronutrients for age, dietary and supplement intakes, total energy intake, alcohol intake, medication use, body mass index, and serum concentrations of cholesterol and triglycerides. Among smokers, serum concentrations of alpha-carotene, beta-carotene, cryptoxanthin, and lycopene averaged only 71-79% of the concentrations among nonsmokers. Mean serum concentrations of vitamins C and E and lutein/zeaxanthin were only slightly lower among smokers relative to nonsmokers, and current smokers had higher serum concentrations of vitamin A. Among current smokers, mean serum concentrations of all five carotenoids decreased with an increase in the amount smoked. The negative effect of smoking on serum concentrations of antioxidant carotenoids may pose a serious health risk in low-income populations already at higher risk for many chronic diseases.

Adult↗
PubMed1994

Oxygen and 99mTc-MAA shunt estimations in patients with pulmonary arteriovenous malformations: effects of changes in posture and lung volume.

BACKGROUND: Patients with arteriovenous malformations are routinely monitored with arterial oxygen saturation (SaO2) estimations (breathing air) from which an oxygen shunt fraction can be calculated. This simple estimation has been compared with an anatomically defined estimate of the right to left shunt using a radioisotopic method. The fall in SaO2 which occurs in patients with pulmonary arteriovenous malformations in the erect posture and at high lung volumes was used to test the ability of SaO2 alone to follow changes in right to left shunt. METHODS: Radiolabelled albumin macroaggregates (99mTc-MAA) or microspheres (MS) were injected intravenously and kidneys and lungs were imaged. The shunt fraction (QS/QTTc) in the supine position at functional residual capacity (baseline) was obtained by quantifying right kidney radioactivity. On standing or while breath holding at total lung capacity, shunt fraction was calculated from baseline QS/QTTc and from lung counts and the injected dose. Arterial oxygen saturation (SaO2) was recorded by a pulse oximeter for calculation of the oxygen shunt (QS/QTO2) (breathing air). RESULTS: In the postural study (n = 8) SaO2 decreased from a mean (SD) value of 89 (5)% supine to 80 (6)% erect, corresponding to QS/QTO2 28 (8)% and 44 (8)% respectively. QS/QTTc increased from 28.7 (10.3)% to 39 (14.3)%. In the lung volume study (n = 8) QS/QTTc increased from 16.6 (11.5)% at functional residual capacity to 23.3 (11.9)% at total lung capacity while QS/QTO2 increased from 19.5 (7.5)% to 25.9 (10.6)% respectively. When all measurements were compared for QS/QTTc% and QS/QTO2% (n = 32) the difference in the mean values was 2.5% (absolute) and the limits of agreement between the two methods were +38% to -18% (relative). In neither the postural nor the volume study did delta (QS/QTO2) reliably predict delta (QS/QTTc)%. CONCLUSIONS: In pulmonary arteriovenous malformations the simple physiological shunt calculated from SaO2 breathing air agreed well with the anatomical right to left shunt measured with 99mTc-MAA, but predicted poorly the changes in anatomical shunt induced by postural or lung volume changes.

Adult↗
PubMed1993

Changes in intra- or extracellular pH do not mediate P-glycoprotein-dependent multidrug resistance.

P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) is thought to result from active extrusion of lipid-soluble, titratable chemotherapeutic agents. Given the lack of demonstration of coupling between ATP hydrolysis and drug transport, the resistance to chemically unrelated compounds, and findings of elevated intracellular pH (pHi), it has been proposed that reduced intracellular accumulation of drugs in MDR is due to changes in the pH difference across the plasma membrane. Elevation of pHi or decrease in local extracellular pH (pHo) could reduce the intracellular accumulation of the protonated chemotherapeutic drugs and account for Pgp-mediated MDR. Alternatively, changes in pHi or pHo could increase drug efflux by other mechanisms, such as coupled transport involving H+ or OH-, or allosteric effects on Pgp or other proteins. Both mechanisms could operate independently of the charge of the substrate. The possibility of a role of pHi in drug efflux is important to test because of the clinical significance of the phenomenon of MDR of tumors. We tested this hypothesis and found that MDR can occur in cells with low, normal, or high pHi. Further, resistant cells exhibited reduced steady-state drug accumulation and increased efflux without changes in local pHo. Finally, acute changes in pHi had no appreciable effect on Pgp-mediated drug efflux. We conclude that Pgp-mediated MDR is not a consequence of changes in pHi or pHo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗