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PubMed2003

Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction.

B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A'GFCC'C" face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1-deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.

Amino Acid Sequence↗
PubMed2003

PD-1 inhibits antiviral immunity at the effector phase in the liver.

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

Animals↗
PubMed2005

Effect of iodinated contrast agents on residual renal function in PD patients.

BACKGROUND: Residual renal function (RRF) is an important predictor of outcome in peritoneal dialysis (PD) patients. Although increasing emphasis has been placed on preserving RRF, the nephrotoxicity associated with contrast medium administration in PD patients remains a controversial issue. In the present prospective study, we evaluated the evolution of RRF 2 weeks after iodinated contrast medium administration (ICMA) in a group of stable PD patients, and compared it with that in a non-treated control group of stable PD subjects. METHODS: The study was conducted from January 2003 to October 2004. RRF was quantified by the average of 24 h urinary urea and creatinine clearance and peritoneal creatinine clearance (PcrCl) were analyzed, the levels of which were analysed prior to and 2 weeks following ICMA in 36 PD patients and also assessed at the same time points in a group of 36 PD non-ICMA control subjects, matched according to RRF characteristics. Two weeks following ICMA, the values for RRF, daily urine volume and PcrCl were assessed against those at baseline, and the evolution of RRF was compared between the two groups. In the ICMA group, this study was performed with adequate pre-hydration and a minimum dose of contrast medium. RESULTS: Compared with baseline values, RRF, daily urine volume and PcrCl were not found to be significantly different 2 weeks after ICMA (7.0+/-4.3 vs 7.2+/-4.3 ml/min/1.73 m(2), P = 0.12; 1324+/-696 vs 1360+/-755 ml/day, P = 0.5; and 41.1+/-9 vs 40.6+/-9 l/week/1.73 m(2), P = 0.6, respectively). Following ICMA, variations in RRF and daily urine volume were found to be comparable with those of the control group (0.1+/-0.5 vs 0.1+/-0.5 ml/min/1.73 m(2), P = 0.9; 36+/-440 vs 40+/-493 ml/day, P = 0.8, respectively). CONCLUSION: In this study, 2 weeks following ICMA, no accelerated decline in RRF was determined in stable PD patients with adequate pre-hydration, i.e. subjects treated under optimal circumstances compared with the control group.

Case-Control Studies↗
PubMed1998

PD 142893, SB 209670, and BQ 788 selectively antagonize vascular endothelial versus vascular smooth muscle ET(B)-receptor activity in the rat.

The purpose of this study was to determine whether vascular endothelial and vascular smooth-muscle endothelin ET(B) receptors could be quantitatively differentiated by PD 142893 (PD), SB 209670 (SB), and BQ 788 (BQ) in the same species by using closely matched experimental conditions. The isolated perfused rat kidney (vascular smooth muscle) and isolated perfused rat mesentery (vascular endothelium) were challenged with increasing bolus doses of sarafotoxin S6c in the absence and presence of antagonist. PD, SB, and BQ produced parallel concentration-dependent rightward shifts in the S6c dose-response curve in the kidney. PD and SB also produced parallel concentration-dependent rightward shifts in the S6c dose-response curve in the mesentery. In contrast, BQ produced an insurmountable antagonism. Schild-derived pA2 values for PD and SB were significantly greater for inhibiting endothelial versus smooth-muscle ET(B) receptors. Furthermore, PD and SB differed in their relative potency between the two assays. Because BQ produced an insurmountable antagonism in the mesentery, it was not possible quantitatively to compare the antagonist activity in the two assays. These results indicate that PD, SB, and BQ selectively antagonize endothelial ET(B)-receptor activity over smooth-muscle ET(B)-receptor activity.

Animals↗
PubMed1987

Pharmacological profile of PD 117302, a selective kappa-opioid agonist.

1 PD 117302, a new nonpeptide opioid compound shown in in vitro studies to be a selective kappa-opioid agonist, has been evaluated in vivo for antinociceptive activity and other effects characteristic of kappa-receptor activation. 2 Dose-related long lasting antinociception was produced by PD 117302 against a mechanical noxious stimulus in rats following intravenous, subcutaneous or oral administration. 3 PD 117302 was effective in raising the nociceptive threshold to mechanical and chemical but not to thermal noxious stimuli in the mouse. This effect was attenuated in animals pretreated with the opioid antagonist naloxone. 4 In addition to producing antinociception, PD 117302 also caused naloxone-reversible locomotor impairment and diuresis, effects that are typical of kappa-agonists. 5 PD 117302 did not cause respiratory depression, inhibition of gastrointestinal motility or naloxone-precipatated withdrawal jumping in mice, effects that are associated with actions at the mu-opioid receptor. 6 The pharmacological profile of PD 117302 in vivo is consistent with in vitro data suggesting that PD 117302 is a selective agonist at the kappa-opioid receptor.

Analgesics↗
PubMed1993

Use of the endothelin antagonists BQ-123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF.

1. We have compared the receptors mediating the contractions of rings of rat thoracic aorta or rabbit pulmonary artery and rat stomach strips in response to the endothelin/sarafotoxin (ET/SX) family of peptides and to those mediating endothelium-dependent vasodilations within the isolated perfused mesentery of the rat. To discriminate ETA receptors from ETB receptors we have used the criteria that ET-1 is more active than SX6c on ETA receptors, and that the ET/SX peptides are equiactive on ETB receptors. We have also assessed the effects of the ETA receptor-selective antagonist BQ-123, and the non-selective ET receptor antagonist PD 142893 on the responses of each preparation to the ET/SX peptides. 2. ET-1-induced constrictions of the rat thoracic aorta (EC50 3 x 10(-10) M), a prototypic ETA receptor-mediated response, or isolated perfused mesentery of the rat were antagonized by BQ-123 (10(-5) M) or PD 142893 (10(-5) M). SX6c did not constrict either the rat isolated perfused mesentery or the rat thoracic aorta. Thus, ETA receptors mediate these constrictions. 3. ET-1 and SX6c were approximately equipotent in constricting rabbit pulmonary artery rings (EC50S 3-6 x 10(-10) M). Neither BQ-123 (10(-5) M) nor PD 142893 antagonized the contractions induced by ET-1. These effects suggest mediation by ETB receptors but PD 142893 (10(-5) M) did give a 3 fold antagonism of constrictions induced by SX6c. 4. SX6c was more potent than ET-1 in contracting the rat stomach strip (threshold concentrations 10(-10) and 3 x 10(-10) M). Contractions to ET-1 or SX6c were unaffected by BQ-123 (10-5 M), again indicative of ETB receptor-mediated events. PD 142893 (10-5 M) was ineffective against ET-1 but produced a 3 fold antagonism of SX6c.5. In the rat isolated perfused mesentery ET-1 or SX6c (0.3-300pmol) were equipotent in producing dose-related vasodilatations that were unaffected by BQ-123 (10-6 M), indicative of an ETB receptor mediated response. In contrast to the other ETB-mediated responses, PD 142893 (10-6 M) strongly antagonized these vasodilatations.6. Thus, ETA receptors mediate constrictions of the rat thoracic aorta and rat isolated perfused mesentery whereas ETB receptors mediate constrictions of the rabbit pulmonary artery and rat stomach strip and endothelium-dependent dilatations within the mesentery. However, within the group of ETB receptor-mediated responses, endothelium-dependent vasodilatations are sensitive to PD 142893, whereas contractions of the isolated smooth muscle preparations are not. Thus, the receptor present on the endothelium responsible for the release of nitric oxide in response to the ET/SX peptides is most probably different from that present on smooth muscle that mediates BQ-123-insensitive contractions.

Amino Acid Sequence↗
PubMed2005

PD-0200347, an alpha2delta ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: a PKCalpha dependent effect.

OBJECTIVE: To explore the in vivo effects of PD-0200347, an alpha(2)delta ligand of voltage gated Ca(2+) channels, on cell signalling in osteoarthritic (OA) chondrocytes from an experimental dog model, and examine the effect of PD-0200347 on the major signalling pathways involved in OA cartilage degradation. METHODS: OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were divided into three groups and treated orally with (a) placebo; (b) 15 mg/kg/day PD-0200347, or (c) 90 mg/kg/day PD-0200347. The animals were killed 12 weeks after surgery. Cartilage specimens from femoral condyles and tibial plateaus were processed for immunohistochemistry. Specific antibodies against the phosphorylated form of PKCalpha, Ras, c-Raf, the MAP kinases Erk1/2, p38, JNK, and the transcription factors, CREB and Elk-1, were used. RESULTS: Levels of all the tested signalling mediators were increased in the placebo treated (OA) group compared with the normal group. PD-0200347 treatment significantly reduced the levels of the active forms of PKCalpha, c-Raf, Erk1/2, and Elk-1; however, the levels of the active forms of Ras, p38, JNK, and CREB were not affected by the PD-0200347 treatment. CONCLUSION: The action of PD-0200347 on OA chondrocytes is probably mediated through the inhibition of Erk1/2 activation via a Ras independent mechanism. This effect is associated with reduction of the activation of transcription factors such as Elk-1, which leads to the inhibition of the induction of the major catabolic factors involved in the degradation process of OA cartilage.

Animals↗
PubMed1998

Delivered dialysis dose with PD Plus therapy. A multicenter study.

AIM: To evaluate the effect of PD Plus on weekly Kt/Vurea and creatinine clearance (Kcr) among patients undergoing CAPD/CCPD (continuous ambulatory peritoneal dialysis/continuous cyclic peritoneal dialysis). METHODS: The kinetic studies of 92 CAPD and 18 CCPD patients who transferred to PD Plus were analyzed. All patients underwent CAPD/CCPD and PD Plus for a minimum of 3 months. Standard collection methods were used and kinetic indices calculated with the Pack PD Kinetic Modeling program. 57 patients had transport data and were modeled for a target weekly Kt/Vurea >/=2.1 using PD Plus with </=15 liters dialysate/day. 6 patients were supervised during the collection periods by research nurses. The actual results for all patients (110) and for the supervised patients were compared against the modeled results. RESULTS: [table] 45% of the patients achieved a Kt/Vurea >/=2.1 and 47% a Kcr >/=60 liters/1.73 m2 with PD Plus, but only 20% did so with CAPD/CCPD. A close correlation between the supervised patients and modeled therapy was observed. CONCLUSIONS: Adequate dialysis is possible by using higher fill volumes, the supine position, and optimal dwell times (PD Plus) in most patients. The discrepancy between modeled and achieved dose is likely due to poor compliance with therapy, inadequate training, or poor specimen collection.

Creatinine↗
PubMed2005

In-situ deposition of Pd nanoparticles on tubular halloysite template for initiation of metallization.

Halloysite template has a tubular microstructure; its wall has a multi-layer aluminosilicate structure. A new catalytic method is adopted here, through the in-situ reduction of Pd ions on the surface of tubular halloysite by methanol to initiate electroless plating; the detailed deposition features of Pd nanoparticles are investigated for the first time. The results indicate that an in-situ reduction and deposition of Pd occurs at room temperature, in which the halloysite template plays an important role. Impurities in halloysite (such as ferric oxide) influence the formation and distribution of the Pd nanoparticles. The Pd nanoparticles are of a non-spherical shape in most cases, which would be caused by the irregular appearance of halloysite. No intercalation of the nanoparticles occurs between the aluminosilicate layers in the halloysite. The diameter of Pd nanoparticles increases with time; the average diameter ranges from 1 nm to 4 nm. Pd nanoparticles on a halloysite template can catalyze electroless deposition of Ni to prepare a novel nano-sized cermet at low cost. This practicable catalytic method could also be used on other clay substrates for the initiation of metallization.

Aluminum Silicates↗
PubMed2005

Histological and functional characteristics of peritoneal membrane in peritoneal sclerosis of PD patients.

BACKGROUND: Function and structure of peritoneal membrane (PM) are impaired on peritoneal dialysis (PD). Peritoneal sclerosis is a common finding in peritoneal biopsies (PB) of PD patients. The aim of this study was to examine the impact of peritoneal sclerosis on peritoneal function and clinical parameters in PD patients submitted to peritoneal biopsy. METHODS: A PB was performed on 31 PD patients during catheter removal due to malfunction or after drop-out from treatment. For each patient PM transport was evaluated by the last peritoneal equilibration test before PB. Each daily glucose load was calculated. Tissue was formalin-embedded and stained for histological and immunohistochemical studies. RESULTS: Patients with submesothelial sclerosis and those with impairment of submesothelial basement membrane and subendothelial vascular membrane were submitted to a larger daily glucose load. Peritoneal sclerosis > 50 microns was more frequent in high transporters, who were exposed to larger daily glucose load compared to medium-high transporters. Mesothelial loss is correlated to peritoneal sclerosis and vascular injuries. CONCLUSIONS: Peritoneal sclerosis is not constant in PD patients: it is related to the loss of mesothelium integrity, to the daily glucose load of PD treatment and to vascular injuries, but apparently not to the presence of inflammatory infiltrate. It remains a matter of debate how much the peritoneal sclerosis modifies the function of PM and how new more biocompatible PD solutions could reduce PM injury.

Actins↗
PubMed2006

The catheter as Ariadne's thread to follow the path of Peritoneal Dialysis (PD) through the long-term experience of a Center.

In our institution, the first patient was treated by HD in 1955. In the middle of the '60s, the PD technique, revised by Maxwell (1), was implemented. The access to peritoneum was obtained by repeated puncturing of the abdomen, the catheter being removed after each session. In 1966, our first results on one year of PD were published (20 patients treated, 13 affected by ARF and 7 by CRF, for a total number of 150 sessions). Since 1967, the procedure of the repeated punturing was improved by the Seldinger technique. The efficiency of the PD intermittent treatment was increased with the "fast shift" schedule and PD automation was pursued with the project of a cycler (1968). The first CRF patients were treated by fast shift PD. In the late intermittent PD phase, the adoption of permanent catheters, destined to endure in our practice, the rigid and the soft indwelling for long-term treatments, allowed us to launch programs of home and nocturnal PD. With the incoming CAPD age, the greatest care was directed to the role of the catheter. The adoption of the surgical insertion by paramedian approach through rectus muscle, minimized, in our experience, the early complications. With the reduction of peritonitis rate, the later catheter complications increased in terms of patient discomfort, hospitalization and technique survival. On those grounds, in our institution a prospective trial on a ten year period was undertaken to compare, in terms of late complications rate, new versions of the classic Tenckhoff straight catheter (ST). The surgical insertion method was adopted for all the types, for a total of 196 catheters in 163 CRF patients. The tip displacement rate (12.2% with ST) decreased, albeit non significantly, with Swan Neck (7.9%), but was markedly and significantly reduced (1.0%) with the Self-Locating (SL) catheter experience. The surgical insertion of SL was comparable to that of ST. For those reasons, in recent years, in our institution the SL catheter became the first choice catheters for CRF patients.

Catheterization↗
PubMed1999

SPECT imaging of pre- and postsynaptic dopaminergic alterations in L-dopa-untreated PD.

BACKGROUND: In PD, presynaptic dopamine transporters are known to be decreased, whereas postsynaptic striatal D2 receptors are proposed to be upregulated. However, the relationship between these alterations is not clear. OBJECTIVE: To evaluate the ability of SPECT to detect both the pre- and postsynaptic dopaminergic alterations of the striatum in patients with L-dopa-untreated PD. METHODS: We studied 10 L-dopa-untreated patients with clinically mild PD and 21 age-matched normal controls. Individuals had both presynaptic [123I]beta-CIT dopamine transporter and postsynaptic [123I]IBF D2 SPECT studies 1 week apart. RESULTS: In PD patients, the dopamine transporter binding potential Rv ipsilateral/contralateral to the most affected limbs was 30%/41%, 41%/50%, and 59%/68% lower than controls for caudate, anterior putamen, and posterior putamen, respectively. These bilateral Rv decreases showed a lateralized difference more reduced in the contralateral striatum as well as intrastriatal differences most reduced in the posterior putamen. In contrast, in PD patients the D2 binding potential Rv ipsilateral/contralateral was 15%/16% higher for caudate, 18%/14% higher for anterior putamen, and 28%/31% higher for posterior putamen. These bilateral Rv increases showed no lateralized differences and less marked intrastriatal differences. The motor Unified Parkinson's Disease Rating Scale scores negatively correlated with dopamine transporter Rv but not with D2 Rv. CONCLUSIONS: SPECT imaging can detect characteristic dopaminergic alterations in the striatum of dopa-untreated PD patients including the upregulation of postsynaptic D2 receptors (denervation supersensitivity). SPECT is widely available and is a promising clinical tool to evaluate PD patients.

Aged↗
PubMed1999

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE: To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND: Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS: A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS: The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS: Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.

Adult↗
PubMed2001

Freezing of gait in PD: prospective assessment in the DATATOP cohort.

OBJECTIVE: To study the development of freezing of gait in PD. BACKGROUND: Freezing of gait is a common, disabling, and poorly understood symptom in PD. METHODS: The authors analyzed data from 800 patients with early PD from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial who were assigned either placebo, deprenyl, tocopherol, or the combination of deprenyl and tocopherol. The primary outcome measure was the time from randomization until the freezing of gait score on the Unified Parkinson's Disease Rating Scale (UPDRS) became positive. RESULTS: Fifty-seven patients (7.1%) had freezing of gait at study entry and 193 (26%) of the remaining patients experienced the symptom by the end of the follow-up period. Those with freezing of gait at baseline had significantly more advanced disease than those without the symptom, as measured by total UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing freezing of gait during the follow-up period were the onset of PD with a gait disorder; higher scores of rigidity, postural instability, bradykinesia and speech; and longer disease duration. In contrast, tremor was strongly associated with a decreased risk for freezing of gait. At the end of follow-up, the signs most strongly associated with the freezing phenomenon were gait, balance, and speech disorders, not rigidity or bradykinesia. Deprenyl treatment was strongly associated with a decreased risk for developing freezing of gait; tocopherol had no effect. CONCLUSIONS: Freezing of gait is directly related to duration of PD. Risk factors at onset of disease are the absence of tremor and PD beginning as a gait disorder. The development of freezing of gait in the course of the illness is strongly associated with the development of balance and speech problems, less so with the worsening of bradykinesia, and is not associated with the progression of rigidity. These results support the concept that the freezing phenomenon is distinct from bradykinesia. Deprenyl, in the absence of L-dopa, was found to be an effective prophylactic treatment and should be considered for patients with PD who have an onset of gait difficulty.

Aged↗
PubMed2002

Caffeinated clues and the promise of adenosine A(2A) antagonists in PD.

Large prospective epidemiologic studies have linked the consumption of coffee and other caffeinated beverages to a reduced risk of subsequently developing PD. Caffeine as well as more specific antagonists of the adenosine A(2A) receptor have also now been found to attenuate neurotoxicity in a mouse model of PD. The convergence of these epidemiologic and laboratory data supports the possibility that caffeine may reduce the risk of developing PD. However, a neuroprotective effect of caffeine in PD remains unproven; current evidence does not provide a rational basis for recommending caffeine consumption to modify the risk or progression of PD. In addition to possessing neuroprotective potential, caffeine and other A(2A) antagonists have long been known to acutely reverse motor deficits in a variety of PD models. This symptomatic antiparkinsonian benefit of blocking A(2A) receptors, coupled with their remarkably restricted expression in the basal ganglia, have made A(2A) antagonists attractive targets for drug development. Now, with the prospect of a neuroprotective bonus, the novel therapeutic potential of A(2A) antagonists appears all the more promising just as they are entering clinical trials for PD.

Age of Onset↗
PubMed2000

Bioavailability assessment of disopyramide using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

The relationship between the serum concentration and the pharmacological effect of disopyramide was investigated quantitatively to estimate the extent of its oral bioavailability (EBA(p.o.) and to evaluate the drug interaction with miconazole, a CYP3A4 inhibitor. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was used to describe the relationship between the serum concentrations and changes in QT interval (pharmacological data) of disopyramide after intra-vascular infusion for 15 min (i.v. short-term infusion) to rats. A two-compartment model was applied to the pharmacokinetics of disopyramide. The pharmacological data after short-term infusion were well explained using a PK-PD link model. To validate the present PK-PD model. disopyramide was administered intra-vascularly in separate experiments, and the doses were predicted only from the pharmacological data. The model predicted doses were identical to the actual doses, regardless of the dosing rates. This result indicates that the PK-PD model used in the present study is appropriate, and that the relationship between the serum concentrations and changes in QT intervals is independent of the dosing (input) rate. When miconazole was co-administered orally 1 h before disopyramide infusion, the serum disopyramide concentrations were significantly higher than that following disopyramide alone. The raised serum concentrations under miconazole co-administration were well explained by nonlinear elimination clearance. The pharmacological effects of disopyramide under miconazole co-administration, were also greater than those following disopyramide alone. The results of the PK-PD analysis indicated that the enhanced pharmacological response under miconazole co-administration was simply caused by a pharmacokinetic change. The EBA(p.o.) values estimated from the pharmacological effects predicted the observed values reasonably well. In conclusion, we demonstrated following: (1) the pharmacological effect after intra-vascular administration of disopyramide is related quantitatively to the serum concentrations using a PK-PD model; (2) miconazole affects only the elimination clearance of disopyramide to enhance the pharmacological effect; (3) the EBA of disopyramide can estimated reasonably only well from the pharmacological data using the PK-PD model; (4) there is no dosing-rate-dependent or dosing-route-dependent pharmacological effect of disopyramide.

Algorithms↗
PubMed1979

Effects of environmental oxidant stressors on individuals with a G-6-PD deficiency with particular reference to an animal model.

Individuals with a G-6-PD deficiency have long been known to be at increased risk to experience acute hemolysis following exposure to elevated levels of certain oxidant drugs and industrial chemicals. However, the recognition of enhanced susceptibility to environmental (or ambient) pollutants has generally not been considered. Recent theoretical studies have suggested that elevated levels of ambient ozone may be an etiologic factor in the onset of acute hemolysis in the G-6-PD deficient individual. Furthermore, the proposed usage of either chloramines or chlorine dioxide as replacements for chlorine for the disinfection of drinking water should be investigated with respect to their potential adverse effects of individuals at increased risk to oxidant stressors. In order to test these theoretical associations, two mouse strains, one with low and the other with high levels of G-6-PD activity in their red blood cells are being investigated to determine if they simulate human G-6-PD deficient and normal individuals, respectively. Preliminary results indicate that the mouse strain with low G-6-PD activity is markedly more susceptible to sodium chlorite than mice of the high G-6-PD strain. This differential susceptibility to sodium chlorite toxicity between the high and low G-6-PD mouse strains suggests that further research designed to validate the efficacy of this mouse model as a predictor of the human situation is warranted.

Air Pollutants↗
PubMed2004

Plasma and erythrocyte magnesium, manganese, zinc, and plasma calcium levels in G-6-PD-deficient and normal male children.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is the most common human enzymopathy in the world. Trace elements are important for normal hematopoiesis and can play a role in acute hemolytic anemia induced by G-6-PD deficiency. For this purpose, we studied two groups consisting of 10 male children who are G-6-PD-deficient and 12 age-matched normal male children to compare plasma and erythrocyte magnesium, manganese, zinc, and plasma calcium levels between G-6-PD-deficient and normal children. All assays were performed under normal conditions free of any oxidative attack that may result in hemolytic crisis in G-6-PD-deficient subjects. All parameters in each group did not differ significantly except for erythrocyte G-6-PD activities. These data show that plasma and erythrocyte trace element contents of G-6-PD-deficient subjects do not differ in normal conditions.

Calcium↗