The influence of active transport systems on morphine -6-glucuronide transport in MDCKII and MDCK-PGP cells

Background and the purpose of the study

Morphine-6-glucuronide (M6G) is a potent metabolite of morphine which has high penetration into the brain despite its high polarity, which could be the result of an active transport system involved in M6G transport through blood brain barrier. Examples of such transporters are p-glycoprotein (PGP), probenecid-sensitive transport mechanism, multidrug resistance related protein 1-3, the organic anion transporter family, and the organic anion transporter polypeptide family. The aim of present study was to elucidate the mechanisms involved in transporting morphine''s potent metabolite, M6G.

Methods

M6G permeability via two cell lines; MDCKII and MDCK-PGP, was compared with that of sucrose. M6G transport was examined in different concentrations and in the presence of inhibitors of different transport systems such as cyclosporine, digoxin and probenecid. M6G concentration was measured using ELISA assay. The method was sensitive, reliable and reproducible.

Results

The results confirmed that M6G could cross a layer of MDCK II or MDR-PGP cells more than sucrose could. It was also observed that M6G is a PGP transporter substrate. Its permeability was increased by the use of a PGP expressed cell line, and also in the presence of a strong PGP inhibitor. Digoxin related transporters such as Oatp2 may also involved in transport of M6G. M6G seemed to be a glucose transporter 1 substrate, but was not a substrate to probenecid sensitive transporters.

Major conclusion

It is concluded that different transporters are responsible for M6G transports via different membrane, which could have effects on its pharmacokinetics or pharmacodynamics.     

Early‐onset,progressive, frequent,extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1–associated primary hyperparathyroidism

Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1–related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT. However, studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking. In this cross‐sectional study, performed in a tertiary academic hospital, 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual‐energy X‐ray absorptiometry (DXA) scanning of the proximal one‐third of the distal radius (1/3DR), femoral neck, total hip, and lumbar spine (LS). The mean age of the patients was 38.9 ± 14.5 years. Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77.8%). In the younger group (<50 years of age), demineralization in the 1/3DR was more frequent, more severe, and occurred earlier (40%; Z‐score ?1.81 ± 0.26). The older group (>50 years of age) had a higher frequency of bone demineralization at all sites (p < .005) and a larger number of affected bone sites (p < .0001), and BMD was more severely compromised in the 1/3DR (p = .007) and LS (p = .002). BMD values were lower in symptomatic (88.9%) than in asymptomatic HPT patients (p < .006). Patients with long‐standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. Urolithiasis occurred earlier (<30 years) and more frequently (75%) and was associated with related renal comorbidities (50%) and renal insufficiency in the older group (33%). Bone mineral– and urolithiasis‐related renal complications in HPT/MEN1 are early‐onset, frequent, extensive, severe, and progressive. These data should be considered in the individualized clinical/surgical management of patients with MEN1‐associated HPT. © 2010 American Society for Bone and Mineral Research.     

High patient satisfaction amongst males participating in men's educational group appointments (MEGA) for routine physical exams

Background

There is an insidious health crisis facing men in the United States today. They have a higher age-adjusted death rate, compared with that of women, from nearly all of the leading causes of death. Although genetics play a role, unhealthy behavior, avoidance of health care, and making poor health-related decisions also significantly contribute to premature death and disability amongst men. Having identified that behavior change amongst men is needed, and using the observation that group dynamics have been shown to benefit in other behavior change programs (such as weight loss and alcohol cessation), we have applied the same group dynamic principle to men's health maintenance. Herein we report on patient satisfaction using this approach, and outline a plan to study its long term effect on men's health-related behavior.

Methods

We initiated a small group appointment program for routine male physical examinations, termed the Men's Educational Group Appointment (MEGA). It was designed to emphasize patient education about male-specific health issues, to increase patient/provider face time, and to provide an interactive environment that encourages men to learn from their and other patients’ questions. It involved a private physical exam segment, a group review of laboratory data and their significance, a didactic PowerPoint presentation using visual aids (and humor) to illustrate key elements of health issues facing men, and a lengthy question and answer session. Satisfaction surveys were administered at the conclusion of each session and compiled for analysis.

Results/Conclusions

We observed high patient satisfaction amongst males participating in the MEGA for routine physical exams (100% of patients responded that it was either ‘worthwhile’ (21%) or ‘extremely worthwhile’ (79%). This model appears to foster increased patient education based upon both more time with the health care providers, and the ability of patients to benefit from the questions of other patients. Our current challenge is to demonstrate its superiority to the traditional one-on-one visit with respect to information retention, follow-through with recommended health screening practices, and overall better health-related decisions.     

Multigland Disease and Slower Decline in Intraoperative PTH Characterize Mild Primary Hyperparathyroidism

Background

Many patients with primary hyperparathyroidism (PHPT) present with less severe biochemical parameters. The purpose of this study was to compare the presentation, operative findings, and outcomes of these patients with “mild” PHPT to patients with “overt” disease.

Methods

A retrospective review of a prospectively collected parathyroid database was performed to identify cases of PHPT undergoing an initial neck operation. Patients were classified as mild when either the preoperative calcium or PTH was within the normal limits. Comparisons were made with the Student’s t test, Chi-squared test, or Wilcoxon rank-sum test where appropriate. Kaplan–Meier estimates were plotted for disease-free survival and compared by the log-rank test.

Results

Of the 1,429 patients who met inclusion criteria, 1,049 were classified as overt and 388 (27.1 %) were mild. Within the mild group, 122 (31.4 %) presented with normocalcemic PHPT and 266 (68.6 %) had a normal PTH. The two groups had similar demographics and renal function. Interestingly, the mild group had more than double the rate of kidney stones (3.1 vs. 1.3 %, p = 0.02). The mild group was less likely to localize on sestamibi scan (62.4 vs. 78.7 %, p < 0.01). Intraoperatively, more mild patients exhibited multigland disease (34.3 vs. 14.1 %, p < 0.01). When examining intraoperative PTH (IoPTH) kinetics where single adenomas were excised, the IoPTH fell at a rate of 6.9 pg/min in mild patients compared with 11.5 pg/min in the overt group (p < 0.01). Accordingly, 62.2 % of patients in the overt group and 53.3 % in the mild group were cured at 5 min postexcision (p < 0.01). There was no difference in the rates of persistence or recurrence between the groups, and disease-free survival estimates were identical (p = 0.27).

Conclusions

Patients with mild PHPT were more likely to have multigland disease and a slower decline in IoPTH, but these patients can be successfully treated with surgery.     

Inhaled nitric oxide in neonates and children with pulmonary hypertension

Fourteen critically ill neonatal and paediatric intensive care patients with various primary diagnoses and signs of associated pulmonary hypertension received inhaled nitric oxide (NO), 20–80 ppm, after failure of conventional therapy to improve oxygenation. NO administration was found to be associated with a significant improvement in postductal arterial oxygen tension (pre-NO: 3.75 (SD 1.39) kPa; post-NO: 6.05 (SD 1.70) kPa; p = 0.004). In 10 patients, NO was found to increase arterial oxygen tension with more than 1 kPa. In 2 of these patients, ECMO treatment could be avoided due to the pronounced improvement in gas exchange seen after the initiation of NO administration. The remaining 4 patients failed to respond to NO administration. One patient developed methaemoglobinaemia (13.9%) which required treatment with methylthionine. Since we were unable to produce any beneficial effect of NO in the late phase of the pulmonary disease process, we believe that, in order to be successful, inhaled NO should be instituted when conventional treatment has failed and the administration of an iv vasodilator is usually considered.     

Decreased plasma gelsolin levels in patients with Plasmodium falciparum malaria: a consequence of hemolysis?

Mammalian plasma contains a high-affinity actin-binding protein, plasma gelsolin, that severs actin filaments. Destruction of erythrocytes could result in the release of erythrocyte cytoskeletal actin into the plasma where it could bind to gelsolin. If the clearance of actin- gelsolin complexes exceeds its synthesis, lowering of the plasma gelsolin concentration might follow. To test this hypothesis, we measured plasma gelsolin levels in patients with falciparum malaria, a disease where at least part of the hemolysis takes place in the intravascular space and that is usually not accompanied by dysfunction of other organs. Two functional gelsolin assays showed that the mean plasma gelsolin concentration of 18 Nigerian children with Plasmodium falciparum malaria was less than 50% (P less than .001) of healthy Nigerian control subjects tested at the same time. Patients with pneumonia and febrile seizures also had depressed gelsolin levels, which indicates that factors other than hemolysis can lower gelsolin concentrations. Gelsolin levels were measured in 11 patients from The Gambia with P falciparum malaria before and approximately 3 weeks after treatment. In all cases the gelsolin level increased after treatment. To confirm the hypothesis that hemolysis can result in a lowering of plasma gelsolin levels, hemolysis was induced in rabbits, either acutely (by the injection of human serum) or subacutely (by the administration of phenylhydrazine). A fall in plasma gelsolin levels was seen, the rate of fall differing with the extent of hemolysis. Affinity adsorption of plasma from animals undergoing acute hemolysis with Sepharose beads coupled to the actin-binding protein DNase I, followed by immunoblotting of adherent proteins with antiactin antiserum demonstrated the presence of actin in circulating rabbit plasma. These studies suggest that under some conditions components of the red cell cytoskeleton are exposed to plasma proteins and that accelerated clearance of actin-gelsolin complexes may explain in part the depressed plasma gelsolin levels seen in patients with falciparum malaria.