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1Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, 2Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3Division of Cardiovascular Drugs and Therapy, Kindai University Graduate School of Pharmacy, Higashi-Osaka, and 4Department of Transplantation, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan Objective: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration-time curve (AUC) of EVL in heart transplant patients. Methods: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). Results: AUC0–4h, peak concentration (Cmax), Cmax/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Half-life and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC0–12h in the active period was similar (p = 0.154) and correlated with that in the resting period (r2 = 0.93). Two-point blood samplings, C0 and C2, correlated more strongly with AUC0–12h for EVL, compared with C0 alone (0.92 vs. 0.79, respectively, for r2 in the active period). Conclusions: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC0–12h. A 2-time-point model that included C0 and C2 was more accurate for predicting the AUC0–12h of EVL than C0 alone in heart transplant patients. Correspondence to: Kyoichi Wada, PhD
Department of Pharmacy
National Cerebral and Cardiovascular Center
5-7-1 Fujishirodai, Suita 565-8565, Japan Email:[email protected]
Original
Prescription patterns and drug costs in German patients with dementia in nursing homes and home-care settings
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (9-15)
Prescription patterns and drug costs in German patients with dementia in nursing homes and home-care settings
Louis Jacob1, Jens Bohlken2, Karel Kostev3
1Department of Biology, École Normale Supérieure de Lyon, Lyon, France, 2Praxis Bohlken, Berlin, Germany, and 3IMS Health, Real World Evidence Solutions, Frankfurt, Germany Aims: To analyze prescription patterns and drug costs in German patients with dementia who are in home-care settings and nursing homes. Methods: The present retrospective study based on the Disease Analyzer epidemiological database and included 41,064 patients treated by general practitioners (GPs) and 20,649 patients treated by psychiatric practitioners (PPs), who were diagnosed with dementia in 2014. Four different types of antidementia therapy were included in the analysis. The shares of prescriptions and the associated costs in dementia patients in home-care settings and nursing homes were estimated. Regression analyses were performed to study the impact of the type of residence on the likelihood of receiving a defined therapy and incurring its associated cost. Results: Antidementives were more frequently prescribed to patients in home-care settings, whereas antidepressants, antipsychotics, and benzodiazepines were more commonly administered to nursing-home patients in both the GP and the PP groups. Individuals residing in nursing homes had a lower likelihood of receiving antidementives but exhibited a higher likelihood of being prescribed antidepressants, antipsychotics, and benzodiazepines. The total cost of therapy was higher in nursing homes than in home-care settings (GPs: difference of € 27.20; PPs: difference of € 107.90). The cost of antidementives was significantly lower in GP patients residing in nursing homes than in GP patients living at home. There was no significant difference in the cost of antidementives in the PP groups. By contrast, the costs of the three other families of drugs were lower in individuals cared for at home than in individuals residing in nursing homes, in both practice types. Conclusion: Prescription patterns and the drug costs in dementia patients significantly differed between home-care settings and nursing-home settings. Correspondence to: Prof. Dr. Karel Kostev
IMS Health, Epidemiology
Darmstädter Landstraße 1089
60598 Frankfurt am Main, Germany Email:kkostev@ de.imshealth.com
Original
Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
Marcus-Hillert Schultze-Mosgau, Barbara Schuett, Frank-Thorsten Hafner, Frank Zollmann, Andreas Kaiser, Joachim Hoechel, Beate Rohde
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (16-24)
Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women
Marcus-Hillert Schultze-Mosgau1, Barbara Schuett1, Frank-Thorsten Hafner1, Frank Zollmann2, Andreas Kaiser1, Joachim Hoechel1, Beate Rohde1
1Bayer AG and 2pharma consult, Berlin, Germany Objectives: Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. Methods and materials: In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and – after a wash-out period – daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Results: Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 – 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 µg/L (1 mg) to 68.6 µg/L (30 mg) and 58.5 µg×h/L to 1,590 µg×h/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0–24)md/AUC(0–24)sd ratios: 1.9 to 3.2). The ratio AUC(0–24)md/AUCsd increased with dose from ~ 1 (1 mg) to 1.5 (30 mg). Conclusions: Exposure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t1/2, indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range. Correspondence to: Dr. Marcus-Hillert
Schultze-Mosgau Bayer AG
13353 Berlin, Germany Email:marcus.schultze- [email protected]
Original
Utilization of population pharmacokinetics in drug development and provision of the results to healthcare professionals
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (25-31)
Utilization of population pharmacokinetics in drug development and provision of the results to healthcare professionals
Megumi Watanabe-Uchida, Mamoru Narukawa
Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan Objective: The aim of this research is to understand the level of utilization of population pharmacokinetics (PPK) in drug development in the United States of America (US) and Japan, and to discuss what kind of PPK information should be provided to healthcare professionals. Methods: Information on PPK was identified on the label, package insert, and pharmaceutical evaluation report disclosed by the US Food and Drug Administration and the Pharmaceutical Medical Devices Agency of Japan for new molecular entities approved between January 2012 and December 2015. Results: Between January 2012 and December 2015, 152 new molecular entities were approved in the US and 176 in Japan. The proportion of documents using PPK data in the US increased each year, but in Japan the proportion plateaued. The proportion of US labels and that of Japanese package inserts containing PPK parameters was 37.2% (32/86) and 41.9% (13/31), respectively. Conclusions: PPK use in drug development in the US is increasing each year, there is no similar increase occurring in Japan. We expect that the use of pharmacometrics, including PPK and PPK/pharmacodynamics (PD), will become more common in drug development, and that by sharing the PPK model obtained from clinical trial promptly within medical practice they can be effectively utilized in individualized drug administration plans. Correspondence to: Megumi Watanabe-Uchida, MSc
Department of Clinical Medicine (Pharmaceutical Medicine)
Graduate School of Pharmaceutical Sciences
Kitasato University
Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan Email:[email protected]
Original
Berberine promotes antiproliferative effects of epirubicin in T24 bladder cancer cells by enhancing apoptosis and cell cycle arrest
Yumin Zhuo, Qibiao Chen, Bo Chen, Xiongyu Zhan, Xiaoping Qin, Jun Huang, Xiuxiu Lv
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (32-40)
Berberine promotes antiproliferative effects of epirubicin in T24 bladder cancer cells by enhancing apoptosis and cell cycle arrest
Yumin Zhuo1*, Qibiao Chen1*, Bo Chen1, Xiongyu Zhan1, Xiaoping Qin1, Jun Huang1, Xiuxiu Lv2
1Department of Urology, The First Affiliated Hospital of Jinan University, and 2Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, China Objective: The present study was aimed to observe the effect of berberine (Ber) on epirubicin (EPI)-induced growth inhibition, apoptosis, and cell cycle arrest in T24 bladder cancer cells. Methods: The cancer cells were exposed to EPI, with or without different concentrations of Ber. The viability of the cancer cells was measured by cell counting Kit-8, the apoptosis was determined by Hoechst 33258 staining and the expression of cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, and P53 proteins were detected by Western blot assay. In addition, cell cycle arrest and the production of reactive oxygen species (ROS) were also measured. Results: We found that Ber enhanced the inhibitory effect of EPI on the viability of T24 cells and promoted EPI-induced cell cycle arrest at G0/G1 and apoptosis in T24 cells. EPI increased the expression of cleaved caspase-3, cleaved caspase-9, Bax, P53, and P21 proteins, all of which were enhanced by treatment with Ber. In contrast, Ber exposure further decreased the expression of Bcl-2 in EPI-treated T24 cells. Furthermore, we also demonstrated that Ber significantly increased ROS production in EPI-treated T24 cells. Conclusions: These data indicate that Ber enhances the antiproliferative effects of EPI in bladder cancer cells by promoting apoptosis and cell cycle arrest.
*Both contributed equally to this study.Correspondence to: Xiuxiu Lv
Department of Pathophysiology
Key Laboratory of State Administration
of Traditional Chinese Medicine
School of Medicine, Jinan University
Guangzhou 510632, China Email:[email protected]
Original
Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study
Kasra Shakeri-Nejad, Vassilios Aslanis, Uday Veldandi, Anne Gardin, Andreas Zaehringer, Angela Dodman, Zhenzhong Su, Eric Legangneux
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (41-53)
Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study
Kasra Shakeri-Nejad1, Vassilios Aslanis1, Uday Veldandi2, Anne Gardin1, Andreas Zaehringer1, Angela Dodman1, Zhenzhong Su3, Eric Legangneux1
1Novartis Pharma AG, Basel, Switzerland, 2Novartis Healthcare Pvt. Ltd., Hyderabad, India, and 3Beijing Novartis Pharma Co. Ltd., Shanghai, China Objective: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). Methods: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. Results: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, –13%, and –16%; AUC by 5%, –13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. Conclusions: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI. Correspondence to: Kasra Shakeri-Nejad, MD
Director, Senior Translational Medicine Expert
Neuroscience Profiling
Novartis Institutes for Biomedical Research (NIBR) CHBS, WSJ-386.12.48.55
Novartis Pharma AG, Forum 1
Novartis Campus, 4056 Basel, Switzerland Email:[email protected]
Original
Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study
Anne Gardin, Angela Dodman, Sampath Kalluri, Srikanth Neelakantham, Xuemei Tan, Eric Legangneux, Kasra Shakeri-Nejad
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (54-65)
Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study
Anne Gardin1, Angela Dodman1, Sampath Kalluri2, Srikanth Neelakantham2, Xuemei Tan3, Eric Legangneux1, Kasra Shakeri-Nejad1
1Novartis Pharma AG, Basel, Switzerland, 2Novartis Healthcare Pvt. Ltd., Hyderabad, India, and 3Novartis Institutes for Bio Medical Research, Beijing, China Objective: To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected inactive metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). Methods: The study enrolled subjects with severe RI (n = 8) and matched HS (n = 8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥ 50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects vs. HS. All subjects received a single oral dose of siponimod 0.25 mg on day 1; PK and safety were evaluated during the follow-up (~ 13 days). Results: PK of siponimod was marginally affected in severe RI subjects vs. HS: Cmax decreased by 8%, and AUClast and AUCinf increased by 23% and 24%, respectively; half-life (37 vs. 26 hours) and systemic clearance (2.9 vs. 3.4 L/h) were comparable. Siponimod plasma unbound (u) fraction at 4 hours post-dose was similar between the two groups (range: 0.0172 – 0.0550%). Cmax(u) was comparable while AUClast(u) and AUCinf(u) were increased by 33% compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment (RI) compared with matched HS. No adverse events were reported during this study. Conclusions: Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further to severe RI, investigation of PK in subjects with mild and moderate RI was not warranted. Correspondence to: Anne Gardin, PhD
Institutes for BioMedical Research,
WSJ 386.12.48.7, 4002 Basel, Switzerland Email:[email protected]
Original
Elevated fractional exhaled nitric oxide (FeNO) is a clinical indicator of uncontrolled asthma in children receiving inhaled corticosteroids
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (66-77)
Elevated fractional exhaled nitric oxide (FeNO) is a clinical indicator of uncontrolled asthma in children receiving inhaled corticosteroids
Sha-Sha Yin, Hong Liu, Xing Gao
Department of Pediatric Medicine, Linyi People’s Hospital, Linyi, PR China Objective: Our study aims to explore the correlation between fractional exhaled nitric oxide (FeNO) and inhaled corticosteroids (ICS) efficacy in childhood bronchial asthma (BA). Methods: 247 pediatric BA patients were selected and divided into 3 treatment groups based on drug therapy: treatment group 1 (seretide, n = 86), treatment group 2 (budesonide, n = 79), and treatment group 3 (salbutamol, n = 82). Another 90 healthy children were recruited as control group. FeNO, FEV1%pred, FEV1/FVC, MEF25%, MEF50% and PEF%, total serum IgE, EOS%, induced sputum EOS% and supernatant inflammatory indexes (ECP, IL-8, and TNF-α) of sputum, ECP, IL-8 and TNF-α were detected. Results: Compared with pretreatment, 6 months posttreatment, FeNO, induced sputum EOS%, supernatant inflammatory indexes decreased (all p < 0.05), but pulmonary function indexes and childhood asthma control test (C-ACT) increased in treatment groups (all p < 0.05). FeNO, induced sputum EOS%, and supernatant inflammatory indexes in treatment group 1 were lower than those in treatment group 2 and 3 (all p < 0.05); total serum IgE and peripheral blood EOS% in treatment group 1 and 2 were lower but pulmonary function indexes were higher than those in treatment group 3 (all p < 0.05); according to Pearson correlation analysis, in both ICS and non-ICS groups, FeNO was positively correlated to ECP but negatively to C-ACT. Conclusion: ICS is effective in BA treatment, and FeNO associated with ICS efficacy is an indicator for BA intervention. FeNO combing with pulmonary function indexes had a predictive value in BA response.Correspondence to: Dr. Xing Gao
Department of Pediatric Medicine
Linyi People’s Hospital
No. 27, Jiefang Road, Lanshan District,
Linyi 276000, Shangdong, PR China Email:[email protected]
Original
N-terminal probrain natriuretic peptide in patients with acute coronary syndrome
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (78-84)
N-terminal probrain natriuretic peptide in patients with acute coronary syndrome
Qi Kang1, Zheng Wan1 and Zhenwen Huang2
1Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin and 2Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhenzhou, China Objective: To observe the changes and evaluate the significance of serum N-terminal probrain natriuretic peptide (NT-proBNP) levels in patients with acute coronary syndrome and to discuss its clinical significance and relationship with the severity of disease. Methods: Serum NT-proBNP levels were determined rapidly by using the triage BNP test for 98 consecutive patients with coronary heart disease (CAD) admitted to the hospital from March 2013 to December 2013; the correlation between the concentration of NT-proBNP and the degree of severity of the disease was analyzed. Results: The levels of NT-proBNP in the acute myocardial infarction (AMI) group were higher compared with unstable angina pectoris (UAP), stable angina pectoris (SAP), and control groups, and the levels of NT-proBNP in UAP were higher compared to the SAP and control groups. Levels of NT-proBNP in the extensive anterior wall infarction group were higher compared to that of the inferior or anteroseptal wall infarction groups: p < 0.05; the levels of NT-proBNP in the inferior wall and posterior wall infarction group were higher compared with the inferior wall infarction group and anteroseptal wall infarction group: p < 0.05; the levels of NT-proBNP in the multi-vessel group were higher than those in the single-vessel group: p < 0.05. The BNP level was positively correlated with age, heart rate, creatinine kinase-myocardial band (CK-MB), cardiac troponin T (cTnT), and blood urea nitrogen (BUN), whereas it was negatively correlated with left ventricular ejection fraction (LVEF). Conclusions: NT-proBNP is related to the lowering of left ventricular ejection fraction and the severity of myocardial ischemia. Correspondence to: Zheng Wan, MD
Department of Cardiology
General Hospital of Tianjin Medical University
Anshan Road, 300052 Tianjin, China Email:[email protected]
Short Report
Usefulness of thyroglobulin in cervical lymph node fine-needle aspirations at initial thyroidectomy for the diagnosis of metastases in papillary thyroid cancer
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 1/2017 (85-88)
Usefulness of thyroglobulin in cervical lymph node fine-needle aspirations at initial thyroidectomy for the diagnosis of metastases in papillary thyroid cancer
Jing Yu1, Yanpeng Song2, Zhibing Wang1
1Department of Diagnostic Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao and 2Department of Diagnostic Ultrasound, Jiaozhou Central Hospital, Qingdao, China Objective: To study the role of fine-needle aspiration biopsy and thyroglobulin measurement (FNAB-Tg) in diagnosing cervical lymph node (CLN) metastases in patients with papillary thyroid cancer (PTC) before thyroidectomy. Methods: Ultrasonography (US)-guided FNAB was performed on 92 patients with PTCs with 105 CLNs before surgery. The wash-out of the FNAB-Tg level was detected. Results: Based on the final pathology, 67 lymph nodes (LNs) were positive for metastasis, and 38 LNs were negative for metastasis. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FNAB-Tg in thyroidectomized patients was 100%, 86.8%, 95.2%, 97.3%, and 95.2%, respectively. Conclusions: FNAB-Tg is a useful technique for diagnosing CLN metastasis of PTC before thyroidectomy. Correspondence to: Dr. Zhirong Jiang
Department of Diagnostic Ultrasound
The Affiliated Hospital of Qingdao University
Qingdao, China Email:[email protected]
Case Report
Replacement of SFC-DPI with SFC-MDI exhaled through the nose improved eosinophilic chronic rhinosinusitis with bronchial asthma
Yoshiki Kobayashi, Mikiya Asako, Takahisa Yamamoto, Hirotaka Yasuba, Koichi Tomoda, and Akira Kanda
1Department of Otolaryngology, Kansai Medical University, Osaka, 2Department of Airway Medicine, Mitsubishi Kyoto Hospital, Kyoto, and 3Department of Mechanical Engineering, National Institute of Technology Gifu College, Gifu, Japan Objective: Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is a refractory disease closely associated with bronchial asthma. We recently reported on the efficacy of ultra-fine particle inhaled corticosteroids (ICS) (hydrofluoroalkane-134a-beclomethasone dipropionate: HFA-BDP) exhalation through the nose (ETN) treatment for mild-to-moderate asthmatics with ECRS. However, the effect of HFA-BDP ETN was found to be transient in some cases with severe ECRS and asthma, requiring treatment with higher-dose ICS and long-acting β2-agonists (LABA). Here, we present a case of refractory ECRS with severe asthma treated with a combination of high-dose ICS and LABA ETN, and we discuss the mechanisms for its effectiveness. Methods: A 57-year-old man was treated with the combined regimen of HFA-BDP ETN and salmeterol/fluticasone combination (SFC) dry powder inhaler (DPI) for his refractory ECRS with severe asthma. For better control, we replaced SFC-DPI with SFC metered-dose inhaler (MDI) ETN and evaluated the clinical effect and corticosteroid sensitivity. We also examined the flow and deposition of fine particles released by SFC-MDI ETN. Results: After switching to SFC-MDI ETN, the patient’s conditions markedly resolved with the restoration of corticosteroid sensitivity and PP2A activity. The fine particles released by SFC-MDI ETN at least partially flowed out through the external nares and seemed to be deposited on the ethmoid sinus. Conclusion: Fine particle ICS/LABA ETN might be an additional therapeutic option for refractory ECRS with severe asthma and corticosteroid insensitivity.
A full movie of the fine particles released by SFC-MDI ETN using the fine particle visualization system is shown in Video 1:
Correspondence to: Yoshiki Kobayashi, MD, PhD
Department of Otolaryngology
Kansai Medical University
2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japan Email:kobayosh@ hirakata.kmu.ac.jp
Bioavailability Section
Comparative pharmacokinetic and bioequivalence evaluation of two formulations of morniflumate 350-mg tablets in healthy male subjects
Heechan Lee, Sung-Vin Yim, Bo-Hyung Kim, SeungHwan Lee
1Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea Background: Morniflumate is a nonsteroid anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-1, 2 (COX-1, 2). Objective: This study aimed to compare the pharmacokinetics (PKs) and assess the bioequivalence of two different formulations of morniflumate 350-mg tablets in healthy Korean male subjects. Methods: A randomized, single-dose, two-period, two-sequence crossover study was conducted with 38 subjects. Subjects received a single dose of two tablets of either a test or a reference formulation and the alternated formulation in the next period. Serial blood samples for the PK analysis were collected over 12 hours. PK parameters were determined by a noncompartment analysis. PK parameters, including the maximum concentration (Cmax) and the area under-the-concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) were compared in bioequivalence tests. Results: The Cmax of the test and reference formulations were 985.72 ± 6.80 mg/L and 947.09 ± 6.73 mg/L, respectively, while the AUClast values were 2675.92 ± 7.84 mg×h/L and 2653.06 ± 7.78 mg×h/L, respectively. The geometric mean ratios (90% confidence interval) of the test formulation to the reference formulation for Cmax and AUClast were 1.0715 (0.9469 – 1.2124) and 1.0592 (0.9592 – 1.1695), respectively. Conclusions: The new formulation of morniflumate 350-mg tablet showed a PK profile similar to that of the marketed formulation, and the results of this study fell within in the conventional criteria of bioequivalence. Correspondence to: SeungHwan Lee, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University Hospital and College of Medicine
Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea Email:[email protected]
Bioavailability Section
Pharmacokinetic comparison of two formulations of talniflumate 370 mg tablets in healthy Korean volunteers
1Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University, College of Medicine and Hospital, 3Department of Clinical Pharmacology and Therapeutics, and 4East-West Medical Research Institute, Kyung Hee University College of Medicine and Hospital, Seoul, Korea Background: Talniflumate, a prodrug of niflumic acid, is a potent analgesic and anti-inflammatory drug that has been widely used for the treatment of rheumatoid diseases. Objective: The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two formulations of talniflumate 370 mg tablets (test formulation: Flumagen® 370 mg tablet; reference formulation: Somalgen® 370 mg tablet). Methods: A randomized, open-label, single dose, two-sequence, two-period crossover clinical study was conducted. After oral administration of the study drug in each period, blood samples were collected up to 15 hours post-dose. The plasma concentration of niflumic acid, a metabolite of talniflumate, was determined using HPLC-MS/MS. The pharmacokinetic parameters were estimated by non-compartmental method. Results: The maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the time point with the last measurable concentration (AUClast) for the test formulation were 290.7 ± 199 µg/L and 1,154 ± 643 µg×h/L, respectively, and the corresponding values for the reference formulation were 286.8 ± 193 µg/L and 1,151 ± 577 µg×h/L, respectively. The geometric mean ratio and 90% confidence intervals (CI) of the test formulation to the reference formulation for the Cmax and AUClast were 0.983 (0.829 – 1.166) and 0.979 (0.856 – 1.121), respectively. Conclusions: The pharmacokinetic profiles of the test and reference formulations were found not to be significantly different, meeting the Korean regulatory criteria for bioequivalence. Correspondence to: SeungHwan Lee, MD, PhD
Department of Clinical Pharmacology and Therapeutics
Seoul National University
College of Medicine and Hospital
Daehak-ro, Jongno-gu, Seoul, 03080, Korea Email:[email protected]
The Int. Journal of Clinical Pharmacology and Therapeutics articles should be submitted as email attachment to [email protected].
Enzyme replacement therapy for Fabry disease, an inherited nephropathy
R.J. Desnick, M. Banikazemi and M. Wasserstein
Volume 57 (2002) p. 1 - 8
Abstract
R.J. Desnick, M. Banikazemi and M. Wasserstein
Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York, NY, USA Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme a-galactosidase A (a-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified “renal variants” who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, “cardiac variants” who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant a-Gal A replacement for this inherited nephropathy.
Originals
Early progressive interstitial fibrosis in human renal allografts
H. Abo-Zenah, S. Katsoudas, D. de Takats, J. Shortland, G. Wild, C.B. Brown and A.M. El Nahas
Volume 57 (2002) p. 9 - 18
Abstract
H. Abo-Zenah, S. Katsoudas, D. de Takats, J. Shortland, G. Wild, C.B. Brown and A.M. El Nahas
1Sheffield Kidney Institute, 2Histopathology,
and 3Immunology Departments, Northern General Hospital Trust, Sheffield, UK Background: Early fibrosis has been described in renal allografts and implicated in the progression of chronic allograft nephropathy (CAN). The precise factors implicated in the initiation and progression of early allograft fibrosis remain uncertain. Patients and methods: We studied retrospectively 23 cadaveric renal allograft recipients over a 3-year period, who had paired renal biopsies (Bx) (at implantation and as clinically indicated) within 3 months of transplantation (Tx). Eight of them have progressed over an average period of 3.16 ± 0.83 years to CAN. Histological evaluation of interstitial fibrosis (IF) relied on point count analysis of Masson’s trichrome (MT) staining as well as immunostainable collagens III (iCol III) and IV (iCol IV). The severity of the IF scores was correlated with the clinical, biochemical and histological parameters. The nature and severity of the interstitial inflammatory infiltrate were also evaluated by immunofluorescence. In addition, patients were subdivided into those whose fibrosis progressed (> 50% increase in IF/iCol III; Group 1) and non-progressors (< 50% increase in fibrosis score; Group 2) in an attempt to determine discriminatory features. Results: In the whole group, there was a significant increase in the IF score, as estimated by MT staining and iCol III, from implantation to follow-up Bx (p = 0.0027 and p = 0.0088, respectively). The changes in iCol IV were not significant. Further, the increase in interstitial inflammatory infiltrate of total T lymphocytes, and not of macrophages, from implantation (modal category = 2) to follow-up (modal category = 0) was significant (p = 0.0121). The predictive value of such increase was significant (R2 = 0.617, p = 0.03). The donor’s age (R2 = 0.892, p = < 0.0001), death from cerebrovascular accident (CVA) (R2 = 0.822, p = 0.047), as well as recipient’s body weight (R2 = 0.892, p = 0.001), male gender (R2 = 0.687, p = 0.041) and elevated mean arterial pressure (MAP) (R2 = 0.892, p = < 0.0001) were all significant risk factors for early IF. Delayed graft function (DGF) proved to be a significant predictor of early IF (R2 = 0.822, p = 0.003) and became more significant in the presence of superimposed acute rejection (AR) (p = 0.0001). Proteinuria > 1 g/day (R2 = 0.882, p = 0.004) and hypertriglyceridemia > 2.25 mmol/l (R2 = 0.808, p = < 0.0001) were also associated with early IF. Of the implantation histological parameters, iCol III proved to be a highly significant predictor of early IF (R2 = 0.892, p = < 0.0001). Interestingly, the predictive value of iCol III for graft survival in terms of CAN was significant (Cox p = 0.088). Group 1 progressor patients (n = 10) were all males (p = 0.038) and received their kidneys from donors who died from CVAs in 90% of cases (p = 0.011). They had, compared to non-progressors, a lower cyclosporin A level (p = 0.047), a higher incidence of AR episodes (80% versus 54%), a higher serum creatinine at 10 days post-Tx (p = 0.005), a higher proteinuria (2.07 ± 3.89 g/l vs 0.96 ± 0.97 g/l, p = 0.041) and a higher serum triglyceride (2.48 ± 1.37 mmol/l vs 1.69 ± 0.81 mmol/l, p = 0.039) level. 8% of Group 1 patients had DGF compared to 30% in Group 2 (p = 0.023). Of note, the modal category of cytotoxic: helper T lymphocytes ratio was greater than 1 in Group 1 (2 : 1) patients and not in Group 2 (1 : 1). Conclusion: Implantation histology, and in particular iCol III, is a predictor of early IF in a subgroup of patients with DGF and AR. Additional risk factors include hypertension, proteinuria and hypertriglyceridemia especially in patients receiving kidneys from older donors who died of CVAs.
Originals
Type 2 angiotensin II receptor expression in human renal allografts: an association with chronic allograft nephropathy
B.N. Becker, L.M. Jacobson, D.A. Hullett, N.A. Radke, T.D. Oberley, P.C. Brazy and A.D. Kirk
Volume 57 (2002) p. 19 - 26
Abstract
B.N. Becker, L.M. Jacobson, D.A. Hullett, N.A. Radke, T.D. Oberley, P.C. Brazy and A.D. Kirk
1Department of Medicine, Division of Nephrology, 2Department of Surgery, Division of Transplantation, 3Department of Pathology and Laboratory Medicine, University of Wisconsin, Department of Veterans Affairs Hospital, Madison, WI, and 4NIDDK-Navy Transplantation and Autoimmunity Branch, National Naval Medical Center, Bethesda, MD, USA Aims: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type 1 angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. Materials and methods: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA, matrix-modulating genes and histologic evidence of chronic rejection were assessed. Results: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (rs) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-b (TGF-b) (rs 0.59; p = 0.044), matrix metalloproteinase-1 (MMP-1) (rs 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (rs 0.74; p = 0.001) and TIMP-3 (rs 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). Conclusions: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.
Originals
HLA matching for simultaneous pancreas- kidney transplantation in the United States: a multivariable analysis of the UNOS data
M.J. Mancini, A.F. Connors Jr., X.-Q. Wang, S. Nock, C. Spencer, C. McCullough, P. Lobo and R. Isaacs
Volume 57 (2002) p. 27 - 37
Abstract
M.J. Mancini, A.F. Connors Jr., X.-Q. Wang, S. Nock, C. Spencer, C. McCullough, P. Lobo and R. Isaacs
Departments of 1Medicine, 2Surgery, 3Sociology and 4Health Evaluation Sciences, The University of Virginia Health System, Charlottesville, Virginia, USA Background: As the incidence of diabetic nephropathy increases, especially in minority populations, more simultaneous pancreas-kidney (SPK) transplants are being performed both in the United States and worldwide. The role of matching on SPK outcomes and organ allocation remains controversial. The purpose of this analysis was to determine the influence of HLA matching using currently employed criteria on 5-year SPK graft survival. Methods: We performed an analysis of all 3,316 SPK transplants performed in the United States reported to the United Network for Organ Sharing (UNOS) between December 31, 1988 and December 31, 1994. Kaplan-Meier unadjusted 1- and 5-year graft survival with log rank comparisons and Cox multivariable regression models that adjusted for 12 confounding variables were used to analyze the influence of HLA matching on outcomes. Results: Despite low-grade HLA or DR matching or high levels of common reactive groups (CREG) mismatching, 1- and 5-year allograft survival rates were 90% and 78% for kidney, and 85% and 75% for pancreas transplantation. Conclusions: SPK transplantation is associated with excellent outcomes independent of the level of HLA matching. These data support the hypothesis that SPK transplants need not be allocated based on matching criteria, thus minimizing organ ischemia time and promoting a more racially equitable allocation for SPKs in the US today.
Originals
Biocompatible membranes do not promote graft recovery following cadaveric renal transplantation
Y.M. Woo, A.-M. Craig, B.B. King, B.J.R. Junor, M.A. McMillan, J.D. Briggs and R.S.C. Rodger
Volume 57 (2002) p. 38 - 44
Abstract
Y.M. Woo, A.-M. Craig, B.B. King, B.J.R. Junor, M.A. McMillan, J.D. Briggs and R.S.C. Rodger
1Renal Unit, Western Infirmary, Glasgow, Scotland, and 2Renal Unit, Nelson Hospital, Nelson, New Zealand Background: Controversy surrounds the role of biocompatible membrane dialyzers in treatment of acute renal failure. Studies that have shown a benefit have involved critically ill patients where renal recovery and patient mortality are influenced by other comorbid disease. The aim of the present work is to clarify this issue in a more homogeneous population of patients with acute renal failure following cadaveric renal transplantation. Methods: All patients with delayed graft function between January 1996 and February 1998 were randomized to receive either a biocompatible (BCM, polysulfone) membrane or bioincompatible (BICM, cuprophane) membrane for dialysis until onset of graft function. Results: Forty-one patients were randomized, 23 to receive BCM and 18 BICM. Five patients (2 BCM, 3 BICM; p = NS) with primary non-function of graft were excluded from analysis, leaving 36 cases of acute tubular necrosis (ATN). Patient and donor characteristics were similar in both groups. The BCM group had significantly longer periods of dialysis dependency compared to the BICM group (14 vs 10 days; p = 0.03). There was a tendency towards higher serum creatinine levels in the short term in the BCM group (318 vs 164 mmol/l at 1 month (p = 0.1), 190 vs 169 mmol/l at latest visit (p = 0.07)) and a greater number of acute rejection episodes in the BCM group (3.7 vs 1.7 episodes per 100 days of dialysis dependency, p = 0.1). With an intention-to-treat analysis of all 41 patients originally randomized, there was no significant difference in time to graft recovery between the 2 groups (p = 0.18). Conclusions: In the setting of ARF post-transplantation, we have found no evidence to support the use of biocompatible membranes for dialysis. Rather, our study provides argument against a large benefit for the use of BCM in the recovery of ARF, as suggested by earlier studies.
Originals
Resistive index in chronic nephropathies: predictive value of renal outcome
G. Splendiani, C. Parolini, L. Fortunato, A. Sturniolo and S. Costanzi
Volume 57 (2002) p. 45 - 50
Abstract
G. Splendiani, C. Parolini, L. Fortunato, A. Sturniolo and S. Costanzi
Department of Nephrology, Tor Vergata University of Rome, Italy The study of renovascular resistances by color Doppler ultrasound has become a useful diagnostic resource for nephrologists. In recent nephrological literature, many papers deal with the correlations between resistive index, anatomo-pathological patterns and renal function. Aims: In our study, we have tried to discover if resistive index represents a prognostic index of progressive renal failure. Material and methods: To this purpose we compared renal resistive index and blood creatinine obtained from 28 nephropathic patients at their first control, with blood creatinine values after a 3-year follow-up period. Using a linear regression test, we found a strong correlation between the initial value of resistive index and the value of creatinine variation (p = 0.006). Results: All of the patients with normal resistive index at the beginning maintained a stable renal function. Conversely, the patients with high resistive index at their first control showed a progressive renal failure. Conclusion: Our study shows the reliability of resistive index in the prognostic evaluation of renal outcome.
Originals
Racial differences in parathyroid hormone levels in patients with secondary hyperparathyroidism
B.P. Sawaya, M.-C. Monier-Faugere, P.Ratanapanichkich, R. Butros, P.J. Wedlund and P.Fanti
Volume 57 (2002) p. 51 - 55
Abstract
B.P. Sawaya, M.-C. Monier-Faugere, P.Ratanapanichkich, R. Butros, P.J. Wedlund and P.Fanti
1Division of Nephrology, Bone and Mineral Metabolism and 2College of Pharmacy, University of Kentucky, Lexington, KY, USA Aim: African-Americans (AA) with normal renal function have higher parathyroid hormone (PTH) levels than Caucasians (C). This difference was also noted in cross-sectional studies of patients on dialysis. In this study, we evaluated patients with end-stage renal disease who have just began dialysis and who were not receiving any vitamin D therapy. Methods: A total of 363 patients were recruited (C: 260; AA: 103). All patients had serum calcium, phosphorus, alkaline phosphatase and intact PTH (iPTH) levels measured within 3 months of initiating dialysis. Results: Serum PTH levels were significantly higher in AA vs. C (383 ± 33 vs. 246 ± 19, p < 0.001). This difference was present despite similar calcium, phosphorus and alkaline phosphatase levels between the 2 groups and regardless of gender or diabetes status. However, PTH levels in patients younger than 47 years of age were similar in both groups. Conclusion: PTH levels in ESRD patients over 47 years of age are higher in AA compared to C. The difference is, in part, due to an age-dependent reduction in PTH seen only in C. Further studies are needed to understand the mechanisms of these racial differences and to verify whether they mirror similar alterations at the level of the end-organ tissue.
Originals
The usefulness of F-18 deoxyglucose wholebody positron emission tomography (PET) for re-staging of renal cell cancer
A. Safaei, R. Figlin, C.K. Hoh, D.H. Silverman, M. Seltzer, M.E. Phelps and J. Czernin
Volume 57 (2002) p. 56 - 62
Abstract
A. Safaei, R. Figlin, C.K. Hoh, D.H. Silverman, M. Seltzer, M.E. Phelps and J. Czernin
1Ahmanson Biological Imaging Clinic/Nuclear Medicine, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, 2Department of Medicine, UCLA School of Medicine, Los Angeles, CA, 3Department of Nuclear Medicine, UCSD School of Medicine, San Diego, CA, USA Purpose: The use of whole-body PET for re-staging of renal cell carcinoma has not been investigated. The aim of the current study was to examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer. Patients and methods: Clinical PET was performed for re-staging in 36 patients with advanced renal cell cancer. Written reports of imaging studies (including CT, MRI, US, plain film and bone scan), patient history, and extensive chart notes were used to define the clinical stage before PET (pre-PET stage). The written PET report was used to define the clinical stage after PET (PET stage). Reports were used to determine the accuracy of PET for re-staging renal cell cancer and for defining biopsy proven lesions. Clinical parameters and biopsy proven lesions served as reference for the accuracy of PET for re-staging renal cell cancer. Results: PET classified the clinical stage correctly in 32/36 patients (89%) and was incorrect in 4/36 (11%) (sensitivity and specificity: 87% and 100%). In 20 patients, 25 suspicious lesions were biopsied within 3.2 ± 6.7 months of the PET study. Of these, 17 were malignant and 8 were benign. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%). Conclusion: PET re-stages renal cell cancer with a diagnostic accuracy of 89%. Its diagnostic accuracy for classifying biopsy proven anatomic lesions as malignant or benign was 84%. These findings suggest that PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer.
Case reports
Nephrotic IgA nephropathy<br /> associated with disseminated tuberculosis
N. Matsuzawa, K. Nakabayashi, T. Nagasawa and Y. Nakamoto
Volume 57 (2002) p. 63 - 68
Abstract
N. Matsuzawa, K. Nakabayashi, T. Nagasawa and Y. Nakamoto
1First Department of Internal Medicine, Kyorin University School of Medicine, and 2Department of Internal Medicine, Kichijyouji Asahi Hospital, Tokyo, Japan A 35-year-old woman who had been suffering from ascites more than 3 months after the delivery of her first baby, developed generalized edema, pyrexia, pleural effusion, and right lower abdominal pain. The laboratory data revealed 5.6 g of 24-hour urinary protein, increased ESR and CRP, a positive skin test for tuberculosis, and a positive culture for tuberculous bacilli from pleural effusion. A renal biopsy showed mild proliferative glomerulonephritis, IgA and C3 depositions along the capillary loop, in the mesangium and also in the focal tubular basement membrane, and scattered membranolysis of the glomerular basement membrane in addition to paramesangial and intramembranous electron-dense deposits. A positive culture of tuberculous bacilli led anti-tuberculous drugs resulted in the complete disappearance of proteinuria, inflammation, and various organ manifestations. As far as we know, the association of tuberculosis with glomerulonephritis is an uncommon occurrence. In addition to describing this case, we also discussed the role of tuberculosis in the pathogenesis of glomerulonephritis, and reviewed the pertinent literature.
Case reports
Association of parvovirus B19 infection with acute glomerulonephritis in healthy adults: case report and review of the literature
Y. Mori, H. Yamashita, Y. Umeda,Y.U. Uchiyama-Tanaka, A. Nose,N. Kishimoto, Y. Kijima, T. Nagata,M. Mori, H. Matsubara, H. Yoshida and T. Iwasaka
Volume 57 (2002) p. 69 - 73
Abstract
Y. Mori, H. Yamashita, Y. Umeda,Y.U. Uchiyama-Tanaka, A. Nose,N. Kishimoto, Y. Kijima, T. Nagata,M. Mori, H. Matsubara, H. Yoshida and T. Iwasaka
1Department of Medicine II, Kansai Medical University, Osaka, and 2Department of Clinical Laboratory Medicine, Fukui Medical University,
Fukui, Japan An otherwise healthy 20-year-old woman presented with an erythematous rash on her face as well as arthralgia and anemia. She also had systemic edema, proteinuria and hypertension. Laboratory data on admission showed hypocomplementemia, human parvovirus B19 (HPV) DNA and both immunoglobulin (Ig) M and IgG antibodies to HPV in her serum. Renal biopsy specimens showed features of endocapillary glomerulonephritis under light microscopy. Electron microscopy showed massive subendothelial electron-dense deposits. No cause was probable other than immune complex-mediated glomerulonephritis associated with HPV infection. In a review of this and similar cases reported in the literature, several characteristic features come to light: female dominance, onset in the second or third decade of life, hypocomplementemia, histologic renal endocapillary and/or mesangioproliferative glomerulonephritis with subendothelial deposits and spontaneous recovery.
Case reports
A unique renal lesion in common variable immunodeficiency: a case report
C. Stigant, D. Sapir, J. Sweet, G.Downey and J. Bargman
Volume 57 (2002) p. 74 - 79
Abstract
C. Stigant, D. Sapir, J. Sweet, G.Downey and J. Bargman
1Nephrology Fellow, University of Toronto, 2Staff Pathologist,
Toronto General Hospital, 3Faculty of Medicine, University of Toronto, Division of Nephrology, Toronto General Hospital, University Health Network, Toronto This article reports the case of a 33-year-old woman with common variable immunodeficiency (CVI) who developed renal failure 17 years after diagnosis and initiation of treatment with monthly IVIG. A renal biopsy revealed mesangial and paramesangial immune complex deposition and interstitial granulomatous infiltration. Renal function improved with oral corticosteroids, but did not return to normal. Decreasing the dose of IVIG had no effect on renal function. Immune dysfunction can be associated with both granulomatous disease and immune complex glomerulonephritis, or the latter may be related to chronic infection or immunoglobulin use. This is the first report of concomitant glomerular-tubulointerstitial lesions in this immunodeficiency syndrome. Renal function should be closely followed in patients with CVI.
Case reports
Carcinoid tumor and membranous glomerulonephritis: coincidence or malignancy-associated glomerulonephritis?
C. Luyckx, B. Van Damme,Y. Vanrenterghem and B. Maes
Volume 57 (2002) p. 80 - 84
Abstract
C. Luyckx, B. Van Damme,Y. Vanrenterghem and B. Maes
1Department of Nephrology, and 2Department of Pathology, University Hospital Gasthuisberg, Leuven, Belgium Membranous glomerulonephritis is known to be associated with malignancies. A 43-year-old man with a history of chronic renal insufficiency secondary to 20-year-old membranous glomerulonephritis was operated on for an infrarenal aneurysm. During surgical intervention, multiple nodular liver lesions were detected. Histologic examination of these lesions showed metastases of a carcinoid tumor. Despite extensive examination, the primary tumor site could not be detected. The patient remained asymptomatic 3 years postoperatively without any treatment for carcinoid tumor. This clinical report is the second case of a membranous glomerulonephritis associated with a carcinoid tumor. Whether the association is merely a coincidence or a real malignancy-related glomerulopathy remains unclear. Because survival of 23 years after the onset of symptoms of carcinoid tumor has occurred, it is possible that our patient already had an asymptomatic carcinoid tumor at the time the diagnosis of membranous glomerulonephritis was made. Comparison with other paraneoplastic glomerulonephritis as well as diagnosis of a carcinoid tumor in renal insufficiency are discussed.
Case reports
Severe hyponatremia as the presenting feature of clinically non-functional pituitary adenoma with hypopituitarism
S.-H. Lin, Y.-H. Hung and Y.-F. Lin
Volume 57 (2002) p. 85 - 88
Abstract
S.-H. Lin, Y.-H. Hung and Y.-F. Lin
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C. Hyponatremia can result from a wide range of causes. While hyponatremia is known to occur in patients with hypopituitarism, severe hyponatremia occurring as the presenting feature of hypopituitarism is very rare. We present two cases in which severe hyponatremia developed with weakness, light-headedness and seizure. The hyponatremia in these 2 cases mimicked the laboratory diagnostic criteria of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, the hormone studies displayed hypopituitarism. Hyponatremia was completely corrected after administering a supplement of prednisolone and L-thyroxine. Computerized tomography of the brain revealed an adenoma of the pituitary gland. These two cases illustrate that severe hyponatremia may be the presenting feature of clinically non-functional pituitary adenoma with hypopituitarism, which should be kept in mind in the differential diagnosis of hyponatremia mimicking SIADH.
Letters to the Editor
Hypokalemic rhabdomyolysis aggravated by diuretics complicating Conn?s syndrome without acute renal failure
B.
Volume 57 (2002) p. 89 - 91
Abstract
B.
Letters to the Editor
Biological evolution of renal osteodystrophy after decreasing dialysate calcium from 1.75 to 1.6 mmol/l
G. Jean, C. Chazot and B. Charra
Volume 57 (2002) p. 91 - 92
Abstract
G. Jean, C. Chazot and B. Charra
Letters to the Editor
Spurious hyperchloremia and cerebellar ataxia: clue to suggest chronic bromvalerylurea intoxication
C.-F. Su, C.-C. Wu, J.-C Yeh and S-H Lin
Volume 57 (2002) p. 93 - 94
Abstract
C.-F. Su, C.-C. Wu, J.-C Yeh and S-H Lin
Review
Lupus nephritis: a clinical review for practicing nephrologists
G. Contreras, D. Roth, V. Pardo, L.G. Striker and D.R. Schultz
Volume 57 (2002) p. 95 - 107
Abstract
G. Contreras, D. Roth, V. Pardo, L.G. Striker and D.R. Schultz
1Dialysis Unit VAMC, 2Division of Nephrology, 3Electron Microscopy VAMC, 4Renal Cell Biology Laboratory and 5Division of Rheumatology and Immunology, Veterans Affairs Medical Center and University of Miami School of Medicine, Miami, FL, USA The renal manifestations in systemic lupus erythematosus (SLE) are protean and difficult to categorize into clinical syndromes and histologic classes. Lupus nephritis is frequently unrecognized until full-blown nephritic and/or nephrotic syndrome with renal failure emerge. Epidemiologically, approximately one third of SLE patients from unselected populations have renal involvement early during the disease. Most renal abnormalities emerge within the first few years of SLE diagnosis. Currently, most nephrologists agree that an early renal biopsy is worthwhile in those SLE patients with abnormal urinalysis and/or reduced renal function. First, it provides a histologic categorization of the glomerulonephritis as well as an assessment of the degree of activity and chronicity. Second, it provides vital prognostic information. Third, it is beneficial in planning a more rational therapy with or without potentially toxic immunosuppressive agents. Over the last 3 decades, many controlled clinical trials for treatment of lupus nephritis have been completed with a few therapeutic immunosuppressive regimens. Among those agents used, cyclophosphamide and azathioprine provide a reduction of morbidity in those patients afflicted with proliferative forms of lupus glomerulonephritis. A new immunosuppressive agent, mycophenolate mofetil, is being studied for treatment of proliferative forms of lupus glomerulonephritis in a controlled clinical trial at our institution. Immunosuppressive agents and the availability of dialysis and transplantation have improved the survival of patients with lupus nephritis, in particular those with proliferative forms.
Originals
Comparative effects of plasmapheresis and intravenous cyclophosphamide on urinary podocyte excretion in patients with proliferative Lupus nephritis
T. Nakamura, C. Ushiyama, M. Hara, S. Osada, K. Ugai, N. Shimada, K. Hayashi, I. Ebihara and H. Koide
Volume 57 (2002) p. 108 - 113
Abstract
T. Nakamura, C. Ushiyama, M. Hara, S. Osada, K. Ugai, N. Shimada, K. Hayashi, I. Ebihara and H. Koide
1Department of Medicine, Misato Junshin Hospital, Saitama, 2Department of Pediatrics, Yoshida Hospital, Niigata, 3Department of Medicine, National Rehabilitation Center, Saitama, 4Housei Kidney Clinic, and 5Department of Medicine, Koto Hospital, Tokyo, Japan Intravenous cyclophosphamide (IVC) in combination with steroids is standard therapy for Lupus nephritis. Reduction of autoantibodies and circulating immune complexes can be used in the treatment of autoimmune diseases. The aim of the present study was to compare the effects of IVC pulse therapy and double-filtration plasmapheresis (DFPP) on proteinuria and urinary excretion of podocytes in adult patients with diffuse proliferative Lupus nephritis (DPLN). Twenty patients were
randomly assigned to two groups. Group A (n = 10) was treated with IVC (0.75 – 1.0
g/m2 body surface area) pulse therapy, given as boluses once a month for 6
consecutive months, combined with oral corticosteroid (up to 1 mg/kg/day) administration.Group B (n = 10) was treated with a combination of DFPP (performed 1 – 2 times weekly) and corticosteroid (up to 1 mg/kg/ day). The total average number of treatments was 8.4 and the therapeutic efficacies were evaluated after 6 months. Twenty healthy individuals participated as a control group. Urinary podocytes were examined by immunofluorescence with monoclonal antibodies against podocalyxin. Both Group A and Group B reduced proteinuria (p < 0.001) as well as the number of urinary podocytes (p <0.001). Differences between the 2 treatment outcomes were not statistically significant.
Cyclophosphamide pulse therapy and DFPP may be similarly effective in the treatment of podocyte injury in patients with DPLN.
Originals
Lupus nephritis: a retrospective review of 78 cases from a single center
L. Martins, G. Rocha, A. Rodrigues, J. Santos, C. Vasconcelos, J. Correia, F. Farinha, I. Almeida, P. Barbosa and S. Guimarães
Volume 57 (2002) p. 114 - 119
Abstract
L. Martins1, G. Rocha1, A. Rodrigues1, J. Santos1, C. Vasconcelos2, J. Correia2, F. Farinha2, I. Almeida2, P. Barbosa2 and S. Guimarães1
1Nephrology and 2Medicine Department, Hospital de Santo António, Porto, Portugal Lupus nephritis (LN) is a frequent and serious manifestation of systemic lupus erythematosus. However, the outcome has
progressively improved in the last 3 decades and this was due to more efficient and early
treatment of LN and comorbid situations. The aim of our study was to analyze our
experience and outcome in LN, to evaluate clinicopathologic and clinicolaboratory
correlations and to search for risk factors for renal and patient survival. Patients and methods: We conducted a retrospective study of 78 patients with biopsy-proven LN. Results:Acute renal failure and subnephrotic proteinuria with microhematuria occurred each one in 39.7% of the patients, nephrotic syndrome in 16.7% and nephritic syndrome in 3.8%. The mean serum creatinine at presentation was 1.45 ± 1.03 mg/dl and the creatinine clearance was 68.2 ± 40.3 ml/min. Class IV LN existed in 71.8%, Class III in 20.5%, Class V in 6.4% and Class VI in 1.3%. The treatment included steroids and cytotoxic agents in 87.5% of the patients with proliferative LN. Hypertension, serum creatinine and acute renal failure at
presentation, as well as significant chronicity on renal biopsy, were significantly correlated with the progression to chronic renal failure in our population. Males were more prone to develop renal flares. 3.8% of the patients died, 9% lost their renal function, 26.9% are in remission, 33.3% still have subnephrotic proteinuria and microhematuria, 7.7% have nephrotic syndrome and 19.2% have chronic renal failure. The mean global follow-up was 102 ± 74 months and 96.2% of the patients survived. The actuarial renal survival was 96.1% in the first year; 89.9% at 5 years; and 83.7% at 10 and 20 years. Conclusion: We can say that hypertension, serum creatinine and acute
renal failure at the onset and significant chronicity on renal biopsy, proved to be risk
factors for chronic renal failure in our study population. Male gender was a risk factor
for renal flares. The achieved global outcome can be considered a good result.
Originals
Minimal change disease in systemic lupus erythematosus
G.K. Dube, G.S. Markowitz, J. Radhakrishnan, G.B. Appel and V.D. D’Agati
Volume 57 (2002) p. 120 - 126
Abstract
G.K. Dube1, G.S. Markowitz1, J. Radhakrishnan2, G.B. Appel2 and V.D. D’Agati1
1Department of Pathology and 2Department of Medicine, Columbia University, New York Presbyterian Hospital, New York, NY, USA We report the clinical and pathologic findings in 7 patients with systemic lupus erythematosus and minimal change disease. All 7 patients presented with full nephrotic syndrome including peripheral edema, nephrotic range proteinuria (mean 9.6 g/day), and hypoalbuminemia (mean 1.8 g/dl). In all cases, renal biopsy revealed diffuse foot process effacement in the absence of significant peripheral capillary wall immune deposits, findings consistent with minimal-change disease. In addition, 5 cases displayed mesangial electron-dense deposits, with or without associated mesangial proliferation, consistent with underlying lupus nephritis class II. In all cases, steroid therapy induced a rapid remission of nephrotic syndrome. Minimal change disease is an underrecognized and readily reversible form of nephrotic syndrome in systemic lupus erythematosus. Because it may occur superimposed on mild mesangial proliferative lupus nephritis, this entity may be misinterpreted as an atypical presentation of lupus nephritis class II. Proper recognition of this entity requires careful integration of the renal biopsy immunofluorescence and electron microscopic findings.
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