Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P<0.01). Liver dysfunction (n=5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (<10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view. Received: 2 May 1997 / Accepted: 13 October 1997     

Therapeutic Potential of Monteplase in Acute Myocardial Infarction

Thrombolysis with conventional thrombolytic agents prior to percutaneous coronary intervention (PCI) has had no impact on the treatment of acute myocardial infarction (AMI). However, the development of mutant tissue type plasminogen activators (mt-PA) has prompted us to reassess the combination of thrombolysis and PCI. Monteplase is a newly developed mt-PA that can be administered as a single intravenous bolus injection. The results of the COMA (COmbining Monteplase with Angioplasty) trial, suggest that monteplase administration prior to emergent PCI in AMI improves 6-month outcomes and possibly the long-term prognosis of myocardial infarction. Combining monteplase administration on presentation at a community hospital with prompt transfer to a tertiary center for PCI would be an ideal strategy for the treatment of AMI.     

Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion

Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 microg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of beta-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing beta-cell volume, primarily through accelerated neogenesis from ductal lining cells.     

Bone fracture receiving LH-RH agonists for prostatic cancer

BACKGROUND: Luteinizing hormone-releasing hormone (LHRH) agonists are popularly used drugs in the treatment of prostatic cancer. However, it has been reported that continuation of a low testosterone level following a longterm administration of these drugs reduces the bone mineral density and makes for osteoporosis, which is accountable for fracture, we measured the bone mineral density and bone metabolic markers in the cases who suffered fracture receiving LHRH agonists for prostatic cancer. PATIENTS AND METHODS: Between 1994 and 1998, 196 patients (mean age 78.1 years) were treated with LHRH agonists for prostatic cancer. Of these patients, 13(7%) who had bone fracture during treated with LHRH agonists were divided into fracture group, and 70 patients who had not bone fracture divided into non-fracture group. Fracture by traffic accident was excluded. The bone density in the third lumbar vertebra was measured using quantitative computed tomography (QCT). Osteocalcin, 1, 25- (OH)2 vitamin D, urinary type 1 collagen cross-linked N-telopeptides (NTx), parathyroid hormone (PTH) and calcitonin were measured as bone metabolic markers. RESULTS: The mean age of fractured cases was 78 years. The period from the start of treatment to fracture was 11 to 45 months (mean 27 months). No case of fracture at the site of metastasis of prostatic cancer was found. The bone density was significantly low in the fracture group compared with that of non-fracture group. Of the bone metabolic markers, NTx showed high values in the fracture group. CONCLUSION: There is a need to measure bone mineral density and bone metabolic markers periodically and to evaluate secondary osteoporosis in the patients receiving LHRH agonists for prostatic cancer.     

Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure.

AIMS: To evaluate the prognostic predictive values of cytochrome c, cytokines, and other laboratory measurements in serum collected during neurological onset in acute encephalopathy with multiple organ failure. METHODS: In addition to general laboratory examinations, the concentrations of cytochrome c (apoptosis marker) and cytokines (inflammatory markers) were measured in serum samples collected at the initial phase in 29 patients with acute encephalopathy. The obtained values were evaluated as predictors for the development of severe encephalopathy. RESULTS: Cytochrome c, tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble TNF-receptor 1 (sTNF-R1), and aspartate aminotransferase (AST) concentrations at the initial phase were high and correlated well with patient outcome. High concentrations of serum cytochrome c (>45 ng/ml), sTNF-R1 (>2000 pg/ml), AST (>58 IU/dl), IL-6 (>60 pg/ml), and TNF-alpha (>15 pg/ml) predicted an unfavourable prognosis (sequelae and death) at 93%, 79%, 82%, 77%, and 60%, respectively. The specificity of those markers was 100%, 89%, 83%, 100%, and 100%, respectively. CONCLUSIONS: Serum cytochrome c is the most sensitive and specific predictor for the development of severe encephalopathy at the initial phase. Results suggest that this marker might be used to guide decisions regarding the start of the initial treatment and further intensive care.     

Alteration of regional cerebral blood flow to thyrotropin-releasing hormone therapy in acute encephalitis and encephalopathy during childhood.

BACKGROUND: Thyrotropin-releasing hormone (TRH) is now used as a therapeutic agent for various neurological disorders. Animal study has shown that TRH was attributable to increased cerebral blood flow (CBF). AIMS: There have been occasional reports that TRH therapy was effective for improving symptoms of persistent disturbance of consciousness after acute encephalitis or encephalopathy during childhood. To determine whether TRH has an effect on increasing CBF to patients who have consciousness disturbance caused by acute encephalitis or encephalopathy, and to determine the optimal method of administration. METHODS: Sixteen patients aged 0.7-10.9 years (mean age, 3.2+/-3.1 years) who presented with persistent disturbance of consciousness resulting from acute encephalitis or encephalopathy and were treated with TRH. Regional CBF (rCBF) was measured by single photon emission computed tomography before and after TRH therapy. The alteration rates of rCBF were compared between the divided two groups concerning the dose levels, dosing periods, and treatment lags. RESULTS: The alteration rates of rCBF of the high dose group were higher than those of the low dose group. Differences in the dosing periods and treatment lags did not cause any significant difference of the alteration rates of rCBF. CONCLUSION: The study showed that higher alteration rates of the CBF were observed in the higher dosing group, and TRH have the potency of increasing CBF. TRH therapy would have the potential for effective treatment of persistent consciousness disturbance caused by childhood acute encephalitis or encephalopathy.     

Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.

We investigated influx and efflux transporters involved in blood-brain barrier transport of the nonsedative H1-antagonist epinastine. The basal-to-apical transport of [14C]epinastine was markedly higher than that in the opposite direction in LLC-GA5-COL150 cells stably transfected with human multidrug resistance (MDR)1 gene. The brain-to-plasma concentration ratio of [14C]epinastine in mdr1a/b(-/-) mice was 3.2 times higher than that in wild-type mice. The uptake of both [3H]mepyramine and [14C]epinastine into immortalized rat brain capillary endothelial cells (RBEC)1 showed temperature and concentration dependence. The kinetic parameters, K(m), V(max), and uptake clearance (V(max)/K(m)), of the initial uptake of [3H]mepyramine and [14C]epinastine by RBEC1 were 150 microM, 41.8 nmol/min/mg protein, and 279 microl/min/mg protein for mepyramine and 10.0 mM, 339 nmol/min/mg protein, and 33.9 microl/min/mg protein for epinastine, respectively. The uptake of [3H]mepyramine and [14C]epinastine by RBEC1 was inhibited by organic cations such as quinidine, amantadine, and verapamil, but not by other organic cations, tetraethyl ammonium, guanidine, and carnitine. Organic anions such as benzoic acid, estrone-3-sulfate, taurocholate, and neutral digoxin were not inhibitory. Furthermore, some cationic H1 antagonists (chlorpheniramine, cyproheptadine, ketotifen, and desloratadine) inhibited the [3H]mepyramine and [14C]epinastine uptake into RBEC1. In conclusion, the present study demonstrated that the combination of efficient efflux transport by P-glycoprotein and poor uptake by the influx transporter, which is identical with that responsible for the uptake of mepyramine, account for the low brain distribution of epinastine.     

Involvement of catalase in the endometrium of patients with endometriosis and adenomyosis

OBJECTIVE: To determine the distribution of catalase in eutopic and ectopic endometria in patients with endometriosis or adenomyosis. DESIGN: Retrospective randomized study. SETTING: Department of obstetrics and gynecology in a university hospital. PATIENT(S): Thirty-three patients with endometriosis, 36 with adenomyosis, and 47 fertile controls (total, 116 women). MAIN OUTCOME MEASURE(S): Semiquantitative immunostaining of endometrial cells obtained by biopsy sampling, followed by calculation of an evaluation nomogram score. RESULT(S): The score of catalase in the glandular epithelium of controls group fluctuated during the menstrual cycle; it was lowest in the early proliferative phase and peaked in the late secretory phase. In patients with endometriosis, catalase scores did not fluctuate during the cycle, and scores were high compared with controls throughout the menstrual cycle. Catalase scores did not vary in patients with adenomyosis, and scores in this group were consistently higher than those in patients with endometriosis throughout the cycle. CONCLUSION(S): Abnormal expression of catalase in the eutopic and ectopic endometrium strongly suggests pathologic involvement of free radicals in endometriosis and adenomyosis.