Timing of adjunctive therapy in the treatment of depression: a chart review.

INTRODUCTION: The objective of this study was to examine the evolution of antidepressant switch and adjunctive therapy. METHODS: This chart review was conducted at 6 primary psychiatric clinics or hospitals, in Tokyo, Japan. A chart review of longitudinal prescriptions was conducted regarding 633 outpatients with major depressive disorder for up to 2 years after their first visit. Patients who had already received antidepressants prior to the visit were excluded. RESULTS: 22.6% (N=143) of the patients completed or continued the outpatient treatment over the 2 years while 27 (4.3%), 23 (3.6%), and 439 (69.4%) patients discontinued it due to hospitalization, referral to another clinic, and loss to follow-up, respectively. A total of 597 episodes of antidepressant treatment were identified. Among them, 482 episodes (80.7%) were associated with the suggested dose ranges while antidepressant drugs were under-dosed in 19.3% (N=115) of the episodes. 50 patients (7.9%) received adjunctive therapy; it was employed after a median of only one antidepressant had been tried. CONCLUSION: Psychiatrists may be hasty in prescribing an adjunctive therapy in the treatment of depression.

Dose-response to a jelly preparation of calcium polystyrene sulfonate in patients with hyperkalemia--changes in serum potassium levels with or without a RAAS inhibitor.

AIMS: In this study, dose-response of the serum potassium-lowering effect of a calcium polystyrene sulfonate (PS) preparation was investigated. Changes in the serum potassium level were also examined with or without application of a RAAS inhibitor, which is said to increase the serum potassium level. SUBJECTS AND METHODS: 23 patients diagnosed to have hyperkalemia associated with chronic renal failure were enrolled in this study. The study drug, a PS-Ca jelly preparation (Argamate jelly), was started at a daily dose of 1 preparation (5 g as PS-Ca), and the dose was increased by 1 preparation every month to finally reach 3 preparations per day. Blood samples were collected once a month and serum levels of creatinine and electrolytes were measured. RESULTS: PS-Ca jelly decreased serum potassium levels in a dose-dependent manner. Decreases were 0.67 mEq/l at 5 g of PS-Ca/day, 1.06 mEq/l at 10 g/d, and 1.33 mEq/l at 15 g/d. Irrespective of the use of the RAAS inhibitor, serum potassium levels decreased significantly in a dose-dependent manner. Furthermore, no major change in serum creatinine levels occurred in subjects in which the RAAS inhibitor was used, although in subjects in which the RAAS inhibitor was not used, serum creatinine level tended to gradually increase. CONCLUSION: Serum potassium levels were reduced in a dose-dependent manner by administration of 5-15 g/d of PS-Ca, and it appeared that together with control of serum potassium levels, renal function should be maintained by continuous administration of RAAS inhibitor.

Interferon-beta induction/interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C.

Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin improves the rate of eradication of the virus by less than 20% in patients with genotype 1b and a high viral load. In this study we assessed whether IFN-beta induction/IFN-alpha2b plus ribavirin enhances the efficacy of the therapy in patients with chronic hepatitis C. The efficacy of IFN-beta induction/IFN-alpha2b plus ribavirin therapy (group A, n=7) was compared with that of IFN-alpha2b plus ribavirin (group B, n=7) in 14 patients with high levels of HCV-RNA (> 100 K/U/ml). No significant differences were observed in the clearance of HCV-RNA between the two groups (A and B, respectively) 2 weeks after the start of the treatment (0% and 14.3%), at the end of the treatment (71.4% and 100%) and 6 months after the end of the treatment (28.6% and 14.3%). Recovery was complete in 28.6% and 14.3%, transient in 42.9% and 85.7% and absent in 28.6% and 0% in groups A and B, respectively. Early log changes in the viral load from the baseline after 2 weeks of treatment were 2.41 +/- 0.91 and 2.77 +/- 0.20 in groups A and B, respectively, with no significant difference between the two groups. In the present study, we were not able to demonstrate that IFN-beta induction/IFN-alpha2b plus ribavirin therapy was superior to IFN-alpha2b plus ribavirin therapy in patients with genotype 1b and high viral loads.

The hypocholesterolemic action of TA-7552 and its effects on cholesterol metabolism in the rat.

The hypocholesterolemic property of 1-(3,4-dimethoxyphenyl)-2,3- bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene (TA-7552) and its effects on cholesterol metabolism were investigated in the rat. TA-7552 incorporated into a hypercholesterolemic diet at a concentration of 0.2% and administered for 7 days reduced serum cholesterol by 72% and liver cholesterol by 90%, and its minimal effective dose was 0.01% in the diet. Its hypocholesterolemic effect was associated with an elevation of serum HDL-cholesterol. Inclusion of 0.1% TA-7552 in the normal laboratory chow accelerated fecal excretion of 14C derived from orally administered 4-[14C]cholesterol or carbonyl-[14C]taurocholate. The net amounts of fecal neutral sterols and bile acids were markedly increased by the same treatment. Hepatic bile acid production and hepatic and intestinal cholesterol biosynthesis as measured by cholesterol 7 alpha-hydroxylase activity and 1-[14C]acetate incorporation into tissue cholesterol, respectively, were both stimulated by the drug treatment. All these data indicate that this hypocholesterolemic agent inhibits intestinal absorption of both cholesterol and bile acids and compensatorily stimulates hepatic production of bile acids and cholesterol.

Inhibitory effect of a new butadiene derivative on the production of plasminogen activator inhibitor-1 in cultured bovine endothelial cells.

Tissue-type plasminogen activator (t-PA) and its physiological inhibitor, plasminogen activator inhibitor-1 (PAI-1), are known to be synthesized by vascular endothelial cells and to play important roles in regulating the fibrinolytic activity of plasma. We found that a new butadiene derivative, (3E, 4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)pyrrolidine -2,5-dione (T-686), inhibits PAI-1 production without affecting plasminogen activator (PA) synthesis in cultured bovine endothelial cells. T-686 (1-10 microM) dose-dependently decreased the accumulation of PAI-1 in conditioned medium from the treated cells and elevated PA activity in the conditioned medium. Analysis of the conditioned medium by the zymography technique indicated that T-686 decreased the activities of PAI-1 with an M(r) of 55,000 and t-PA/PAI-1 complex with an M(r) of 99,000. Furthermore, T-686 attenuated the augmentation of PAI-1 antigen induced by lipopolysaccharide in the conditioned medium. The decrease of PAI-1 antigen was in parallel with the reduction of the PAI-1 mRNA level (Northern blots). These results suggest that T-686 can promote net fibrinolytic activity through suppression of PAI-1 production without affecting PA elaboration in endothelial cells.

T-686, a novel inhibitor of plasminogen activator inhibitor-1, inhibits thrombosis without impairment of hemostasis in rats.

The aim of this study was to evaluate the antithrombotic potential of T-686 ((3E,4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene)-pyrr olidine-2,5-dione), a novel inhibitor of plasminogen activator inhibitor-1 (PAI-1), in rat thrombosis models. T-686 (0.1-100 mg/kg per day, p.o.) dose dependently decreased the weight of venous thrombi induced by a combination of stasis and hypercoagulability. The antithrombotic effect was enhanced by repeated administration of T-686. Warfarin (0.1 mg/kg per day for 3 days) also prevented thrombus formation. The antithrombotic action by warfarin was accompanied by prolongation of coagulation time, while no effect on coagulation time was observed in T-686-treated rats. T-686 lowered the activity of PAI-1 in plasma. In the arterio-venous shunt model, pretreatment with T-686 (10 mg/kg per day) or ticlopidine (100 mg/kg per day) for 8 days inhibited thrombus formation by 33% and 44%, respectively. T-686 had no effect on collagen-induced platelet aggregation ex vivo, while ticlopidine inhibited platelet aggregation. T-686 did not affect bleeding time at 10-100 times the antithrombotic dose, while warfarin dose dependently prolonged bleeding time at and around the antithrombotic dose. These results suggest that T-686 prevents thrombus formation in rats without impairment of hemostasis.

A new butadiene derivative, T-686, inhibits plasminogen activator inhibitor type-1 production in vitro by cultured human vascular endothelial cells and development of atherosclerotic lesions in vivo in rabbits.

Plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of tissue-type plasminogen activator and urokinase, is abundantly expressed in atherosclerotic vascular wall. To determine the role of PAI-1 in vascular wall, we have used a novel inhibitor of PAI-1, (3E, 4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene) -pyrrolidine-2,5-dione (T-686). T-686 was given to human vascular endothelial cells in vitro and to rabbits subjected to high cholesterol diet and mechanical injury in vivo. T-686 attenuated the augmentation of PAI-1 antigen accumulation induced by transforming growth factor beta in conditioned medium from the human umbilical vein endothelial cells. In rabbits with aortic atherosclerosis induced by hypercholesterolemia and implantation of indwelling plastic tubing, oral administration of T-686 (30mg/kg body weight/day) for 8 weeks attenuated the increase in plasma PAI-1 activity induced by vascular injury without decreasing blood triglyceride and cholesterol. This was accompanied by the reduction in aortic PAI-1 mRNA expression and the inhibition of development of atherosclerosis lesions. Thus, T-686 not only decreased PAI-1 synthesis in vascular cells in vitro but also protected against the development of vascular lesions in vivo. This compound may be useful in defining the role of PAI-1 in atherothrombotic states.

A case of partial 5q trisomy associated with partial 7q monosomy.

A 1-year-old girl with partial 5q trisomy and partial 7q monosomy had ocular abnormalities that included bilateral blepharoptosis and Leber's congenital amaurosis. A single bright-flash electroretinogram (dark-adapted, white stimulation) disclosed subnormal bilateral responses. Her maculas showed a reddish spot surrounded by a broad, greyish retinal zone. Cytogenetic studies disclosed deletion of q22 to the terminal of chromosome 7 and partial trisomy of q31 to the terminal of chromosome 5. Because all reported patients with 5q trisomy have not had Leber's congenital amaurosis, the ocular abnormalities noted in our patient may be explained by the 7q monosomy.

Effect of acid-suppressive therapy on Helicobacter pylori production of interleukin-8 in the gastric mucosa.

BACKGROUND: Recent studies have shown that acid-suppressive therapy increases the severity of Helicobacter pylori- associated gastritis in the corpus. PURPOSE: To evaluate interleukin (IL)-8 production in the gastric corpus mucosa before and during acid-suppressive therapy in H pylori-infected patients. PATIENTS AND METHODS: Ten patients with reflux esophagitis (five H pylori-positive and five H pylori-negative) were treated with omeprazole 20 mg. Serum gastrin concentrations, H pylori colonization density and mucosal IL-8 levels in the corpus were investigated at entry and two weeks after starting therapy. IL-8 levels were measured by ELISA. The organism density was determined, and scored according to area occupied by the bacterial colonies. The presence of H pylori was assessed by rapid urease testing and histological finding of gastric biopsy specimens. RESULTS: In H pylori-positive patients, concentrations of IL-8 during therapy significantly exceeded those before therapy (36.2+/-6. 8 versus 18.3+/-3.8 pg/mg protein; P<0.05) without altering H pylori density. In H pylori-negative patients, IL-8 levels were similar before and during therapy (6.1+/-2.7 versus 6.3+/-3.0 pg/mg protein). Concentrations of gastrin during therapy were significantly higher than those before therapy in all patients. CONCLUSIONS: The results suggest that acid suppression increases mucosal IL-8 levels in H pylori-infected patients with reflux esophagitis.

Pharmacokinetic interactions between HIV-1 protease inhibitors in rats: study on combinations of two kinds of HIV-1 protease inhibitors.

The drug interactions between four human immune deficiency virus (HIV-1) protease inhibitors have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration. In this study, a new HPLC analytical method developed by us was used for the simultaneous determination of saquinavir and nelfinavir in rat plasma and microsomes. The metabolic clearance rates (Vmax/Km) of saquinavir, nelfinavir, and indinavir were 170.9 +/- 10.9, 126.1 +/- 4-4, and 73.0 +/- 2.0 microL min(-1) (mg protein)(-1), respectively. Ritonavir was the strongest inhibitor with inhibition constants (Ki) of 1.64 microM for saquinavir, 0.95 microM for indinavir, and 1.01 microM for nelfinavir. Nelfinavir was the second strongest inhibitor with Ki's of 2.35 microM for saquinavir and 2.14 microM for indinavir. Indinavir was the third strongest inhibitor with Ki's of 2.76 microM for nelfinavir and 3.55 microM for saquinavir. Saquinavir was the weakest inhibitor for the other three HIV- 1 protease inhibitors. After oral co-administration in combination with another HIV-1 protease inhibitor, the AUCs of saquinavir, indinavir, and nelfinavir were significantly increased compared with mono-treatment. The AUCs of saquinavir were increased about 10.1-, 3.1- and 45.9-fold in the presence of indinavir, nelfinavir and ritonavir, respectively. The AUCs of indinavir were increased about 6.8-, 5.9- and 9.4-fold in the presence of nelfinavir, saquinavir and ritonavir, respectively. The AUCs of nelfinavir were increased about 2.2-, 6.6- and 8.5-fold in the presence of indinavir, saquinavir and ritonavir, respectively. The in-vivo effects observed after co-administration of two kinds of HIV-1 protease inhibitor were not always expected from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. These results provide useful information for the treatment of AIDS patients receiving combination therapy with two HIV-1 protease inhibitors.

Elimination of iomeprol in patients undergoing continuous ambulatory peritoneal dialysis.

OBJECTIVE: To examine the elimination of iomeprol, its safety in clinical use, and its peritoneal permeability in continuous ambulatory peritoneal dialysis (CAPD) patients with variable degrees of residual renal function (RRF). DESIGN: A nonrandomized comparison study. SETTING: Hospitalized patients in CAPD unit of Chikuho and University Hospitals. PARTICIPANTS: Fourteen patients treated by CAPD and 6 by hemodialysis (HD). INTERVENTIONS: Total dialysate, blood, and 24-hour urine collections were obtained for 4 consecutive days after the administration of iomeprol. A peritoneal equilibration test was performed just before and after the administration of iomeprol. MEASUREMENTS: Iomeprol (iodine) concentration was measured. Residual renal function was estimated as the mean of renal creatinine and urea clearances. Dialysate-to-plasma ratios (D/P) of creatinine and iomeprol were also determined. RESULTS: In all CAPD patients, plasma iomeprol clearance was markedly slow, with a biological half-life (T1/2) of over 32 hours. However, no patients suffered from any adverse effects, and over 80% of plasma iomeprol was eliminated during the 4-hour HD. The plasma iomeprol elimination rate was significantly higher from 4 hours after the iomeprol administration in CAPD patients with RRF [mean estimated creatinine clearance (CCr) 3.8 mL/min, n = 7] compared to the remaining patients (mean estimated CCr 0.6 mL/min, n = 7); however, T1/2 in patients with RRF was over 24 hours. D/P creatinine was significantly correlated with D/P iomeprol, and peritoneal iomeprol permeability may depend on an individual's peritoneal solute transport properties. CONCLUSIONS: A prolonged elimination rate of iomeprol was documented in our CAPD patients both with and without RRF. A HD procedure or intensive peritoneal dialysis just after the use of iomeprol may be advisable to promptly remove circulating iomeprol.

Pressure apparatus of split-octahedron type for x-ray diffraction studies.

An apparatus of split-octahedron type has been developed for the study of x-ray diffraction at high pressure. The apparatus consists of a cylinder, a sphere, and an octahedron, all split up and assembled in a multistaged arrangement. Three ways of splitting the innermost octahedron are utilized in matching the cell geometry to the standard camera method. High pressures in excess of 220 kilobars can be generated in the center of the split octahedron by using a composite mixture of diamond powder and epoxy resin as a pressure-transmitting medium. The pressures required for the semiconductor-to-metal transitions of ZnTe, ZnS, GaAs, and GaP are determined by simultaneously monitoring the electrical resistance of the semiconductors and the lattice parameter of sodium chloride.

Pharmacokinetics of bisoprolol and its effect on dialysis refractory hypertension.

The efficacy, safety, and pharmacokinetics of bisoprolol were investigated following oral administration once daily for 12 weeks in hyperreninemic patients with dialysis-refractory hypertension. Mean blood pressure rapidly fell from 132 to 112 mmHg in the 5.0-mg/day (n = 6) and from 142 to 128 mmHg in the 2.5-mg/day patients (n = 5), which were accompanied by a fall in plasma renin activity. On nondialysis days, Cmax and T1/2 were significantly higher in patients than in healthy control subjects. However, Cmax in the 2.5-mg/day patients was almost equal to that in healthy control subjects receiving 5.0 mg/day of bisoprolol. Plasma bisoprolol was dialyzable. During the course of the study, dialysis hypotension and bradycardia occurred in two patients receiving 5.0 mg/day of bisoprolol. In conclusion, a daily dose of 2.5 mg bisoprolol seems to be an adequate and relatively effective dose in our patients with dialysis-refractory hypertension.

[Effectiveness of a new toothbrush with irrigation and suctioning capabilities (ty e-Brush) for removing supragingival plaque].

Patients with dysphagia typically have poor oral health. Because of improper swallowing, they cannot easily and safely clean their mouths. As a solution for such a problem, a manual toothbrush with both irrigation and suctioning functions has been developed, called the "e-Brush". The purpose of this study was to evaluate the cleaning effectiveness of the new e-Brush (9 mm and 11 mm in bristle length) for removing supragingival plaque, compared with a conventional toothbrush, GUM # 211 by Butler. In this study, 12 subjects (12 female of average age 20.6) were selected, and plaque control record (PCR) and scrubbing method were used. The following results were obtained: 1. Significant differences (p < 0.05) were recognized between e-Brush/9 mm (55.54 +/- 18.27%) and the others (e-Brush/11 mm: 30.88 +/- 8.14%, GUM # 211: 35.42 +/- 9.32%). 2. Bristles 9 mm in length were more effective than 11 mm bristles (p < 0.05). 3. Irrigation/suctioning function is more effective than the conventional tooth-brushing method. 4. The irrigation function of e-Brush was meritorious in making almost all users comfortable. These results suggest that this new oral hygiene device, "e-Brush/9 mm", is effective for improving oral care management for patients with dysphagia.

Proton-exchange mechanism of specific Cs+ adsorption via lattice defect sites of Prussian blue filled with coordination and crystallization water molecules.

We have revealed the fundamental mechanism of specific Cs(+) adsorption into Prussian blue (PB) in order to develop high-performance PB-based Cs(+) adsorbents in the wake of the Fukushima nuclear accident. We compared two types of PB nanoparticles with formulae of Fe(III)4[Fe(II)(CN)6]3·xH2O (x = 10-15) (PB-1) and (NH4)0.70Fe(III)1.10[Fe(II)(CN)6]·1.7H2O (PB-2) with respect to the Cs(+) adsorption ability. The synthesised PB-1, by a common stoichiometric aqueous reaction between 4Fe(3+) and 3[Fe(II)(CN)6](4-), showed much more efficient Cs(+) adsorption ability than did the commercially available PB-2. A high value of the number of waters of crystallization, x, of PB-1 was caused by a lot of defect sites (vacant sites) of [Fe(II)(CN)6](4-) moieties that were filled with coordination and crystallization water molecules. Hydrated Cs(+) ions were preferably adsorbed via the hydrophilic defect sites and accompanied by proton-elimination from the coordination water. The low number of hydrophilic sites of PB-2 was responsible for its insufficient Cs(+) adsorption ability.

A scatter-compensated crystal interference factor in component-based normalization for high-resolution whole-body PET.

On a positron emission tomography (PET) scanner consisting of block detectors, coincidence responses to scattered radiation may differ from those to true depending on the crystal pair position within a coincidence block pair. Furthermore, these differences are considered to vary according to the radial position of the coincidence block pair. These conditions create ringing artifacts in the reconstructed image due to the lack of scatter compensation in detector normalization. In component-based normalization, a scatter-compensated crystal interference factor is therefore required in addition to the scatter-compensated block profile and intrinsic crystal efficiencies. In this study, we propose a scatter-compensated component-based normalization scheme using an annulus phantom, which provides true and scattered radiations over a large transaxial field of view, and evaluates the quality of three different-sized phantom images with whole-body PET. The results showed that the proposed normalization method significantly reduces the ringing artifacts in reconstructed images with different scattered/true fractions. The proposed algorithm, which introduced the scatter-compensated crystal interference factor, worked well under different scattered/true ratio conditions and was considered to be a robust, practical normalization method in high-resolution whole-body PET.