Changes in energy during treatment of depression: an analysis of duloxetine in double-blind placebo-controlled trials.

AIMS: The aim of this study was to assess how quickly and effectively duloxetine improves energy compared with placebo in patients with major depressive disorder (MDD). METHODS: Data from 10 randomised, double-blind, placebo-controlled clinical trials examining duloxetine (40-60 mg/day) vs. placebo in patients diagnosed with MDD were analysed. Change from baseline at Week 1 through Week 8 in Hamilton Depression Rating Scale (HAM-D) retardation subscale score (Item 1 - depressed mood, Item 7 - work and activities, Item 8 - retardation and Item 14 - genital symptoms) was assessed with mixed model repeated measures analysis. Positive predictive values and negative predictive values were calculated for predictor analysis. RESULTS: Patients treated with duloxetine (N = 1522) experienced statistically significantly (p ≤ 0.05) greater reductions in HAM-D retardation subscale scores vs. placebo (N = 1180) starting at Week 1 throughout Week 8 of treatment. Of the patients with early energy improvement (≥ 20% reduction in HAM-D retardation subscale scores) at Week 1, 48% achieved remission (HAM-D total score ≤ 7) at Week 8; 48% and 46% of patients who experienced early energy improvement at Weeks 2 and 4, respectively, achieved remission at Week 8. DISCUSSION: We demonstrated that treatment with duloxetine, quickly and with increasing magnitude over treatment time, improves low energy symptoms. As early as 1 week after starting treatment with duloxetine, improvement of low energy may serve as a predictor of remission at end-point. CONCLUSIONS: Treatment with duloxetine improves energy in patients with MDD and early response in retardation may serve as a modest predictor of remission at end-point. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Study Identifiers: NCT00036335; NCT00073411; NCT00406848 and NCT00536471. Studies HMAQa, HMAQb, HMATa, HMATb, HMBHa and HMBHb predate the registration requirement. DATA POSTING: ClinicalTrials.gov. Study Identifiers: NCT00406848; NCT00536471.

Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil.

The effects of food intake and age on intestinal absorption of AS-924, a novel prodrug-type cephem antibiotic, were examined in 16 healthy adult volunteers (eight young volunteers and eight elderly volunteers) by the cross-over method, using cefpodoxime proxetil (CPOD-PR) as the control drug. The gastrointestinal absorption of AS-924 and CPOD-PR was increased slightly by food intake and the extent of increase was slightly greater after administration of CPOD-PR. The absorption of AS-924 was not affected by age, whereas intestinal absorption of CPOD-PR increased with age. In conclusion, these results confirmed that AS-924 has the unique characteristics as a novel prodrug and that its absorption is less likely to be affected by food intake and age.

Effect of antacid pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic--comparison with cefteram-pivoxil.

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons.

Phosphorylation of the neurofilament-H subunit (NF-H) was investigated in rat embryonic brain neurons in culture. A portion of the NF-H was phosphorylated in vivo at embryonic day 17 when brain neurons were prepared. When the neurons were isolated and cultured, the NF proteins disappeared once and then reappeared over the next several days in the following order: (1) NF-L/NF-M, (2) dephosphorylated NF-H and (3) phosphorylated NF-H. Phosphorylation of NF-H began around 4 days after cell plating, at about the time of synapse formation. Treatments that appeared to modulate the timing of synapse formation also affected the timing of NF-H phosphorylation: (1) earlier phosphorylation was observed at higher neuronal cell density, (2) earlier phosphorylation was observed in neurons cultured on a coating substrate that promotes rapid neurite extension and (3) phosphorylation was suppressed when neurite extension was inhibited by brefeldin A. Three possible synapse formation-induced events, excitation, cell-cell contact through adhesion proteins and elevated concentrations of neurotrophic factors, were examined for their possible involvement in generating the signal for NF-H phosphorylation. Neither excitation nor cell contact enhanced NF-H phosphorylation. Neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) stimulated phosphorylation of NF-H. The BDNF-stimulated phosphorylation was inhibited by an anti-BDNF antibody and K252a, an inhibitor of BDNF receptor TrkB tyrosine kinase. Among known NF-H kinases of cyclin-dependent kinase 5 (CDK5), external signal-regulated protein kinase (ERK) and stress-activated protein kinase (SAPK), CDK5 and SAPK showed an increase in kinase activity or an active form with a time course similar to NF-H phosphorylation in control culture. On the other hand, BDNF stimulated the kinase activity of CDK5 and induced appearance of an active form of ERK transiently. These results suggest a possibility that synapse formation induces NF-H phosphorylation, at least in part, through activation of CDK5 by BDNF.

An immunohistochemical study on a case of granulocyte-colony stimulating factor-producing gall-bladder carcinoma.

Primary gall-bladder carcinoma producing granulocyte-colony stimulating factor (GCSF) is extremely rare. Only four cases, histologically investigated, have been reported to date in the English literature. We report a case of a 48-year-old female with primary gall-bladder carcinoma, associating with leukocytosis (15 700/mm3) and a high level of serum GCSF (54.0 pg/mL). The tumor was, histologically, a poorly differentiated adenocarcinoma with marked interspersed neutrophils invading into the primary tumor itself and the right lobe of the liver. Tumor cells distinctly showed positive immunoreaction in the cytoplasm with anti-GCSF antibody, and in the nucleus for anti-p53 antibody. After surgery, the leukocytosis and serum level of GCSF began to decrease. These findings confirmed the present case of GCSF-producing gall-bladder carcinoma, exhibiting leukocytosis. A total of five cases, including our case, reported as a GCSF-producing gall-bladder carcinoma were clinicopathologically reviewed.

Neuroleptic malignant-like syndrome: a complication of acute organophosphate poisoning.

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.

Peritoneal lavage versus drainage for perforated appendicitis in children.

A total of 231 children with acute appendicitis were treated at our hospitals during the 10 years between 1984 and 1993, 53 of whom had a perforated appendix. These 53 patients were randomly assigned to two groups at the time of surgery according to the different procedures performed. Thus, 29 children were managed by appendectomy followed by peritoneal lavage using a large amount of saline, and intravenous antibiotic therapy consisting of aminoglycoside and cephem (lavage group), while the other 24 children were treated by appendectomy with silicon tube drainage and the same systemic antibiotic therapy (drainage group). The mean length of hospitalization, and the mean durations of fever and the need for fasting after laparotomy in the lavage group were significantly less than those in the drainage group: 10.1 versus 18.8 days, 2.8 versus 7.7 days, and 1.8 versus 3.5 days, respectively. The operation wounds healed well in the lavage group due to the fact that there was no drain. Wound infections occurred in two children from the lavage group and six from the drainage group. Intra-abdominal abscesses occurred in two children from the drainage group. Accordingly, peritoneal lavage appears to be superior to intraperitoneal tube drainage for the management of perforated appendicitis in children.

[Gastric cancer presenting fine stippled calcification in radiography: a case report and a review of the Japanese literature].

A case of calcified gastric cancer is reported, with a review of the Japanese literature with special reference to the genesis of calcification. A male patient, 51 years of age, given a partial gastrectomy for an advanced gastric cancer 5 years earlier, presented general malaise. Plain X-rays revealed fine, stippled calcifications widely distributed in the upper abdomen. Additionally, computed tomography revealed a wide expanse of high density shadows with CT numbers of calcifications. On laparotomy, a histologic examination of a specimen taken for biopsy from part of the metastatic liver tumor led to a diagnosis of a mucinous adenocarcinoma showing identical histologic features of the previously resected gastric cancer, this diagnose then confirmed by Kossa's staining of fine calcified deposits in the tumor parenchyma.

[A case of gastric carcinoma disappearing after short-term preoperative chemotherapy].

A 58-year-old male visited the Kochi Municipal Central Hospital on May 17, 1984. A barium meal study and endoscopy revealed a huge crater surrounded by a thick embankment on the posterior wall of the stomach body. Biopsy specimens taken from the lesion revealed tubular adenocarcinoma, UFT (600 mg/day) and anti-tuberculous drugs were administered due to the complication of pulmonary tuberculosis. Endoscopic examination on August 6, 1984, revealed a remarkable improvement, showing a shallow irregular depression with converging folds. The patient underwent surgery on August 7, 1984, because from the endoscopic appearance, residual cancer was highly suspect, and also tuberculosis had improved. The histology of the surgically resected specimen showed a chronic peptic ulcer, the base of which was covered with regenerating mucosa. No cancer nests were demonstrated even by serial tissue sections.

Granulocytic sarcoma presenting as a mediastinal tumor. Report of a case and cytological and cytochemical studies of tumor cells in vivo and in vitro.

An unusual case of granulocytic sarcoma in a 23-year-old man is reported. The patient initially presented with mediastinal tumor and was diagnosed clinically as having thymoma. The patient was treated by radiotherapy and surgical removal of the tumor. Histology of the excised tumor had been nondiagnostic because of extensive fibrous changes. Eight months later, the patient developed pleural effusion on the right, which soon was followed by blood and bone marrow pictures consistent with acute promyelocytic leukemia. In vitro culture of pleural effusion cells unexpectedly gave rise to a continuously growing peroxidase-positive myeloid cell line. Autopsy revealed the recurrent mediastinal tumor to be positive for intracytoplasmic naphthol AS-D chloroacetate esterase and lysozyme activity. From these findings, the patient retrospectively was diagnosed as having mediastinal granulocytic sarcoma, which terminated in pleural effusion and acute promyelocytic leukemia.

Adult T-cell leukemia with generalized cytomegalic inclusion disease and pneumocystis carinii pneumonia.

An autopsy case of adult T-cell leukemia with generalized cytomegalic inclusion disease and pneumocystis carinii pneumonia is reported. Tumor cells had T-cell characteristics (E-rosette) and cerebriform nucleus similar to Sèzary cells. Generalized lymphadenopathy, hepatosplenomegaly and an ectopic pancreas in the ileum were found at the time of autopsy. Histologically, leukemic infiltration was observed in almost every organ, and perivascular infiltration, vascular invasion were conspicuous findings. Cytomegalic inclusion bodies were observed in most organs (lungs, salivary glands, pancreas, liver, ectopic pancreas, sweat gland, stomach, thyroid gland, pituitary body, etc.). An acute hepatitis, probably caused by cytomegalovirus, was also noted. Presumed correlation of adult T-cell leukemia, cutaneous T-cell lymphoma and T-cell lymphoma was discussed.