Efficacy and safety of pioglitazone added to alogliptin in Japanese patients with type 2 diabetes mellitus: a multicentre, randomized, double-blind, parallel-group, comparative study.

A phase IV, multicentre, randomized, double-blind, parallel-group, comparative study was conducted in Japanese subjects with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control, despite treatment with alogliptin in addition to diet and/or exercise therapy. Subjects with glycated haemoglobin (HbA1c) concentrations of 6.9-10.5% were randomized to receive 16 weeks' double-blind treatment with pioglitazone 15 mg, 30 mg once daily or placebo added to alogliptin 25 mg once daily. The primary endpoint was the change in HbA1c from baseline at the end of treatment period (week 16). Both pioglitazone 15 and 30 mg combination therapy resulted in a significantly greater reduction in HbA1c than alogliptin monotherapy [-0.80 and -0.90% vs 0.00% (the least squares mean using analysis of covariance model); p < 0.0001, respectively]. The overall incidence rates of treatment-emergent adverse events were similar among the treatment groups. Pioglitazone/alogliptin combination therapy was effective and generally well tolerated in Japanese subjects with T2DM and is considered to be useful in clinical settings.

[Usefulness of urethral descent for evaluating the type of female stress urinary incontinence].

BACKGROUND: To select suitable treatment for stress urinary incontinence (SUI), both urethral function and urethral mobility must be assessed. Abdominal leak point pressure (ALPP) is considered to be useful to evaluate urethral function, and radiographic findings are effective to evaluate urethral mobility. However no adequate methods to measure urethral mobility with videourodynamics study (VUDS) exist. We measured the downward movement of the membranous urethra at the same time as ALPP was measured on VUDS, and examined whether or not the urethral descent on VUDS is useful to evaluate urethral mobility. METHODS: The subjects were 28 women with over grade II SUI (according to McGuire's grading) who underwent bead chain cystography and VUDS. As a classical index of urethral mobility, we measured the change of posterior urethrovesical angle (PUVA) and vesical neck descent during Valsalva maneuver on bead chain cystography. The videourodynamic urethral catheter had a radiographic marker that permitted the identification of the location of the urethral pressure sensing aperture. The catheter was fixed at the position where the urethral pressure aperture reached the point of highest pressure. The urethral descent was defined as the downward movement of the urethral marker during Valsalva maneuver while measuring ALPP. According to the urethral descent the patients were classified as follows: 1) hyper-mobile group; urethral descent was over 5 mm. 2) non-mobile group: urethral descent was under 5 mm. The severity of SUI was evaluated with 1 hr. pad weighting test, ALPP and maximum urethral pressure. RESULTS: The urethral descent was significantly related to vesical neck descent and PUVA change. In the non-mobile group (11 cases), ALPP was significantly lower, and urine loss on the pad weighting test was significantly greater than that in the hyper-mobile group (17 cases). The non-mobile group exhibited more severe incontinence than the hyper-mobile group. When the patients were classified according to Blaivas's classification, all patients in type III and 2 in type I were in the non-mobile group. These 2 type I patients had low ALPP (40 cm. water and 70 cm. water) and a history of radical hysterectomy. Therefore these patients were diagnosed with ISD due to the fixed urethra. CONCLUSIONS: Urethral descent is an useful index of urethral mobility. In the non-mobile group, the pathophysiological cause of SUI was not urethral hypermobility but ISD, and it was diagnosed as type III SUI without urethral mobility. We consider that urethral descent assesses urethral mobility more accurately than vesical neck descent, and that urethral descent is a valuable parameter on VUDS.

Effects of hormone replacement therapy on serum amyloid P component in postmenopausal women.

The pentraxin serum amyloid P component (SAP) is a 9.5Sz1-glycoprotein and it has recently been found to be deposited in atherosclerotic lesions or neurofibrillary tangles, which are related to the aging process and Alzheimer's disease. The level of SAP was measured by micro single radial-immunodiffusion. Sample sera were obtained from 420 healthy humans, from newborn to 86 years old. The changes in SAP during the menstrual cycle were investigated in 6 women that were 20-21 years. Fifty of the postmenopausal women, suffering from climacteric symptoms, were administered either conjugated estrogen (E), or dehydroepiandrosterone (DHEA). The SAP levels increased with age, being 1.12 +/- 0.82 mg/dl (means +/- S.D.) in neonates, and 6.15 +/- 0.92 mg/dl in persons over 80 years. The SAP level in the females between 15 and 49 years (3.32 +/- 0.95 mg/dl) was significantly (P < 0.001) lower than that in the males in the same age group (5.19 +/- 1.25 mg/dl). The SAP level in the follicular phase was significantly (P < 0.01) lower than that in menstrual phase (menstrual: 4.36 +/- 0.90 mg/dl versus follicular: 2.61 +/- 0.99 mg/dl). In the post-menopausal women that were administered E (1.25 mg/day), the SAP decreased significantly (P < 0.001) from the prelevel of 5.64 +/- 1.40 mg/dl to 4.26 +/- 0.98 mg/dl on the 14th day. In the postmenopausal women that were administered DHEA (60 mg/day), the SAP increased rapidly from the prelevel of 4.97 +/- 0.76 mg/dl to 6.17 +/- 1.20 mg/dl on the 21st day. SAP seems to be a marker that can monitor the effect of hormone replacement therapy.

Long-term prognosis of chronic hepatitis C after treatment with interferon alpha 2b and characterization of incomplete responders.

OBJECTIVES: During the long-term follow-up of chronic hepatitis C patients treated with interferon alpha-2b, we have identified some patients who had continuous normalization, or transient elevation of the serum alanine aminotransferase levels within the first 6 months of follow-up and subsequent normalization, but HCV RNA was still found to be positive during the follow-up period (incomplete responder; ICR). We wished to clarify the characteristics of these patients, and to investigate the factors predictive of the response to interferon. METHODS: Seventy patients were treated with 6 MU of rIFN alpha-2b, three times weekly for 24 wk. Sixty-six patients (94%) completed the entire therapy and 2-yr follow-up protocol. RESULTS: Twenty-four months after cessation of IFN treatment, 24 patients (36%) were defined as complete responders (CR; continuously normal alanine aminotransferase levels, and HCV RNA negative). Nine patients (14%) were defined as ICR. Thirty-three patients (50%) were defined as nonresponders (NR). Compared with the CR or NR groups, the patients in the ICR group tended to have the mildest histological severity and lowest histological activity index scores, but there were no significant differences in any of the other histological features. The complete response rate was significantly higher in patients with low concentration of HCV RNA, and genotypes other than type II. CONCLUSIONS: After long-term follow-up of the 66 patients, 24 patients (36%) were CR, nine (14%) were ICR, and 33 (50%) were NR. The histological stage and indices of chronic hepatitis may help to predict a patient's response to IFN therapy.

[Change of serum amyloid P component concentrations in women].

Serum amyloid P component (SAP) is a glycoprotein which was shown to be deposited in periarterial tissues and the glomerular basement membrane. It plays a part in aging, and the onset of amyloidosis and Alzheimer's disease. In order to investigate the effects of sex steroids on the SAP level in menopausal women, SAP was purified. Anti-SAP was raised through the immunization of rabbits. The SAP level was assayed by micro single radial immunodiffusion. The SAP levels increased with aging from 1.1 +/- 0.8mg/dl (mean +/- S.D.) to 5.08 +/- 1.31mg/dl in women. And the SAP level in males was significantly higher in the 15 to 50 year age group than in females of similar ages (p < 0.001). And in the menstrual cycle, the SAP concentrations were significantly higher in the menstrual period (p < 0.05). During hormonal therapy in climacteric women, the SAP levels decreased significantly (p < 0.001) after Premarin treatment (from 5.66 +/- 1.45mg/dl to 4.15 +/- 0.94 mg/dl) and increased (p < 0.001) after dehydroepiandrosterone therapy (from 4.00 +/- 0.74mg/dl to 6.07 +/- 1.14mg/dl). From these findings, the SAP levels in human were concluded to be age dependently increased, and higher in the menstrual period. And it is suggested that a sex difference in SAP is concerned with the effect of estrogen fluctuation.

A controlled study to determine the optimal dose regimen of interferon-alpha 2b in chronic hepatitis C.

OBJECTIVES: The efficacy of three different dose treatments of interferon (IFN) was evaluated in patients with chronic hepatitis C (HCV). METHODS: Ninety-one patients with chronic hepatitis C were allocated to receive 3, 6, or 10 U of recombinant IFN-alpha 2b three times weekly for 24 wk. The number of patients was 26, 35, and 30 in the low, middle, and high dose groups, respectively. Treatment was discontinued, however, in four patients (one in the middle dose group and three in the high dose group) because of depression occurring 1-3 months after therapy began. A total of 87 patients, therefore, was analysed and was comprised of 26 patients in the low dose group, 34 in the middle dose group, and 27 in the high dose group. RESULTS: At the end of treatment, serum levels of ALT were normal in 50% (13/26) of patients in the low dose group, 70% (24/34) in the middle dose group, and 74% (20/27) in the high dose group. Patients with persistent normalization of ALT for 12 months of follow-up were defined as sustained responders. Twelve months after treatment cessation, the percentage of sustained responders was 23% (6/23) in the low dose group, 44% (15/34) in the middle dose group, and 41% (11/27) in the high dose group. Including the four patients who required discontinuation of IFN administration, the percentage of sustained responders was 43 and 37% in the middle and high dose groups, respectively. The clearance of HCV RNA was 40% in the middle dose group and 33% in the high dose group. This decrease in the clearance of HCV RNA was prominent in the high dose group. The percentage tended to be higher in the middle dose group, but the differences were not significant. CONCLUSIONS: The results suggest that a regimen of recombinant IFN-alpha 2b in a dose of 6 U three times weekly for 24 wk may be appropriate for the treatment of chronic HCV.

Craniofacial cleft with naso-ethmoidal encephalocele--case report.

The anterior skull base of a patient with a craniofacial cleft with naso-ethmoidal encephalocele was reconstructed using temporo-parietal and frontal galea-pericranial flaps and free cranial bone grafts, to prevent meningitis caused by trans-nasal infection. The patient had frequent episodes of meningitis before surgery, however, no episodes of meningitis have been observed up to 1 year postoperatively.

Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: a prospective randomized study.

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.

[Three-dimensional MR angiography of the celiac artery with single breath holding].

We performed a three-dimensional MR angiography of the celiac artery with single breath holding. The measuring time was just twenty-three seconds. In four healthy volunteers, celiac arteries were visualized clearly, moved cephalad with expiration and caudad with inspiration. In two patients with the median arcuate ligament compression of the celiac artery, the degree of stenosis increased with deep expiration and decreased with deep inspiration. Using this technique, we obtained different vascular images with each respiratory phase. This technique is considered to be a useful three-dimensional MR angiography in the abdominal region without respiratory artifacts.

[Plasma interleukin-6 in patients with disseminated intravascular coagulation].

Plasma Interleukin-6 (IL-6) level was measured in 60 patients with disseminated intravascular coagulation (DIC). Plasma IL-6 level was high in patients with DIC, and was particularly high in patients with multiple organ failure (MOF) or poor prognosis. Plasma IL-6 level correlated positively with C-reactive protein in patients without DIC, but not in those with DIC. The increased plasma IL-6 level observed in DIC patients suggests that activation of the immune system is involved in the progression of DIC and in the pathology of organ failure.

[Significance of antitumor effects and immunological response on endogenously induced LAK therapy for primary or metastatic liver tumor].

Nineteen patients with metastatic liver tumor (9 of gastric cancer, 5 of colon cancer, 2 of pancreatic cancer, one each of mammary cancer, cholecystic cancer, carcinoid of biliary tract) and one patient with primary liver cancer were treated by endogenously induced LAK therapy consisting of transhepatic arterial infusion with ADM or MMC for induction therapy and OK-432 and rIL-2 (TGP-3) for immunotherapy. The following results were obtained. 1) Clinical response for liver tumor showed no CR but 8 cases of PR, for an overall response rate of 42.1%. 2) Reduced tumor marker value was noted in 76.5% cases, and 50% survival term became 349 days after the therapy. 3) Many CD4 and CD8 positive mononuclear cells had infiltrated around liver tumor after therapy by immuno-histochemical staining of surface marker. 4) NK activity of peripheral blood lymphocytes was markedly reduced soon after the therapy and continued for about 4-7 days, while in cases of combined subcutaneous administration with OK-432, NK activity showed only a slight decrease.

[Analysis of chronic excretors of Mycobacterium bacilli in Aichi Prefecture].

Among the patients diagnosed as having pulmonary tuberculosis who were newly admitted to six major tuberculosis centers in Aichi Prefecture during the period from January 1, 1982 to December 31, 1986, 73 patients were chronic excretors of Mycobacterium bacilli (chronics), whose sputum cultures tested positive at both 11 and 12 months after admission. In this study, those 73 patients were analyzed in March 1988. If the patient was still hospitalized at that time, the patient was re-evaluated six months later. The life table method was used for analysis of clinical procedures. For the analysis of risk factors for chronics, 37 patients who were treated after 1971 when RFP was available for treatment were used. The results in this study are as follows: 1. A total of 49.3% of the patients were determined chronics (those who had initial chemotherapy before 1970 when RFP was not available). This result suggests that the use of RFP may contribute to the reduction of chronics. 2. Patient delay in diagnosis, as well as irregular chemotherapy, was one of the factors for the development of chronics. 3. In the chronics, many patients showed severe findings in their chest X-rays, high bacillary counts in the sputum, and low drug-sensitivity bacilli when treated with the major anti-tuberculosis drugs. 4. The rate of chronics from newly admitted patients with positive sputum cultures following the initial chemotherapy treatment was 1.3%. This rate could increase following longer observation periods. 5. Chronics were more prevalent in patients with Type I (extensive cavitary type) findings in the chest X-rays, and positive sputum smears for Mycobacterium bacilli in the clinical findings when compared with all newly registered active tuberculosis patients during the same period in Aichi Prefecture. 6. Concerning the outcome, 55 patients were discharged (17 improved; 13 personally released; 25 deceased) while 18 remain hospitalized. Among those discharged patients, 17 patients were released as a result in improved health while 25 died. These results indicate poor prognosis. Using the life table method, the estimated mortality rate is 49.7%, and the negative sputum rate is 30.5% five years later. 7. Using a multivariate analysis on the prognosis, the risk factor was greatest for poor prognosis for those patients who had Type I findings in their chest X-rays, initial chemotherapy before 1970, complications, and that were male. 8. The patients with improved health, were more sensitive to the drugs applied when compared to the fatal patients. 9. Careful chemotherapy during the first two years may contribute to the reduction of chronics.

[IgA-lambda type myeloma complicating with autoimmune hemolytic anemia].

A 66-year-old female was admitted to our hospital with lumbago. On admission, laboratory examination revealed hemolytic anemia. Direct Coombs' test was positive, and also direct monospecific-Coombs' test by anti-C3d serum was positive. Immunoelectrophoresis showed IgA-lambda type M proteins in serum. Bone marrow aspiration disclosed increased atypical plasma cells. X-ray of skull showed punched-out lesion. From these findings, she was diagnosed as IgA (lambda) myeloma complicating with autoimmune hemolytic anemia. Hemolysis was improved by chemotherapy. It was thought that IgA and C3 were related well to hemolysis in this case.

[Hemophagocytic syndrome in two elderly men].

Case 1: A 68-year-old male, who was admitted to our hospital because of massive intestinal bleeding, died 1 day after admission. Case 2: An 80-year-old male, who was admitted to our hospital because of a loss of consciousness, died 4 days after admission. In both cases prodromic infection was not detected. At autopsy, phagocytosis of RBC and WBC by histiocytes was shown markedly in the spleen in case 1 and in the bone marrow in case 2. So diagnosis of virus-associated hemophagocytic syndrome was made. It might be related to some underlying immunologic derangement, because both cases were in advanced age.

[Chronic disseminated intravascular coagulation due to abdominal true aneurysm in two cases--effect of anti-platelet and anti-fibrinolytic therapy].

Case 1: 75 years old male was admitted to our hospital with anterior chest subcutaneous bleeding. Coagulation study revealed that fibrinogen and alpha 2-PI decreased, and FDP, FPA, B beta 15 approximately 42 and D-dimer increased. Case 2: 78 years old male was admitted to Shingu City Hospital with a left hip subcutaneous hematoma. Coagulation study revealed that fibrinogen, ATIII and alpha 2-PI decreased, and FDP increased. US and CT showed abdominal true aneurysm in both cases. Either severe infection or malignancy was not found. Ticropidine and T-AMCHA were medicated for 8 days in case 1, and for 18 months in case 2. Symptom and coagulation study improved in these cases. Due to some side effects such as appetite loss and liver dysfunction in case 1, and diarrhea in both cases, we changed the therapy to mini-dose heparin therapy. This therapy also proved effective. It is concluded that anti-platelet and anti-fibrinolytic therapy are effective for chronic DIC with abdominal true aneurysm.