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61.
An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction 总被引:1,自引:0,他引:1
Mulhall JP Bukofzer S Edmonds AL George M;Apomorphine SL Study Group 《Clinical therapeutics》2001,23(8):1260-1271
BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity. 相似文献
62.
Shabtai M Ye H Kono K Takayam T Terashima K Tsukuda K Frischer Z Waltzer WC Malinowski K 《Urologic oncology》2003,21(1):27-32
The presence of tumor infiltrating lymphocytes (TIL) has been attributed to the host cell mediated immune response against the evolving malignancy. However, due to specific evasive and escape mechanisms, the immune competent cells are rendered ineffective. One such mechanism may be the production of immune suppressor substance(s), inhibiting lymphocyte proliferation, and subsequently, their transformation into effector cells. To evaluate a possible impact of RCC extract on lectin and alloantigen-induced proliferation of TIL and peripheral blood lymphocytes (PBL) from renal cell carcinoma (RCC) patients and from healthy control human subjects. Tumor extract and TIL were derived from 13 patients with RCC undergoing radical nephrectomy. Tumor infiltrating lymphocytes and PBL from these patients were activated with Concanavalin A (Con-A), Phytohemoglutinine (PHA) or Pokeweed (PW) and the rate of blastogenesis was measured by (3)H Thymidine incorporation. The same procedure was used in assay with PBL from control healthy blood donors. There was a significant reduction (88.6%) in the proliferative response to ConA of TIL compared to PBL from the same patients (P = 0.007). A similar decrease was seen following stimulation by PHA (85.8%, P = 0.01) and PW mitogen (78.5%, P = 0.001). A 79.5% decrease in response level of TIL to alloantigens compared to PBL from RCC patients (P = 0.021), was observed. Lectin induced proliferative response of RCC patients was significantly lower in the presence of RCC extract (82.9%) compared to normal kidney extract (P = 0.008). Alloantigenic stimulation of healthy individual PBL was also decreased significantly in the presence of RCC extract (92.9%, P = 0.0001) compared to normal kidney extract. Similarly, lectin induced stimulation of healthy control PBL in the presence of RCC extract was significantly lower (83.2%, P = 0.003). Our data suggest that RCC extract contains an immune suppressive substance(s), capable of inhibiting lymphocyte proliferative response of tumor infiltrating lymphocytes as well as of PBL from patients and healthy individuals alike. This may be one of the mechanisms by which the tumor evades the transformation of lymphocytes into effector killer cells, and thus affects the biological inter-relationship between tumor and host. Identification of this substance and its gene may provide an effective anti-tumoral treatment modality. 相似文献
63.
The influence of paternal lymphocyte immunization on the balance of Th1/Th2 type reactivity in women with unexplained recurrent spontaneous abortion 总被引:13,自引:0,他引:13
Szpakowski A Malinowski A Głowacka E Wilczyński JR Kolasa D Dyński M Tchórzewski H Zeman K Szpakowski M 《Ginekologia polska》2000,71(6):586-592
OBJECTIVES: Paternal lymphocyte immunization has been proposed as an efficient treatment for unexplained recurrent spontaneous abortion (RSA), however precise mechanism that underlie the benefits of this immunotherapy are still unclear. It was proposed that successful pregnancy is reminiscent of T helper 2 (Th2)--dominant situation but unsuccessful pregnancy is a Th1-type situation. The aim of the study was the evaluation of influence of paternal lymphocyte immunization on the balance of Th1/Th2--type reactivity in women with unexplained recurrent spontaneous abortion. MATERIAL AND METHODS: 8 patients with a history of 3 or more consecutive primary spontaneous abortions of unknown etiology and no positive autoimmune factors were selected for the study. Immunization with paternal lymphocytes, obtained from 100 ml of peripheral blood, was performed twice prior conception with a 4-week interval. The following immunological parameters were studied: peripheral blood T lymphocyte subpopulations (CD3, CD4, CD8) and secretion of the Th1-type cytokines (IL-2, IFN-gamma), Th2-type cytokines (IL-6) and TGF-beta 1 by phytohaemaglutinin-stimulated peripheral blood lymphocytes. Evaluation of immunity parameters were performed before and 2 weeks after immunotherapy. RESULTS: It was found that paternal lymphocytes immunization significantly increase the percentage of CD4 T lymphocytes (37.11 +/- 7.65 vs. 41.38 +/- 5.57, p = 0.007). Immunotherapy also leads to a significant enhancement in Th2-type cytokines (IL-6) secretion (22,677 +/- 17,907 mg/ml vs. 44,550 +/- 15,907 mg/ml, p = 0.008) and a significant decreasing in Th1-type cytokines (IL-2) secretion (6.50 +/- 5.98 mg/ml vs. 0.00 +/- 0.00 mg/ml, p = 0.0179). CONCLUSIONS: The data of the present studies suggest that paternal lymphocytes immunization modulate of immunity in women with unexplained recurrent spontaneous abortion. Our studies indicate a shift in the balance fo cytokine profiles away from Th1-type reactivity to a Th2-type reactivity after immunotherapy. 相似文献
64.
Antiphospholipid autoantibodies in women treated for infertility 总被引:1,自引:0,他引:1
Malinowski A Dyński MA Głowacka E Nowak M Wilczyński JR Kolasa D Tchórzewski H Szpakowski M 《Ginekologia polska》2000,71(9):1011-1016
OBJECTIVE: To evaluate an occurrence of selected antiphospholipid antibodies (APL) in infertility women. STUDY DESIGN: An enzyme-linked immunoabsorbent assay (ELISA) has been used to determine a titre of anticardiolipin antibodies (ACA). APTT (activated partial thromboplastin time) and PT (prothrombin time) measurements and direct commercial assay have been also used to study occurrence of LAC (lupus anticoagulant antibodies). The group of 268 observed women has been divided into five subgroups according to the cause of infertility: I-endometriosis, II-tubal occlusion caused by others diseases than endometriosis, III-occurrence of antisperm antibodies (ASA), IV-polycystic ovariorum syndrome (PCOS) and V-unexplained etiology. Results have been compared to 44 healthy controls. RESULTS: Occurrence of ACA has been found statistically more often in patients suffering from infertility than in controls (17.9% vs 4.5%, p < 0.05). Moreover ACA have been statistically more often observed in patients with endometriosis (21 from 44, 47.7%). ACA were more common in patients with other cause of infertility (except PCOS) compared to controls, though statistically this was not significant. Frequency of ACA was also more common than LAC (17.9% vs 13.6%). Compared to controls LAC tests were more often positive in infertile women with endometriosis (I), tubal occlusion (II) and with the occurrence of antisperm antibodies (III) but results were not statistically significant. CONCLUSIONS: Antiphospholipid antibodies are observed more often in patients suffering from infertility compared to women with a regular fertility. This suggests a role of APL in etiology of infertility. The occurrence of anticardiolipin antibodies in almost every second woman suffering from endometriosis suggests existing of autoimmunologic disturbances in this disease. 相似文献
65.
OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosing of rosiglitazone, the second thiazolidinedione approved for the treatment of type 2 diabetes mellitus. METHODS: Background information for this article was obtained from searches of MEDLINE , Iowa Drug Information Service, and International Pharmaceutical Abstracts, as well as from data on file with the manufacturer of rosiglitazone. RESULTS: Rosiglitazone is indicated for use alone or in combination with metformin or sulfonylureas for the maintenance of glycemic control in patients with type 2 diabetes mellitus. Rather than stimulation of insulin secretion, rosiglitazone's primary mechanism of action is sensitization of tissues to insulin through activation of the peroxisome proliferator-activated receptor gamma and increasing expression of the glucose transporter-4 receptor. Rosiglitazone is administered orally, is absorbed almost completely, and is 99.8% bound to plasma proteins. The majority of a dose is metabolized by the cytochrome P-450 2C8 isozyme, with the inactive metabolites excreted primarily in the urine. Four to 8 mg/d of rosiglitazone given alone or in combination with metformin, sulfonylureas, or insulin has produced reductions in baseline fasting plasma glucose and glycosylated hemoglobin in studies of up to 1 year's duration. Common adverse effects (occurring in > or = 5.0% of patients) include upper respiratory tract infection, injury, and headache. Edema, weight gain, and increased low-density lipoprotein cholesterol concentrations have also been observed. It is recommended that rosiglitazone be avoided in patients with alanine aminotransferase levels >2.5 times normal. No clinically relevant drug interactions have been documented with rosiglitazone to date. The initial starting daily dose of rosiglitazone is 4 mg in single or divided doses, without regard to meals, to a maximum of 8 mg. CONCLUSIONS: No direct comparative trials of the efficacy and safety of rosiglitazone versus those of the other available thiazolidinedione, pioglitazone, have yet been performed. The role of rosiglitazone as a single agent and in combination with other antidiabetic agents remains to be clarified as additional comparative and long-term data become available. 相似文献
66.
Background: An outbreak of food poisoning in a military establishment mess was investigated and remedial measures suggested. 相似文献
67.
高效液相色谱法测定寒痹停片中士的宁含量 总被引:6,自引:0,他引:6
目的:建立用HPLC测定寒痹停片中士的含量的方法。方法:氰基柱;流动相-甲醇-水-三乙胺-乙酸(9800:155:15:30);紫外检测波长254nm。结果:在4~20ug/ml范围内,标准曲线回归方程为:Y=-2803+8967x(r=0.9997),RSD=1.65%?加样回收率的平均值为99.82%。结论:实验表明,这是一个适用于生产控制和产品质量检验的简单、快速、准确的方法。 相似文献
68.
K W Pankiewicz K Lesiak-Watanabe K A Watanabe K Malinowski 《Current medicinal chemistry》1999,6(7):629-634
Mycophenolic acid (MPA) is the most potent and specific inhibitor of inosine monophosphate dehydrogenase (IMPDH). This compound was reported to bind the NAD site of IMPDH and mimic the binding of nicotinamide moiety of nicotinamide adenine dicnucleotide. We linked MPA derivatives with the adenine moiety of NAD through a methylenebis(phonphonate) birdge to form novel mycophenolic adenine dinucleotides (MADs) which resemble well the intact natural cofactor. The MAD analogues differ by the length of the side chain (linker) between the aromatic ring of mycophenolic derivative and the beta-phosphorus atom of the adenosine bis(phosphonate) moiety. Regardless of the linker size, MADs were found to be potent inhibitors of human IMPDH type I and type II with Ki's = 0.25-0.52 microM, an order of magnitude less potent than MPA itself (Ki = 0.01-0.04 microM). The growth of K562 cells was inhibited by MPA (IC50 = 0.03 microM) and the MAD analogues (IC50 = 0.01-1.15 microM) with a similar potency. Accordingly, a suppression of alloantigen- induced proliferation of human lymphocytes by the MAD analogues at concentration of 10-20 microM was equally effective as that observed for MPA. In contrast to MPA, MAD analogues were found to be resistant to glucuronidation in vitro. Since therapeutic potential of MPA is limited by its undesirable glucuronidation, the glucuronidation- resistant MAD analogues may be superior immunosuppressants if they are not glucuronidated in vivo. 相似文献
69.
Premysl Bercik Elena F. Verdu Jane A. Foster Joseph Macri Murray Potter Xiaxing Huang Paul Malinowski Wendy Jackson Patricia Blennerhassett Karen A. Neufeld Jun Lu Waliul I. Khan Irene Corthesy–Theulaz Christine Cherbut Gabriela E. Bergonzelli Stephen M. Collins 《Gastroenterology》2010,139(6):2102-2112.e1
70.