草酸铂加醛氢叶酸/5-氟尿嘧啶48 h持续静脉滴注双周疗法治疗晚期直肠癌

目的 观察草酸铂（L-OHP）与CF／5-FU 48h持续静脉滴注双周疗法治疗晚期直肠癌疗效及不良反应。方法 经病理证实的55例晚期直肠癌患者随机进入研究钳照组。治疗方案：A组草酸铂（L-OHP）＋CF／5-FU；B组CF／5-FU，两组均2周为1个周期。结果 经过2个周期化疗，A组缓解率33．33％（9／27），B组缓解率21.43％（6／28），A组缓解率高于B组。治疗中无疾病进展及治疗相关死亡，胃肠道反应及骨髓抑制均为轻中度，差异无显著意义。A组周围神经感觉障碍为74．0％（20／27），为轻中度可逆；B组为17．86％（5／28），两组间差异有显著意义（x^2=17．5333，P〈0．001）。结论 草酸铂＋CF／5．FU 48h持续静脉滴注双周疗法治疗晚期直肠癌疗效高，不良反应轻，有希望成为最有效的治疗方案。     

草酸铂、氟脲嘧啶为主化疗方案治疗晚期消化道肿瘤

目的：探讨草酸铂（OXA）、氟脲嘧啶（5－FU）为基础的化疗方案在晚期消化恶性肿瘤治疗中不同的应用方法。方法：110例治疗方案如下：1．OXA＋5FU／CF方案（CF甲酰四氢叶酸），OXA130mg.m^-2静滴d1；CF100mg.m^-2.d^-1静滴2hr，接用5－FU0．5g.m^-2.d^-1静滴6－8hr,d1-5,q3wks,治疗33例；2．FOLFOX方案，OXA130mg.m^-2.d1;CF200mg.m^-2.d^-1静滴2hr，接用5－FU400mg.m^-2.d^-1静推，再5－FU1．6g.m^-2.d^-1持输22小时d1-2,q2wks，治疗43例；3．OXA＋5－FU低剂量长时间持输，OXA100mg静滴d1,d8,d15;5-FU250mg.m^-2.d^-1持输21d,q4wks,治疗23例；4．OXA＋希罗达（CAP）方案，OXA130mg.m^-2静滴d1；希罗达1g,一天2次口连续14d,q3wks，治疗6例；5．OXHLV5FU3方案，即OXA＋5－FU／CF加羟基喜树碱（HCPT），OXA130mg.m^-2静滴d1；CF200mg.m^-2.d^-1静滴2hr，接用5－FU400mg.m^-2.d^-1静推，再5－FU1．6g.m^-2.d^-1持输22hr，d1-3,HCPT10mg.d^-1,d1-5,q3wks,治疗5例。结果：各方案的总有效率（CR＋PR）分别为30．3％（10／33）／51．2％（20／43）／39．1％（9／23）／66．7％（4／6）／100％（5／5）；外周神经感觉异常发生率达71．8％（79／110）。结论：以草酸铂、氟脲嘧啶为基础的化疗方案是较理想的治疗方案，治疗应个体化，神经副作用绝大多数为可逆性，耐受良好。     

羟基喜树碱联合化疗晚期胃肠道癌症的临床观察

对胃癌38例、大肠癌26例分别随机分成治疗组和对照组。胃癌对照组采用四氢叶酸钙（CF）＋5－氟脲嘧啶（5－FU) 顺铂（DDP）方案,治疗组采用羟基喜树碱（HCPT）＋CF＋5－FU＋DDP方案;大肠癌对照组采用CF＋5－FU方案,治疗组采用HCPT＋5－FU＋CF方案。结果显示胃癌治疗组和对照组的疗效分别为52.6%和47.4%,两组疗效无显性差异（P＞0.05);大肠癌治疗组和对照组的疗效分别为38.5%和23．1％,两组疗效有显性差异（P＜0.05)。主要毒副反应为恶心、呕吐和白细胞减少,治疗组稍高于对照组;脱发的发生率治疗组（34．4％）明显高于对照组（15．6％）。HCPT联合治疗晚期胃肠道癌疗效高,尤其是大肠癌。毒副反应少,患能耐受。     

伊立替康联合5-FU/CF治疗转移性结直肠癌46例

目的：评价伊立替康（CPT—11）联合5-FU／CF方案治疗FOLFOX4或LV5FU2方案失败的结直肠癌的客观疗效，临床受益和不良反应。方法：用CPT—11联合5-FU／CF方案治疗晚期结直肠癌患者46例，采用2周方案，即CPT—11 180mg／m^2 iv d1，CF200mg／m^2 iv d1-2，5-FU400mg iv bolusd1，5-FU600mg／m^2 iv，22hd1—2，每2周重复。观察期3—6个月。结果：完全缓解0例，部分缓解18例（有效率39．13％），稳定20例（43．47％），进展8例（17．39％）。临床受益率82．6％（19／23）。临床反应评价有效者36例（78．86％），生活质量显著提高。结论：CPT-11联合5-Fu／CF方案可作为转移性结直肠癌的二线治疗。     

奥沙利铂联合亚叶酸钙、氟尿嘧啶治疗晚期结直肠癌的临床观察

目的评价奥沙利铂（L-OHP）联合亚叶酸钙（CF）及氟尿嘧啶（5-FU）治疗晚期结直肠癌的疗效和毒副反应。方法51例晚期结直肠癌患者,给予L-OHP130mg/m^2静脉滴入,持续2h,第1天;CF：200mg/次,静脉滴入,持续2h,第2-6天;5-FU：500mg/m^2,静脉滴入,持续6h,第2-6天。每3周重复1次,用药2个周期后评价疗效。结果51例患者中,完全缓解（CR）2例,部分缓解（PR）17例,稳定（SD）20例,进展（PD）12例,总有效（CR＋PR）率：37.2%。毒副反应主要是末梢神经毒性、恶心呕吐、骨髓抑制及静脉炎等。结论L-OHP联合CF/5-FU治疗晚期大肠癌具有较好的疗效,毒副反应可以耐受。     

FOLFOX4方案治疗晚期胃肠道肿瘤临床观察

目的观察FOLFOX4化疗方案治疗晚期胃肠道肿瘤的疗效和毒性反应。方法36例晚期胃肠道肿瘤患者，其中胃癌16例，结直肠癌20例。给予奥沙利铂（L-OHP）85mg／m2静脉滴注2h，第1天；亚叶酸钙（CF）200mg／m^2。静脉滴注，2h，第1、2天；氟尿嘧啶（5-FU）400mg／m^2，静脉推注，第1、2天，5-FU600mg／m^2微泵持续静脉滴注，22h，第1、2天，2周重复，4周为1个周期。2个周期后以WHO评价标准评价疗效和毒性。结果总有效（CR＋PR）率为44．6％，其中胃癌总有效率为37．5％，结直肠癌总有效率50％，两组比较差异无统计学意义（P〉0．05），中位缓解时间7．4个月，中位生存期11．4个月，1年生存率为50％。主要毒副反应为急性造血系统，感觉神经毒性和胃肠道反应，对症治疗均能耐受。结论FOLFOX4方案治疗晚期胃肠道肿瘤有提高总生存率的趋势，但远期生存率和后期并发症尚需进一步观察。     

草酸铂加CF／5-FU48小时持续静脉滴注双周疗法治疗晚期胃癌83例疗效分析

目的：观察草酸铂（L-OHP）与CF／5-Fu48小时持续静脉滴注双周疗法治疗晚期胃癌疗效及不良反应。方法：经病理证实的83例晚期胃癌患者随机分为治疗组和对照组。治疗方案：治疗组用L-OHP加CF／5-FU：对照组用VP16加CF／5-FU，两组均2周为1周期。结果：经过2个周期化疗，治疗组有效率（CR＋PR）57．5％比对照组有效率34．9％高，两组比较差异有统计学意义（X^2=4.2702，P=0．0388）。治疗中无疾病进展及治疗相关死亡。胃肠道反应及骨髓抑制均为轻中度。无显著性差异。神经毒性治疗组明显低于对照组，两组差异有统计学意义（P〈0．01）。结论：L-OHP加CF／5-FU48小时持续静脉滴注双周疗法治疗晚期胃癌疗效高，不良反应轻，有希望成为最有效的治疗方案。     

羟基喜树碱静脉化疗加腹腔化疗治疗晚期大肠癌的临床观察

目的探讨晚期大肠癌有效治疗方法，以期改善大肠癌患者生存质量、延长生存时间。方法静脉化疔，应用羟基喜树碱（HCPT）／甲酰四氢叶酸钙（CF）＋5-氟脲嘧啶（5-FU）方案：HCPT 12mg／m^2。静脉滴注第1-5天。CF 200mg＋5-FU 300 mg／m^2静脉滴注4h第1-5天，每3～4周1次，3周期为1个疗程。腹腔化疗：用5-氟脲嘧啶（5-Fu）＋顺铂（CDDP），5-FU750mg／m^2＋CDDP 60mg／m^2自Tenck-hoff管或Port-A-Cath泵系统注入腹腔，腹水者腹腔穿刺注入，每10-15d1次，2-4次为1个疗程。各完成1个疗程后评价。结果近期疗效，32例中，CR3例，PR10例，SD9例，PD9例，总有效率为40．6％。随诊疗2年，中位生存期11．8个月，1年生存率56．2％（18／32），2年生存率21．9％（7／32）。毒副反应主要为骨髓抑制、腹泻、腹膜炎。轻微都能耐受。结论含羟基喜树碱联合方案方法静脉化疗加腹腔化疗是治疗晚期大肠癌安全、有效的方法。     

羟基喜树碱联合化疗晚期胃肠道癌症的临床观察

对胃癌38例、大肠癌26例分别随机分成治疗组和对照组.胃癌对照组采用四氢叶酸钙(CF)+5-氟脲嘧啶(5-FU)+顺铂(DDP)方案,治疗组采用羟基喜树碱(HCPT)+CF+5-FU+DDP方案;大肠癌对照组采用CF+5-FU方案,治疗组采用HCPT+5-FU+CF方案.结果显示胃癌治疗组和对照组的疗效分别为52.6%和47.4%,两组疗效无显著性差异(P＞0.05);大肠癌治疗组和对照组的疗效分别为38.5%和23.1%,两组疗效有显著性差异(P＜0.05).主要毒副反应为恶心、呕吐和白细胞减少,治疗组稍高于对照组;脱发的发生率治疗组(34.4%)明显高于对照组(15.6%).HCPT联合治疗晚期胃肠道癌疗效高,尤其是大肠癌.毒副反应少,患者能耐受.     

FOLFOX4方案治疗晚期结直肠癌的临床观察

目的观察FOLFOX4方案治疗晚期结直肠癌的临床疗效及不良反应。方法采用草酸铂（OXA）85mg／m^2，静脉滴注2h，第1天；亚叶酸钙（LV）200mg／m^2静脉滴注2h，第1～2天；5-氟尿嘧啶（5-FU）400mg／m^2，第1～2天静脉注射；5-FU600mg／m^2持续静脉滴注（22h）第1～2天的方案治疗30例晚期结肠癌患者。2周为1周期，重复4周期后间隔1个月评价疗效。结果全组30例，CR1例（3．3％），PR 10例（33．3％），SD 9例（30．0％），PD 10例（33．3％），总有效率为36．6％。不良反应主要为神经毒性、胃肠道反应和骨髓抑制，多呈Ⅰ～Ⅱ度，可耐受。结论FOLFOX4方案治疗晚期结肠癌安全有效，可作为晚期结肠癌的首选化疗方案。     

Inhibition of alpha-receptor-induced Ca2+ release and Ca2+ influx by Mn2+ and La3+

The influence of Mn2+ and La3+ on alpha-receptor-stimulated Ca2+ movements was examined in arterial smooth muscle of the rabbit aorta. Both cations cause an inhibition of phenylephrine (PE) contractile response which exhibits a different pattern at low and high cation concentrations. At 0.1-1.0 mM inhibition by Mn2+ and La3+ was predominately due to a reduction in Ca2+ influx reflected as inhibition of the slow phase of contraction and reduction in PE-stimulated 45Ca uptake. PE log dose-response curves were shifted to the right in a non-parallel manner by 1 mM Mn2+ such that responses to lower PE concentrations were more inhibited. However, in the presence of 10 mM Mn2+ PE responses are equally inhibited at all PE levels. At 10 mM both Mn2+ and La3+ also inhibited PE-stimulated Ca2+ release resulting in a reduction in both the rapid phase of contraction and in the magnitude of PE stimulation of 45Ca efflux. The effects of Nm2+ (1 or 10 mM) on contraction and 45Ca efflux were rapidly reversible, while the effect of La3+ was not. Inhibition of Ca2+ release by 10 mM Mn2+ and La3+ was not caused by displacement of releasable Ca2+, but appeared to reflect their occupation of a superficially located receptor modulating site. The inhibition of Ca2+ influx by lower concentrations of Mn2+ may illustrate the functional consequence of configurational changes in the alpha 2-form of the receptor which have been recently described at lower concentrations of divalent cations.     

Involvement of tropomyosin in the sensitivity of Na+ + K+ ATPase to ouabain

The Na⁺/K⁺ ATPase sensitivity to ouabain was shown to be increased by 300 to 1000-fold after treatment of the plasma membrane by EDTA. Addition of proteins detached from the plasma membrane with Ca²⁺ ions to EDTA treated membranes reconstituted the original Na⁺/K⁺ ATPase resistance to ouabain inhibition. Tropomyosin with Ca²⁺ ions (not with Mg²⁺ ions) induced the same effect. When suboptimal doses of tropomyosin were used for such a reconstitution, the dose-response curve indicated a full reconstitution of a given percentage of enzyme molecules. This observation led us to assume a direct or indirect effect of tropomyosin on Na⁺/K⁺ ATPase functions.     

Studies on the stable inhibition of Na+ + K+-ATPase by cassaine.

Exposure of rat brain Na+ + K+-ATPase (ATP phosphohydrolase E.C. 3.6.1.3) to concentrations of cassaine greater than 1 x 10(-4) M resulted in a poorly reversible inhibition of this enzyme. Inhibition did not require the presence of ATP and developed rapidly, but the final amount of inhibition observed was independent of time. The amount of inhibition observed at a given concentration of cassaine was reduced by increasing the concentration of membranes in the system. The inhibition of Na+ + K+-ATPase activity was associated with equivalent inhibition of the phosphorylation and (3H)-ouabain binding reactions of this enzyme, while the uninhibited enzyme was apparently kinetically normal. Concentrations of cassaine which produced this stable inhibition of Na+ + K+-ATPase had no effect on the Mg2+-activated ATPase or the NADH cytochrome-c-reductase activities of crude rat brain microsomal preparations. Cassaine inhibited the cholinesterase activity of rat brain microsomes with a Ki of about 5 x 10(-5) M, but his inhibition was fully reversible. The poorly reversible inhibitory actions of cassaine, thus, appeared specific for Na+ + K+-ATPase. Because this stable pattern of inhibition of the Na+ + K+-ATPase by cassaine required drug concentrations at least one hundred-fold greater than those which produce positive inotropic effects, it appears unlikely that this pattern of Na+ + K+-ATPase inhibition is involved in the cardiotonic actions of this drug.     

Abacavir + dolutegravir + lamivudine for the treatment of HIV

Introduction: Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients.

Areas covered: In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies.

Expert opinion: Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration.

In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.     

Vascular activation of K+ channels and Na+-K+ ATPase activity of estrogen-deficient female rats

The goal of the present study was to evaluate vascular potassium channels and Na⁺-K⁺-ATPase activity in estrogen deficient female rats. Female rats that underwent ovariectomy were assigned to receive daily treatment with placebo (OVX) or estrogen replacement (OVX + E2, 1 mg/kg, once a week, i.m.). Aortic rings were used to examine the involvement of K⁺ channels and Na⁺-K⁺-ATPase in vascular reactivity. Acetylcholine (ACh)-induced relaxation was analyzed in the presence of L-NAME (100 μM) and K⁺ channels blockers: tetraethylammonium (TEA, 5 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 mM), charybdotoxin (ChTX, 0.1 mM) and iberiotoxin plus apamin. When aortic rings were pre-contracted with KCl (60 mM) or pre-incubated with TEA (5 mM), 4-aminopyridine (4-AP, 5 mM) and iberiotoxin (IbTX, 30 nM) plus apamin (0.5 μM), the ACh-induced relaxation was less effective in the ovariectomized group. Additionally, 4-AP and IbTX decreased the relaxation by sodium nitroprusside in all groups but this reduction was greater in the ovariectomized group. Estrogen deficiency also increased aortic functional Na⁺-K⁺ ATPase activity evaluated by K⁺-induced relaxation. L-NAME or endothelium removal were not able to block the increase in aortic functional Na⁺-K⁺ ATPase activity, however, TEA (5 mM) restored this increase to the control level. We also found that estrogen deficiency increased superoxide anion production and reduced nitric oxide release in aortic ring from ovariectomized animals. In summary, our results emphasize that the process underlying ACh-induced relaxation is preserved in ovariectomized animals due to the activation of K⁺ channels and increased Na⁺-K⁺ ATPase activity.     

Sodium fluoride produces a K+ efflux by increasing intracellular Ca2+ through Na+-Ca2+ exchange

Acute fluoride intoxication increases intracellular calcium (Cai), manifested by increased twitch tension in cardiac muscle, and by potassium efflux (mediated by Ca2+-dependent K+ channels) in fluoridated erythrocytes. Fluoride, like isoproterenol, stimulates adenylate cyclase, and could increase Cai via the effects of cAMP on Ca2+ channels. However, while the inotropic effects of fluoride mimicked isoproterenol in rat atria, their effects on the time course of isometric contraction were quite different. In addition, acetylcholine negated isoproterenol's effect on twitch tension but did not modulate the effects of fluoride. Further, the Ca2+ channel antagonist verapamil had no effect on fluoride-stimulated K+ efflux from erythrocytes. Fluoride also inhibits Na+-K+ ATPase, and increases intracellular Na+, so could increase Cai via Na+-Ca2+ exchange. Lanthanum, which blocks Na+-Ca2+ exchange, blocks fluoride-induced K+ efflux in erythrocytes. We conclude that the effects of fluoride on adenylate cyclase are not important in intact tissue, and that inhibition of Na+-K+ ATPase and subsequent Na2+-Ca2+ exchange may be the mechanism of increased Cai in acute fluoride toxicity.