Influence of anticancer agents on sexual function: An in vivo study based on the US FDA Adverse Event Reporting System.

BACKGROUND: Patients with cancer are treated with chemotherapeutics that cause adverse effects, including erectile dysfunction (ED). OBJECTIVES: We investigated erectile function in rats after the administration of anticancer agents based on data retrieved through mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. MATERIALS AND METHODS: The statistical signal strength for the association between anticancer drugs and ED was calculated using the reporting odds ratio (ROR). A drug-event combination was detected when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1.00. Rats were administered anticancer agents detected in the FDA AERS analysis. Erectile function was assessed using intracavernous pressure (ICP) and mean arterial pressure (MAP) analysis after electrical stimulation of the cavernous nerve. Statistical significance was determined using Welch's t-test or two-way ANOVA. RESULTS: Melphalan (L-PAM; ROR = 4.72, 95% CI = 2.78-8.00), vincristine (VCR; ROR = 2.47, 95% CI = 1.54-3.97), docetaxel (DTX; ROR = 2.25, 95% CI = 1.28-3.95), methotrexate (MTX; ROR = 1.96, 95% CI = 1.39-2.75), and doxorubicin (DOX; ROR = 1.82, 95% CI = 1.07-3.19) enhanced ED risk. L-PAM and MTX decreased the ICP/MAP ratio 1 week after administration. VCR and DOX decreased erectile function 4 weeks after administration. DTX decreased erectile function at all assessed time points. DISCUSSION AND CONCLUSION: Certain anticancer agents should be considered risk factors for ED. Our results provide possible treatment strategies for maintaining erectile function in cancer survivors, including careful erectile function monitoring after treatment.

Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.

Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts.

Age-dependent deterioration of peak inspiratory flow with two kinds of dry powder corticosteroid inhalers (Diskus and Turbuhaler) and relationships with asthma control.

BACKGROUND: Inhaled corticosteroid (ICS) therapy has improved the quality of life (QOL) for many asthmatics and reduced mortality rates associated with asthma. However, some patients do not obtain therapeutic benefit despite satisfactory adherence. OBJECTIVES: To determine whether asthmatic patients were using ICS devices appropriately, and to clarify relationships between these results and QOL. SUBJECTS AND METHODS: We studied 100 adult asthmatics, divided into two groups: 50 patients consecutively registered as using Diskus (fluticasone; D-group) and 50 consecutively registered as using Turbuhaler (budesonide; T-group). We measured peak inspiratory flows (PIFs) using the In-Check Dial device. Subjects also completed the Asthma Control Test for evaluation of QOL. RESULTS: In the D-group, no patients showed PIF below the optimal range (30-90 L/min), whereas 52% of patients had PIF≥91 L/min. In the T-group, 6% of patients showed PIF over the optimal range (60-90 L/min), and 44% had PIF≤59 L/min. When patients in the T-group were required to deliberately make a maximal inhalation, 14% still had PIF≤59 L/min. The proportion of patients with poor control was significantly greater in the T-group than in the D-group. According to univariate logistic regression analyses, low PIF tended to be associated with poor asthma control in the T-group. No significant correlation was found between PIF and age in the D-group, but PIF decreased significantly with age in the T-group. CONCLUSIONS: Appropriate measures for patients in whom PIF has been judged as lower than optimal include adequate education for inhalation and/or changing to a different inhalation device. These measures should be kept in mind for elderly asthma patients in particular, where appropriate selection of a corticosteroid inhalation device in the early stages of therapy would also be important.

A comparison of the handling and accuracy of syringe and vial versus prefilled insulin pen (FlexPen).

BACKGROUND: To determine the preferable method for self-injecting insulin, we compared the handling, safety, and dose accuracy of a conventional disposable syringe and vial with FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark), a prefilled pen. METHODS: Insulin therapy-naive healthcare professionals (HCPs) (n = 30), unfamiliar with insulin delivery, injected 10 U of insulin into a sponge pad using either a syringe and vial or the FlexPen, both with 30-gauge 8-mm needles, on day 1. The following day, they used the alternative method. They evaluated the handling of the two methods on device-specific questionnaires and compared overall preference on a third questionnaire. To evaluate dose accuracy, 30 insulin therapy-experienced HCPs and 20 insulin therapy-naive HCPs were asked to deliver 10 U of insulin using each method, and the amount discharged was weighed. RESULTS: FlexPen was rated easier to use and overall more preferable than the syringe and vial by insulin therapy-naive HCPs (P < 0.001). The pen device was more accurate than the syringe and vial when used by experienced HCPs (mean +/- SD dose delivered, 9.91 +/- 0.11 U vs. 9.82 +/- 0.25 U, respectively; P < 0.001) and by insulin therapy-naive HCPs (9.91 +/- 0.12 U vs. 9.74 +/- 0.85 U; P < 0.001). CONCLUSIONS: Insulin therapy-naive HCPs found FlexPen easier to handle and preferable to use compared to a conventional syringe and vial. Both insulin therapy-experienced and -naive HCPs were able to deliver insulin significantly more accurately with the FlexPen than with a syringe and vial (P < 0.001).

Novel class of mutations of pilS mutants, encoding plasmid R64 type IV prepilin: interface of PilS-PilV interactions.

The type IV pili of plasmid R64 belonging to the type IVB group are required only for liquid mating. They consist of the major and minor components PilS pilin and PilV adhesin, respectively. PilS pilin is first synthesized as a 22-kDa prepilin from the pilS gene and is then processed to a 19-kDa mature pilin by PilU prepilin peptidase. In a previous genetic analysis, we identified four classes of the pilS mutants (T. Horiuchi and T. Komano, J. Bacteriol. 180:4613-4620, 1998). The products of the class I pilS mutants were not processed by prepilin peptidase; the products of the class II mutants were not secreted; in the class III mutants type IV pili with reduced activities in liquid mating were produced; and in the class IV mutants type IV pili with normal activities were produced. Here, we describe a novel class, class V, of pilS mutants. Mutations in the pilS gene at Gly-56 or Tyr-57 produced type IV pili lacking PilV adhesin, which were inactive in liquid mating. Residues 56 and 57 of PilS pilin are suggested to function as an interface of PilS-PilV interactions.

Positive inotropic effect of purified green tea catechin derivative in guinea pig hearts: the measurements of cellular Ca2+ and nitric oxide release.

Each individual and pure catechin isolated from green tea was investigated as to its myocardial or blood pressure effects. The nitric oxide (NO) electrode and fluorometry were used to monitor changes in the NO and Ca(2+) contents of the heart, together with simultaneous recordings of the left ventricular developed pressure. The low dose of (-)-epigallocatechin-3-gallate (EGCg: 10(-6), 10(-5 )M) increased the left ventricular developed pressure with elevation of the transient fura-2 Ca(2+) signal (T(Ca)), but the high dose of EGCg (10(-4 )M) produced a maximum left ventricular developed pressure with decreases in the basal level of T(Ca) in a manner similar to the administration of the Ca-sensitizer pimobendan. However, the level of the transient NO signal (T(NO)) increased dose-dependently without any increases in the width of T(NO). In the isolated right atria, the contractile force of (-)-gallocatechin-3-gallate (GCg) at 10(-8)-10(-4 )M produced the highest pD(2) value, 6.7, in catechins (EGCg: 5.2, pimobendan: 5.1), but did not affect the heart rate. GCg, an artifact due to the epimerization of EGCg during the heating procedure, showed the most prolonged hypotensive effect in rabbits among the catechins. Each catechin (GCg or EGCg), like the NO donor, may have a therapeutic use as an NO-mediated vasorelaxant and may have an additional protective action in myocardial ischemia-reperfusion induced injury.

Protective effects of sarpogrelate, a 5-HT2A antagonist, against postischemic myocardial dysfunction in guinea-pig hearts.

The protective effects of sarpogrelate (SG), a 5-HT2A antagonist, were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Changes in cellular levels of high phosphorous energy, NO and Ca2+ in the heart together with simultaneous recordings of left ventricular developed pressure (LVDP) were monitored using an nitric oxide (NO) electrode, fluorometry and 31P-NMR. The recovery of LVDP from ischemia by reperfusion was 30.1% in the control, while the treatment with SG (5 x 10(-7) M) in pre- and post-ischemia hearts produced a gradual increase to 73.1 and 53.6%, respectively. At the final stage of ischemia, the intracellular concentration of Ca2+ ([Ca2+]i) and release of NO increased with no twitching and remained at a high steady level. The addition of SG increased the transient NO signal (TNO) level at the end of ischemia compared with the control, but [Ca2+]i during ischemia decreased. Meanwhile, mitochondrial Ca2+ uptake on acidification or Ca2+ content changes of the perfusate was suppressed by pre-treatment with SG or the KATP channel opener diazoxide, but not the KATP channel blocker 5-HD. The myocardial NO elevated with 5-HT in normal Langendorff hearts was suppressed by the treatment with SG. Therefore, the existence of the 5HT2A receptor in a Langendorff heart was anticipated. By in vitro EPR, SG was found to directly quench the hydroxy radical. Thus, these findings suggested that the 5-HT2A receptor induced in ischemia-reperfusion plays an important role in the mitochondrial KATP channel of hearts in close relation with NO and active oxygen radicals.

Protective effects of antioxidative serotonin derivatives isolated from safflower against postischemic myocardial dysfunction.

N-(p-Coumaroyl)serotonin (C) and N-feruroylserotonin (F) with antioxidative activity are present in safflower oil. The protective effects of C and F were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Changes in cellular levels of high phosphorous energy, NO and Ca2+ in the heart together with simultaneous recordings of left ventricular developed pressure (LVDP) were monitored by an nitric oxide (NO) electrode, fluorometry and 31P-NMR. The rate of recovery of LVDP from ischemia by reperfusion was 30.8% in the control, while in the presence of C or F a gradual increase to 63.2 or 61.0% was observed. Changes of transient NO signals (TNO) released from heart tissue in one contraction (LVDP) were observed to be upside-down with respect to transient fura-2-Ca2+ signals (TCa) and transient O2 signals detected with a pO2 electrode. At the final stage of ischemia, the intracellular concentration of Ca2+ ([Ca2+]i) and the release of NO increased with no twitching and remained at a high steady level. The addition of C increased the NO level at the end of ischemia compared with the control, but [Ca2+]i during ischemia decreased. On reperfusion, the increased diastolic level of TCa and TNO returned rapidly to the control level with the recovery of LVDP. By in vitro EPR, C and F were found to directly quench the activity of active radicals. Therefore, it is concluded that the antioxidant effects of two derivatives isolated from safflower play an important role in ischemia-reperfusion hearts in close relation with NO.