Citations

ABSTRACT Purpose. The purpose of this report is to describe acute myopia as an ocular adverse reaction to topiramate (Topamax, Ortho‐McNeil, Raritan, NJ) and discuss the importance of recognizing this syndrome. Methods. Retrospective case report and brief review of the literature. Results. A 27‐year‐old female patient developed decreased vision in both eyes due to acute myopia 2 weeks of after initiating therapy with topiramate. Emergency department evaluation revealed visual acuities of 20/400 right eye and 20/200 left eye. Intraocular pressures were 33 mm Hg right eye and 26 mm Hg left eye. The anterior chambers were shallow. Retinal striae were present in the maculae. The patient stated no previous need for optical correction. However, after initiating treatment with topiramate, she refracted to approximately −5.00 D bilaterally. Ultrasound testing revealed that the patient had suprachoroidal effusions in both eyes. The symptoms and clinical findings resolved completely with discontinuation of topiramate, administration of topical atropine 1% and prednisolone acetate 1%. Conclusions. An acute myopic shift may be the presenting sign of an idiosyncratic drug reaction that can include secondary bilateral angle closure glaucoma. This condition can occur in patients who do not have a history of anterior chamber abnormalities. Recognizing this condition and discontinuing the use of the causative drug may prevent angle closure and associated vision loss.

Background The US Food and Drug Administration issued a black box warning regarding the use of droperidol and the potential for torsade de pointes (TdP). Methods The primary objective of this retrospective study was to determine whether low-dose droperidol administration increased the incidence of TdP in the general surgical population during a 3-yr time period before and after the Food and Drug Administration black box warning. A random sample of 150 surgical patients during each time interval was selected to estimate the droperidol use for each time period. Results During the time period before the black box warning (July 1, 1998 to June 30, 2001), 2,321/139,932 patients (1.66%) had QT prolongation, TdP, or death within 48 h after surgery. We could identify no patients who clearly developed TdP before the black box warning. There was one patient for whom the cause of death could not positively be ruled out as due to TdP. In the time period after the black box warning (July 1, 2002 to June 30, 2005), 2,207 patients (1.46%) had documented QT prolongation, TdP, or death within 48 h after surgery, including only two cases (<0.1%) of TdP. The incidence of droperidol exposure was approximately 12% (exact 95% confidence interval, 7.3-18.3%) before the black box warning and 0% after placement of the black box warning on droperidol. Therefore, we estimate that approximately 16,791 patients (95% confidence interval, 10,173-25,607) were exposed to droperidol, none of whom experienced documented TdP. Conclusions This indicates that the Food and Drug Administration black box warning for low dose droperidol is excessive and unnecessary.

Increases in reactive oxygen species (ROS) have been implicated in age-related diseases, including cancer. The serine/threonine kinase protein kinase D1 (PKD1) is a stress-responsive kinase and sensor for reactive oxygen species, which can initiate cell survival through NF-κB signaling. We have previously shown that in response to ROS, PKD1 is activated at the mitochondria. However, the initial signaling events leading to localization of PKD1 to the mitochondria are unknown. Here, we show that formation of mitochondrial diacylglycerol (DAG) and its binding to PKD1 is the means by which PKD1 is localized to the mitochondria in response to ROS. Interestingly, DAG to which PKD1 is recruited in this pathway is formed downstream of phospholipase D1 (PLD1) and a lipase-inactive PLD1 or inhibition of PLD1 by pharmacological inhibitors blocked PKD1 activation under oxidative stress. To date it has been viewed that monosaturated and saturated DAG formed via PLD1 have no signaling function. However, our data describe a role for PLD1-induced DAG as a competent second messenger at the mitochondria that relays ROS to PKD1-mediated mitochondria-to-nucleus signaling.

Involuntary apnea during sleep elicits sustained arterial hypertension through sympathetic activation; however, little is known about voluntary apnea, particularly in elite athletes. Their physiological adjustments are largely unknown. We measured blood pressure, heart rate, hemoglobin oxygen saturation, muscle sympathetic nerve activity, and vascular resistance before and during maximal end-inspiratory breath holds in 20 elite divers and in 15 matched control subjects. At baseline, arterial pressure and heart rate were similar in both groups. Maximal apnea time was longer in divers (1.7±0.4 versus 3.9±1.1 minutes; P <0.0001), and it was accompanied by marked oxygen desaturation (97.6±0.7% versus 77.6±13.9%; P <0.0001). At the end of apnea, divers showed a >5-fold greater muscle sympathetic nerve activity increase ( P <0.01) with a massively increased pressor response compared with control subjects (9±5 versus 32±15 mm Hg; P <0.001). Vascular resistance increased in both groups, but more so in divers (79±46% versus 140±82%; P <0.01). Heart rate did not change in either group. The rise in muscle sympathetic nerve activity correlated with oxygen desaturation ( r 2 =0.26; P <0.01) and with the increase in mean arterial pressure ( r 2 =0.40; P <0.0001). In elite divers, breath holds for several minutes result in an excessive chemoreflex activation of sympathetic vasoconstrictor activity. Extensive sympathetically mediated peripheral vasoconstriction may help to maintain adequate oxygen supply to vital organs under asphyxic conditions that untrained subjects are not able to tolerate voluntarily. Our results are relevant to conditions featuring periodic apnea.

PurposePerformance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain.Patients and MethodsIndividual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade ≥ 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy.ResultsCompared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade ≥ 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients.ConclusionIn clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.