Analysis of ventricular arrhythmias and sudden death from prospective, randomized clinical trials of acalabrutinib.

This analysis investigated the incidence of sudden deaths (SDs) and non-fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient-years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient-years). Non-fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient-years; median time to event: 46.2 months). SDs and VAs with acalabrutinib occurred at low rates, and there are insufficient data to point to an increased risk of SD or VA with acalabrutinib.

Is Malaysia's "mystery monkey" a hybrid between Nasalis larvatus and Trachypithecus cristatus? An assessment of photographs.

Interspecific hybridization in primates is common but hybridization between distantly related sympatric primate species is rarely observed in the wild. We present evidence for a possible hybridization event between Nasalis larvatus and Trachypithecus cristatus in the Lower Kinabatangan Wildlife Sanctuary, Sabah, through assessment of photographs. We used a set of categorical characters and metric measurements to compare the putative hybrid with the likely parent species. Nonmetric comparison showed that this "mystery monkey" is intermediate in several characters. Measurements of limb proportions on photographs showed that the brachial, humerofemoral, and intermembral indexes are above 100 for N. larvatus and below 100 for T. cristatus on all photographs, whereas the crural index is higher than 100 in both species and the distributions of this index in the two species overlap. Brachial and intermembral indices of the putative hybrid were similar to those of N. larvatus. Crural and humerofemoral indices were closer to the values for T. cristatus than those of N. larvatus. Multiple observers confirmed the occurrence of mixed-species groups in the area, and interspecific mating has been photographed. The putative hybrid is now an adult female and was last photographed in September 2020 with an infant and swollen breast, suggesting lactation. We propose further noninvasive fecal sampling for genetic analyses to confirm the origins of this "mystery monkey." This case of hybridization may be related to anthropogenic changes to the landscape, whereby expansion of oil palm plantations confines N. larvatus and T. obscurus to narrow riverine forest patches along the Kinabatangan. This observation therefore also may have conservation implications, indicating limited mate access and dispersal opportunities for these threatened primates. Supplementary Information: The online version contains supplementary material available at 10.1007/s10764-022-00293-z.

Safety and tolerability of short-term preventive frovatriptan: a combined analysis.

OBJECTIVE: To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods. BACKGROUND: Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen. METHODS: Two multinational trials were included in the analysis: Study 1 was a randomized, placebo-controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates. RESULTS: The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double-blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache. CONCLUSIONS: During treatment of up to 12 perimenstrual periods over a 12- to 15-month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine.

Selective serotonin re-uptake inhibitor treatment-emergent sexual dysfunction: randomized double-blind placebo-controlled parallel-group fixed-dose study of a potential adjuvant compound, VML-670.

Sexual dysfunction is common during acute and continuation treatment of depressed patients with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibitors (ssRIs), but there is no consensus on clinical management. Compounds with 5-HT(1A) agonist properties have been proposed as adjuvant agents in patients continuing with ssRIs. Randomized double-blind placebo-controlled parallel-group fixed-dose 4-week treatment study. Previously depressed male or female patients in symptomatic remission receiving stable doses of fluoxetine or paroxetine but experiencing treatment-emergent sexual dysfunction were randomised to double-blind treatment with placebo or VML-670 (a 5-HT(1A) and 5-HT(1D) agonist). sexual dysfunction was assessed by the Arizona sexual Experiences scale (ASEX). Two-hundred and eighty-eight patients (204 women, 84 men; mean age 44.2 years) received VML-670 (n = 149; 107 women, 42 men) or placebo (n = 139; 97 women, 42 men). In the intention-to-treat, last-observation carried forward analysis (n = 282), proportionately more patients became free of sexual dysfunction with VML-670 (34.3% versus 27.9% with placebo) but this difference was not statistically significant. Male patients treated with VML-670 showed a significantly greater (p =0.01) improvement in ability to achieve and maintain penile erection (a secondary outcome measure). A similar proportion of patients reported on-treatment, treatment-emergent adverse events with VML-670 (71.1%) and placebo (68.3%), and a similar proportion experienced at least one treatment-related adverse event (36.9% versus 35.3%). Double-blind treatment with VML-670 offered no significant advantage over placebo on the primary outcome measure in the overall sample. Further studies may be warranted in larger groups of male patients with sexual dysfunction.