Introduction
Migraine is associated with substantial functional impairment and affects many aspects of daily life.
Methods
Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase ...3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations.
Results
For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (
p
< 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN.
Conclusion
All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose.
Trial registration at clinicaltrials.gov
SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).
ABSTRACT
Introduction: Teriparatide effects are mediated via the preferential stimulation of osteoblastic activity over osteoclastic activity. Amino-terminal propeptide of type I procollagen (PINP) ...is an indicator of osteoblastic activity.
Objective: Develop an algorithm using PINP as an aid in the management of patients with postmenopausal osteoporosis treated with teriparatide.
Research design and methods: For inclusion in this post-hoc analysis, trials had to be investigations of teriparatide 20 µg/day in postmenopausal women with osteoporosis having measurements of PINP at 3 months and bone mineral density (BMD) at 12 months. Signal-to-noise ratio was calculated for a series of markers of bone turnover in the Fracture Prevention Trial. An algorithm was developed to monitor patients treated with teriparatide using PINP.
Results: Three trials met inclusion criteria and included the Fracture Prevention, Forteo-Alendronate Comparator and Anabolic After Antiresorptive trials. PINP had the highest signal-to-noise ratio of all bone-turnover markers. Positive PINP responses defined as increases > 10 µg/L were observed in 77–97% of teriparatide- and in 6% of placebo-treated patients after 3 months of study drug. Mean lumbar spine BMD increases after 12 months of teriparatide in patients having PINP changes > 10 µg/L ranged from 8.3% to 9.5% and in patients with PINP changes ≤ 10 µg/L ranged from 5.9% to 7.6%.
In the algorithm, PINP is measured at baseline and after 1–3 months of therapy. Patients with PINP increases > 10 µg/L are given a positive message. Patients with PINP increases ≤ 10 µg/L are assessed for adherence, teriparatide administration and storage techniques, and for the presence of medical conditions that might limit their therapeutic response, and these issues are addressed as appropriate. Patients without these issues and with PINP increases ≤ 10 µg/L should be given a neutral message because BMD may significantly increase with continued therapy.
Conclusions: The PINP algorithm provides information regarding the anabolic response to teriparatide therapy and has the potential to identify patients requiring help with issues of adherence, injection technique, teriparatide storage, and medical problems limiting therapeutic responsiveness to teriparatide treatment. Data assessing the relationship of changes in PINP to fracture risk reduction are not available. We recommend physicians audit the use of the algorithm in practice so that improvements can be made.
To determine if defects in the atrial natriuretic peptide (ANP) system can cause hypertension, mice were generated with a disruption of the proANP gene. Homozygous mutants had no circulating or ...atrial ANP, and their blood pressures were elevated by 8 to 23 millimeters of mercury when they were fed standard (0.5 percent sodium chloride) and intermediate (2 percent sodium chloride) salt diets. On standard salt diets, heterozygotes had normal amounts of circulating ANP and normal blood pressures. However, on high (8 percent sodium chloride) salt diets they were hypertensive, with blood pressures elevated by 27 millimeters of mercury. These results demonstrate that genetically reduced production of ANP can lead to salt-sensitive hypertension.
Vertebral fractures are the most common osteoporotic fracture and may result in back pain with functional limitations and diminished quality of life. Teriparatide rhPTH (1-34) has been shown to ...increase bone mass and reduce the risk of vertebral and other osteoporotic fractures. The aim of this study was to evaluate the effects of teriparatide on the risk of back pain in patients with osteoporosis. A systematic review of the literature was performed, and five trials were identified and included in our analyses. All trials were randomized, double-blinded, and parallel with either new vertebral fracture (n=1) or bone mineral density as the primary endpoint (n=4). Four studies were in postmenopausal women with osteoporosis, and one was in men with idiopathic or hypogonadal osteoporosis. Two trials were placebo controlled, two trials were alendronate controlled, and one trial involved teriparatide plus hormone replacement therapy versus hormone replacement therapy alone. Reports of back pain, defined as new or worsened back pain after initiating the study drug, were obtained from adverse event databases, and the risk of back pain was analyzed using a multivariate Cox proportional hazards model. Results were not statistically heterogeneous (P=0.60) across trials, and there were no differences between groups administered teriparatide 20 or 40 mcg/day doses (P=0.64). The rates of back pain, moderate or severe back pain, and severe back pain per 100 patient-years were numerically lower in the teriparatide versus comparator groups in each study. Compared with the pooled comparator, patients in the pooled teriparatide group had reduced risk for any back pain relative risk, 0.66 (95% CI, 0.55-0.80), moderate or severe back pain relative risk, 0.60 (95% CI, 0.48-0.75) and severe back pain relative risk, 0.44 (95% CI, 0.28-0.68). Separate meta-analyses comparing teriparatide versus placebo or antiresorptive drugs gave similar results. In conclusion, patients randomized to teriparatide had a reduced risk of new or worsening back pain compared to patients randomized to placebo, hormone replacement therapy or alendronate.
Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ...ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.
Introduction
As 5-HT
1B
receptor agonists, triptans produce vasoconstriction and have cardiovascular contraindications and precautions. Lasmiditan, a selective 5-HT
1F
receptor agonist, has a low ...affinity for 5-HT
1B
receptors, does not cause vasoconstriction, and is free of cardiovascular contraindications and precautions. The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication.
Methods
Patient subgroups, with and without triptan contraindications, were analyzed from pooled patient data from four randomized, double-blind, placebo-controlled clinical trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). Patients experiencing a single migraine attack of moderate or severe intensity were treated with lasmiditan 50 mg (SPARTAN and MONONOFU only), 100 mg, 200 mg, or placebo, and efficacy data were recorded in an electronic diary.
Results
Of 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. Overall subgroup analysis revealed that the effects of lasmiditan on pain freedom, pain relief, freedom from most bothersome symptom, disability freedom, and Patient Global Impression of Change at 2 h post-dose did not differ in patient groups with and without triptan contraindications. These outcomes generally showed a similar benefit pattern for lasmiditan in both subgroups, with all results being statistically significant in patients without contraindications, and pain relief being statistically significant in patients with contraindications. The safety and tolerability profiles of patients with triptan versus without triptan contraindications were similar, including dizziness in 18.3 to 22.8% and somnolence in 7.9 to 9.9% of patients at the highest dose of lasmiditan.
Conclusions
In pooled analyses from four trials, patients with and without triptan contraindications did not differ in their patterns of lasmiditan efficacy. Lasmiditan may be a treatment option in patients with contraindications to triptans.
Trial Registration Numbers
SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738.
This report from the Japan Fracture Observational Study (JFOS) describes the design of the study, baseline characteristics of the patients, and interim results.
This is an interim analysis from an ...ongoing observational study of male and female patients with osteoporosis initiating daily teriparatide treatment observed at baseline, 3, 6 and 12 months. There was no control group. Baseline data were collected on demographic characteristics, medical and osteoporosis history, prior use of medications and health-related quality of life (HRQoL). This interim analysis includes preliminary information concerning incidence of clinical fractures, bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, HRQoL, and adverse events.
Baseline observations were completed for 1810 patients; 90.1% were female. Compared with osteoporotic patients treated with teriparatide in other observational studies, those in JFOS were older but had fewer osteoporosis risk factors. The incidence of clinical fractures was 2.9% at 6 months and 3.7% at 12 months. At 12 months, mean BMD was 8.9% higher at the lumbar spine and 0.8% higher at the total hip compared to baseline. At 6 months, the median serum concentration of P1NP was 187.7% higher than at baseline. At 12 months, back pain scores assessed by visual analog scale (VAS) were lower and HRQoL scores were higher than at baseline. No new safety signals were observed.
This is the first report from an observational study of daily teriparatide in Japanese osteoporotic patients at high risk of fractures. Patients in JFOS were older but had fewer osteoporosis risk factors than those treated with teriparatide in other observational studies. The interim analysis suggests that the clinical profile of teriparatide in the real world is similar to that observed in clinical trials and observational studies conducted in Europe and the United States.
Angiotensin-Converting Enzyme and Male Fertility Hagaman, John R.; Moyer, Jeffrey S.; Bachman, Eric S. ...
Proceedings of the National Academy of Sciences - PNAS,
03/1998, Volume:
95, Issue:
5
Journal Article
Peer reviewed
Open access
The angiotensin-convering enzyme (ACE; EC 3.4.15.1) gene (Ace) encodes both a somatic isozyme found in blood and several other tissues, including the epididymis, and a testis-specific isozyme (testis ...ACE) found only in developing spermatids and mature sperm. We recently used gene targeting to disrupt the gene coding for both ACE isozymes in mice and reported that male homozygous mutants mate normally but have reduced fertility; the mutant females are fertile. Here we explore the male fertility defect. We demonstrate that ACE is important for achieving in vivo fertilization and that sperm from mice lacking both ACE isozymes show defects in transport within the oviducts and in binding to zonae pellucidae. Males generated by gene targeting that lack somatic ACE but retain testis ACE are normally fertile, establishing that somatic ACE in males is not essential for their fertility. Furthermore, male and female mice lacking angiotensinogen have normal fertility, indicating that angiotensin I is not a necessary substrate for testis ACE. Males heterozygous for the mutation inactivating both ACE isozymes sire wild-type and heterozygous offspring at an indistinguishable frequency, indicating no selection against sperm carrying the mutation.
The relationship between prior fractures and risk of new fractures was evaluated in 931 postmenopausal women with prevalent vertebral fractures randomized to daily placebo or teriparatide (20 μg) in ...the Fracture Prevention Trial. The median observation time was 21 months. Among placebo patients with one, two, or three or more prevalent vertebral fractures, 7%, 16%, and 23%, respectively, developed vertebral fractures (by Cochran-Armitage trend test, P < 0.001), and 3%, 9%, and 17% developed moderate or severe vertebral fractures (P < 0.001). Among placebo patients with mild, moderate, or severe prevalent vertebral fractures, 10%, 13%, and 28%, respectively, developed vertebral fractures (P < 0.001), and 4%, 8%, and 23% developed moderate or severe vertebral fractures (P < 0.001). Among placebo patients with zero, one, or two or more prior nonvertebral fragility fractures, 4%, 8%, and 18%, respectively, developed nonvertebral fragility fractures (P < 0.001). In the teriparatide-treated group, there was no significant increase in vertebral or nonvertebral fracture risk in these subgroups. In summary, the number and severity of prevalent vertebral fractures independently predicted the risk for new vertebral fractures, and the number of prior nonvertebral fractures predicted the risk for new nonvertebral fractures in placebo patients. However, in teriparatide-treated patients, the increased fracture risk associated with prior number and severity of fracture was not observed.
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