A novel on-demand therapy for lifelong premature ejaculation using a miniature transperineal electrical stimulator-the vPatch: an as-treated analysis.

BACKGROUND: While premature ejaculation (PE) is a common and disturbing sexual dysfunction in men, current available treatment modalities have limited efficacy and low treatment adherence. AIM: To assess the feasibility, safety, and efficacy of the vPatch, a miniaturized on-demand perineal transcutaneous electrical stimulation device for treating PE. METHODS: This prospective bicenter international first-in-human clinical study consisted of 2 arms, was sham controlled, and had a randomized double-blind design. In terms of statistical power calculation, 59 patients aged 21 to 56 years (mean ± SD, 39.8 ± 9.28) with lifelong PE were included. During the initial visit, intravaginal ejaculatory latency time (IELT) was measured over a 2-week run-in period. Eligibility was confirmed in visit 2, based on IELT values, medical and sexual history, and patients' individualized sensory and motor activation thresholds during perineal stimulation with the vPatch. Patients were randomized to the active (vPatch) and sham device groups in a 2:1 ratio, respectively. The vPatch device's safety profile was determined by comparing the incidence of treatment-emergent adverse events. During visit 3, IELTs, Clinical Global Impression of Change scores, and Premature Ejaculation Profile questionnaire outcomes were recorded. Primary end points assessed vPatch device efficacy as mean change in geometric mean IELT; each person was compared with himself, with and without the device, and the sham group was compared with the active group. OUTCOMES: Outcomes included changes in IELT and Premature Ejaculation Profile before and after treatment, last visit Clinical Global Impression of Change scores, and vPatch safety profile. RESULTS: Of 59 patients, 51 completed the study: 34 in the active group and 17 in the sham group. The baseline geometric mean IELT significantly increased from 67 to 123 seconds (P < .01) in the active group, as compared with an insignificant increase from 63 to 81 seconds (P = .17) in the sham group. The increase in mean IELT in the active group was significantly higher than in the sham group (56 vs 18 seconds, P = .01). IELT significantly increased by 3.1 times in the active vs sham group. The mean ratio of fold change (active:sham) was 1.4, significantly different from 1.0 (P = .02). No serious adverse events were reported. CLINICAL IMPLICATIONS: Therapeutic use of the vPatch during coitus may become an on-demand, noninvasive, and drug-free treatment for PE. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first rigorous study investigating whether transcutaneous electrical stimulation during coitus could improve the symptoms of men with lifelong PE. The study is limited by the small number of patients, the exclusion of patients with acquired PE, the short-term follow up, and the use of a device based on a theoretic mechanism of action. CONCLUSION: We demonstrated the possibility to treat lifelong PE by prolonging coitus on demand, using electric stimulation of ejaculation muscles with the vPatch.Clinical trial registration: NCT03942367 (ClinicalTrials.gov).

Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Automated versus manual urine output monitoring in the intensive care unit.

Acute kidney injury (AKI) is defined by changes in serum creatinine and urine output (UO). Significant limitations exist regarding accurate ascertainment of urine output even within the intensive care unit. We sought to evaluate an automated urine output collections system and compare it to nursing measurements. We prospectively collected urine output using an electronic urine monitoring system and compared it to charted hourly UO in 44 patients after cardiac surgery at a single university hospital ICU. We calculated UO and oliguria rates and compared them to data from the sensor and from nursing charting. A total of 187 hourly UO measurements were obtained and on average, UO was reported 47 min late, with a median of 18 min, and a maximum of almost 6 h. Patients had a mean hourly UO of 76.3 ml over the observation period. Compared to manual measurements by study personnel, nurses significantly overestimated hourly UO by 19.9 ml (95% CI: 10.3; 29.5; p = < 0.001). By contrast, the mean difference between the UO measured with the sensor and by study personnel was 2.29 ml (95% CI: - 6.7; 11.3), p = 0.61. Electronic UO monitoring is significantly more accurate than nurse-performed manual measurements in actual intensive care patients. Furthermore, timely ascertainment of UO is difficult to achieve with manual technique, resulting in important delays in detecting oliguria perhaps leading to missed cases of AKI.

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. METHODS: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. RESULTS: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). CONCLUSIONS: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

Association Between Hyperbaric Bupivacaine Dose and Maternal Hypotension: Retrospective Database Study of 8226 Women Undergoing Cesarean Delivery Under Spinal Anesthesia.

BACKGROUND: Low-dose (≤8 mg) hyperbaric bupivacaine for spinal anesthesia during cesarean delivery results in reduced efficacy, yet as a secondary outcome was associated with reduced frequency of spinal-induced hypotension. Our primary aim was to investigate the relationship between hyperbaric bupivacaine dose and the occurrence of spinal-induced hypotension for cesarean delivery. METHODS: Retrospective study of cesarean delivery under spinal or combined spinal anesthesia with hyperbaric bupivacaine in 1 academic institution (2 centers-tertiary and district) from 2012 to 2018. Data were retrieved from the anesthesia information management systems (Metavision, iMDsoft, Tel Aviv, Israel) and the hospital information system, including potential confounding factors, maternal age and weight, hypertensive disease of pregnancy, single/multiple gestation, gestational age, vasopressor administration, planned/urgent surgery, position during anesthesia placement (sitting/lateral), and anesthesiologist seniority. Spinal-induced hypotension was defined as systolic blood pressure that either dropped >20% from baseline or <100 mm Hg. The primary outcome of interest was the incidence of spinal-induced hypotension according to hyperbaric bupivacaine dose. Logistic regression was used to characterize the association between the dose of hyberbaric bupivacaine and spinal-induced hypotension after adjusting for confounding factors. RESULTS: A total of 8226 women were identified. The hyperbaric bupivacaine dose administered was <9 mg for 2395 (29.1%), 9-9.5 mg for 1031 (12.5%), 10 mg for 4155 (50.5%), and >10 mg for 645 (7.8%). We used a cutoff (<10 vs ≥10 mg) to assess for the primary outcome, using multivariable logistic regression. The incidence of at least 1 spinal-induced hypotension episode was higher in patients who received ≥10 mg hyperbaric bupivacaine, 75.8% vs 62.9% for doses below 10 mg, P < .0001; however, even women with lower doses had hypotension. Hyperbaric bupivacaine dose <10 mg was associated with a lower incidence of spinal hypotension, adjusted odds ratio (OR) of 0.774, 95% confidence interval (CI), 0.669-0.897, and P = .0006, adjusted for confounding factors.Umbilical cord pH was available for 2684 (32.6%) cases. There were significantly more neonates with pH < 7.2, among women who received hyperbaric bupivacaine ≥10 mg (10.1%) versus women who received <10 mg (6.8%), P = .0032; however, in the adjusted model, hyperbaric bupivacaine dose ≥10 mg was not associated with pH < 7.2 and an OR of 0.955 (95% CI, 0.631-1.446, P = .829). CONCLUSIONS: Our major finding was that hypotension occurred at all doses of hyperbaric bupivacaine, yet occurrence of spinal hypotension was significantly associated with doses ≥10 mg after adjustment for potential confounders.

PTL401, a New Formulation Based on Pro-Nano Dispersion Technology, Improves Oral Cannabinoids Bioavailability in Healthy Volunteers.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex®). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma Cmax than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology.

Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects. PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design. Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3-fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray. PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications.

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Cognitive-emotional reactivation during deep transcranial magnetic stimulation over the prefrontal cortex of depressive patients affects antidepressant outcome.

BACKGROUND: Transcranial magnetic stimulation (TMS) enables non-surgical activation of specific brain areas. TMS over the prefrontal cortex (PFC) is emerging as a significant tool that can augment or replace non/partially effective antidepressant medications. Deep TMS (DTMS) utilizes newly developed coils that enable effective stimulation of deeper cortical layers involved in the pathophysiology of depression. OBJECTIVES: We aimed to assess the H1-DTMS coil as an add-on to antidepressants in treating patients with major depression. We also intended to evaluate whether the antidepressant outcome of DTMS treatment is affected by a cognitive-emotional procedure performed during stimulation. METHODS: 57 patients were enrolled in the study that included 4 weeks of daily 20 Hz stimulation sessions and additional 4 weekly sessions as a short maintenance phase. Two subgroups of patients received either positive or negative cognitive-emotional reactivation along with the stimulation sessions. RESULTS: 21 of 46 patients (46%) who received at least 10 stimulation sessions achieved response (improvement of ≥ 50% in the Hamilton Depression Rating Scale (HDRS)) and 13 of them (28%) achieved remission (HDRS-24 ≤ 10) by the end of the daily treatment phase. Improvements were smaller in the negatively reactivated group and Beck Depression Inventory scores were not significantly improved in this group. CONCLUSIONS: DTMS over the PFC proved to be safe and effective in augmenting antidepressant medications. Negative cognitive-emotional reactivation can disrupt the therapeutic effect of DTMS. A large sham controlled study is required to further establish the effectiveness of DTMS as an augmentation treatment and the role of cognitive reactivation during stimulation.