Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.

BACKGROUND: An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM: To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS: Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS: There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION: These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

Teratogenicity of valproic acid and its constitutional isomer, amide derivative valnoctamide in mice.

OBJECTIVES: The anticonvulsant valproic acid (VPA) has a known teratogenic effect capable of inducing major congenital malformations and developmental disorders. A comparative teratogenicity study of VPA and its analog valnoctamide (VCD), which is a new generation candidate antiepileptic drug, was carried out using Swiss Vancouver (SWV) mice. METHODS: Pregnant SWV dams were treated with either a single intraperitoneal injection of VPA (1.8 and 2.7 mmol/kg), VCD (1.8 and 2.7 mmol/kg), or vehicle on E8:12 (gestational day:hour). The numbers of implantation and resorption, viable and dead fetuses, and the presence of gross fetal visceral and skeletal abnormalities were determined (E18). Real-time Polymerase chain reaction (RT-PCR) arrays were used to analyze the expression of 84 genes related to the processes of neurogenesis and neural stem cell differentiation. RESULTS: Significant decreases in pregnancy weight gain and the number of live fetuses were observed when VPA was administered at the high dose, whereas the percentage of exencephalic fetuses was significantly increased in VPA treated compared with an equivalent VCD dosage group. There was a dose-related increase in visceral defects in the VPA-exposed fetuses. Missing skull bones and fused vertebrae in fetuses occurred at the high dose of VPA. Three genes (Mtap2, Bmp8b, and Stat3) were significantly upregulated and one (Heyl) was downregulated in samples from VPA-treated dams. CONCLUSIONS: The study demonstrates that the teratogenicity of VPA was significantly greater than that of an equimolar dose of VCD. Four genes (Mtap2, Bmp8b, Stat3, and Heyl) represent candidate target genes for the underlying teratogenic mechanism responsible for VPA-induced malformations.

Intraperitoneal Local Anesthetic Instillation and Postoperative Infusion Improves Functional Recovery Following Colectomy: A Randomized Controlled Trial.

BACKGROUND: Intraperitoneal local anesthetic is an analgesic technique for inclusion in the polypharmacy approach to postoperative pain management in enhanced recovery after surgery programs. Previously, augmentation of epidural analgesia with intraperitoneal local anesthetic was shown to improve functional postoperative recovery following colectomy. OBJECTIVE: This study determines whether intraperitoneal local anesthetic improves postoperative recovery in patients undergoing colectomy, in the absence of epidural analgesia, with standardized enhanced recovery after surgery perioperative care. DESIGN: This is a multisite, double-blinded, randomized, placebo-controlled trial (ClinicalTrials.gov Identifier NCT02449720). SETTINGS: This study was conducted at 3 hospital sites in South Australia. PATIENTS: Eighty-six adults undergoing colectomy were stratified by approach (35 open; 51 laparoscopic), then randomly assigned to intraperitoneal local anesthetic (n = 44) and control (n = 42) groups. INTERVENTIONS: Patients in the intraperitoneal local anesthetic group received an intraoperative intraperitoneal ropivacaine 100-mg bolus both pre- and postdissection and 20 mg/h continuous postoperative infusion for 48 hours. Patients in the control group received a normal saline equivalent. MAIN OUTCOME MEASURES: Functional postoperative recovery was assessed by using the surgical recovery scale for 45 days; postoperative pain was assessed by using a visual analog scale; and opioid consumption, use of rescue ketamine, recovery of bowel function, time to readiness for discharge, and perioperative complications were recorded. RESULTS: The intraperitoneal local anesthetic group reported improved surgical recovery scale scores at day 1 and 7, lower pain scores, required less rescue ketamine, and passed flatus earlier than the control group (p < 0.05). The improvement in surgical recovery scale at day 7 and pain scores remained when laparoscopic colectomy was considered separately. Opioid consumption and time to readiness for discharge were equivalent. LIMITATIONS: This study was powered to detect a difference in surgical recovery scale, but not the other domains of recovery, when the intraperitoneal local anesthetic group was compared with control. CONCLUSIONS: We conclude that instillation and infusion of intraperitoneal ropivacaine for patients undergoing colectomy, including by the laparoscopic approach, decreases postoperative pain and improves functional postoperative recovery. We recommend routine inclusion of intraperitoneal local anesthetic into the multimodal analgesia component of enhanced recovery after surgery programs for laparoscopic colectomy. See Video Abstract at http://links.lww.com/DCR/A698.

Continuous wound infusion of ropivacaine for the control of pain after thoracolumbar spinal surgery: a randomized clinical trial.

PURPOSE: A prospective randomized clinical trial was carried out to observe the analgesic efficacy of ropivacaine for postoperative pain following thoracolumbar spinal surgery. METHODS: Seventy-one patients with elective posterior thoracolumbar spinal surgery were randomly divided into two groups. Local group received 0.33 % ropivacaine by pump through the wound, and intravenous group received flurbiprofen axetil, pentazocine and palonosetron via intravenous pump. We evaluated the level of pain, the incidence of adverse reactions at 2, 4, 6, 12, 24, 36 and 48 h after operation, and the occurrence of chronic pain 3 months later. RESULTS: There were no significant differences in the pain level between the two groups. However, the incidence of nausea, vomiting and chronic pain was significantly lower in the local group. CONCLUSIONS: Our results showed that local infusion of ropivacaine achieved similar analgesic effects to intravenous delivery of analgesic drugs, but significantly reduced incidence of nausea, vomiting and chronic pain.

Effect of Local Anesthetic Concentration (0.2% vs 0.1% Ropivacaine) on Pulmonary Function, and Analgesia After Ultrasound-Guided Interscalene Brachial Plexus Block: A Randomized Controlled Study.

OBJECTIVE: This study aims to assess diaphragmatic excursion and measure pulmonary functions as measures of the degree to which the phrenic nerve is blocked after ISB with two different concentrations of ropivacaine: 0.2% and 0.1%. DESIGN: Randomized, double-blinded study. SETTING AND PATIENTS: Ambulatory surgical facility. SUBJECTS: Fifty patients undergoing shoulder arthroscopy for rotator cuff repair. METHODS: Patients were randomized to receive ultrasound-guided ISB with 20 mL of either 0.2% or 0.1% ropivacaine. Diaphragmatic excursion was measured using M-mode ultrasound. Pulmonary functions were assessed by portable spirometer. Additional outcome data included oxygen saturation in post-anesthesia care unit (PACU), pain scores, quality of recovery scores (QOR), and opioid consumption over 72 hour period after surgery. RESULTS: Forced vital capacity (FVC) was significantly reduced 30 minutes after block placement and in PACU in the 0.2% group when compared with the 0.1% group (P = 0.04, P = 0.03, respectively). Forced expiratory volume (FEV1) was also significantly decreased in the 0.2% group in PACU when compared with the 0.1% group (P = 0.04). There were no significant differences in pain scores, length of stay, and total opioid consumption in PACU. Patients who received 0.2% ropivacaine had a longer block duration (18 vs 11.9 hours, P = 0.04) and used less opioid in the 72 hours after surgery (55 mg vs 102 mg codeine equivalents, P = 0.02), when they were compared to their counterparts who received 0.1% for their block. CONCLUSION: 0.1% ropivacaine may impair pulmonary function less than 0.2% ropivacaine. The clinical significance of these differences needs to be further studied.

Delayed onset and long-lasting hemidiaphragmatic paralysis and cranial nerve deficit after interscalene nerve block for rotator cuff repair in beach chair position.

Hemidiaphragmatic paralysis is the most common adverse effect associated with interscalene block. In most cases, it resolves with the resolution of nerve blockade with only an estimated incidence of 0.048% persisting for longer duration. Occasionally, interscalene block is also associated with recurrent laryngeal nerve block and seldom with cranial nerve paresis. We present a case of delayed onset and prolonged hemidiaphragmatic paralysis that was associated with 3 cranial nerve deficits after interscalene nerve block for shoulder surgery performed under general anesthesia in the beach chair position. Etiology is unclear, but most likely multifactorial.

Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series.

BACKGROUND/AIM: Herbal and dietary supplement (HDS) hepatotoxicity is increasingly being reported in the USA. This case series describes the presenting clinical features and outcomes of seven patients with liver injury attributed to OxyELITE Pro enrolled in the Drug-Induced Liver Injury Network (DILIN) study. METHODS: The 6-month outcomes of patients with hepatotoxicity attributed to OxyELITE Pro enrolled in the DILIN prospective registry between 2004 and 2015 are presented. RESULTS: Six of the seven patients (86 %) presented in 2013 with symptoms of hepatitis and acute hepatocellular injury. The median duration of OxyELITE Pro use was 18 weeks (range 5-102 weeks). Median age was 36 years (range 28-62), 86 % were female, and 43 % were Asian. One patient had rash, none had eosinophilia, and three had antinuclear antibody reactivity. The median peak ALT was 2242 U/L, alkaline phosphatase 284 U/L and bilirubin 15.0 mg/dL. Six patients (86 %) were hospitalized, three developed acute liver failure and two underwent liver transplantation. DILIN causality scores for OxyELITE Pro were definite in 1, highly likely in 3, probable in 2, and possible in 1. Four of the five patients without liver transplant recovered completely within 6 months, while one patient had mild residual ALT elevations. CONCLUSIONS: Seven cases of severe acute hepatocellular injury attributed to OxyELITE Pro are reported. These results reinforce the need to assess for HDS supplement use in patients presenting with unexplained acute hepatitis and point to the need for additional regulatory oversight of HDS products.

Lack of Analgesic Effect Induced by Ropivacaine Wound Infiltration in Thyroid Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Surgical site infiltration with local anesthetic reduces analgesic requests in various types of surgeries. Because thyroid surgery may induce severe postoperative pain, we tested the hypothesis that ropivacaine surgical site infiltration would significantly decrease postoperative administration of morphine in patients undergoing thyroid surgery. METHODS: We performed a double-blind, placebo-controlled superiority trial to assess the efficacy of surgical site analgesia with ropivacaine (10 mL, 75 mg) performed at the end of thyroid surgery in adult patients. The primary end point was the proportion of patients not requiring IV morphine in the postanesthesia care unit. RESULTS: One hundred sixty-three patients completed the study, 85 in the placebo group and 88 in the ropivacaine group. The proportion of patients requiring morphine administration in the postanesthesia care unit (55% vs 53%, P = 0.80), the dose of IV morphine administered (5.6 ± 6.1 vs 5.5 ± 6.0 mg, P = 0.90), the total dose of opioids administered (expressed as oral morphine equivalent dose: 64 ± 27 vs 69 ± 29 mg, P = 0.20), and the visual analog pain scale over the first 24 hours were not significantly different between groups. The incidence of adverse events (36% vs 39%, P = 0.88), morphine-related adverse events (19% vs 17%, P = 0.84), serious adverse events (0% vs 2%, P = 0.50), and the patient satisfaction scores (9 ± 1 vs 9 ± 1, P = 0.70) was not significantly different between the 2 groups. CONCLUSIONS: Surgical site analgesia with ropivacaine at the end of thyroid surgery is not associated with any significant analgesic benefit.

Promising alternative clinical uses of prostaglandin F2α analogs: beyond the eyelashes.

Prostaglandin F2α analogs, commonly prescribed for glaucoma treatment, have been shown to induce side effects such as cutaneous hypertrichosis and hyperpigmentation. Therefore, these medications have theoretic applications in the treatment of alopecia and disorders of hypopigmentation. We reviewed the literature to find original studies assessing the use of prostaglandin F2α analogs in these settings. Studies and reports were analyzed in regards to androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring. Based on the results of these studies, and consideration of pathophysiologic mechanism, the most promising applications for prostaglandin F2α analogs include androgenic alopecia, chemotherapy-induced alopecia, and alopecia areata concurrently treated with corticosteroids.

Nitrosatable Drug Exposure during Pregnancy and Preterm and Small-for-Gestational-Age Births.

BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.

Comparison of anesthetic efficacy and adverse effects associated with peribulbar injection of ropivacaine performed with and without ultrasound guidance in dogs.

OBJECTIVE: To compare the anesthetic efficacy and adverse effects associated with peribulbar injection of ropivacaine (1% solution) performed with and without ultrasound guidance (UG) in dogs. ANIMALS: 15 dogs without ophthalmologic abnormalities. PROCEDURES: Each dog was sedated and anesthetized. A peribulbar injection of ropivacaine (1% solution; 0.3 mL/kg) was performed with UG in 1 eye and without UG in the contralateral eye (control). For each eye, the intraocular pressure (IOP) immediately after eye centralization and number of punctures were recorded; ophthalmic complications, postinjection corneal sensitivity (determined by Cochet-Bonnet esthesiometry), durations of the sensory and motor blockades (the latter determined as the interval to restoration of the vestibuloocular reflex, pupillary light reflex, and conjugate eye movement), and blockade quality were assessed in both eyes following anesthetic recovery. RESULTS: Needle placement was fully visualized in 8 of the 15 eyes injected with UG. For eyes injected with or without UG, there was no difference with regard to the number of punctures, postinjection corneal sensitivity, and sensory or motor blockade duration and quality; however, restoration of conjugate eye movement occurred later in control eyes. For eyes injected with UG, mean IOP was 18.6 mm Hg, compared with 23.3 mm Hg for control eyes. Incidence of subconjunctival hemorrhage was higher for control eyes; severity of chemosis and hyperemia varied over time within both groups of eyes. CONCLUSION AND CLINICAL RELEVANCE: In dogs, peribulbar injection of ropivacaine with UG is feasible in dogs and provides effective sensory and motor blockades similar to those achieved with conventional techniques.

Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents.

Twenty-three 3-nitrotriazole-based and 2-nitroimidazole-based amides and sulfonamides were screened for antitubercular (anti-TB) activity in aerobic Mycobacterium tuberculosis H37Rv by using the BacTiter-Glo (BTG) microbial cell viability assay. In general, 3-nitrotriazole-based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 2-nitroimidazole-based amides and sulfonamides were inactive. Three 3-nitrotriazole-based sulfonamides (compounds 4, 2, and 7) demonstrated 50% inhibitory concentration (IC50), IC90, and MIC values of 0.38, 0.43, and 1.56 µM (compound 4), 0.57, 0.98, and 3.13 µM (compound 2), and 0.79, 0.87, and 3.13 µM (compound 7), respectively. For 3-nitrotriazole-based sulfonamides, anti-TB activity increased with lipophilicity, whereas the one-electron reduction potential (E1/2) did not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were significantly more active in the low-oxygen assay and more active than the 3-nitrotriazoles. All active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) against resistant strains, with the exception of compounds 2, 3, 4, and 8, which demonstrated greater MIC values against isoniazid-resistant strains. Five 3-nitrotriazole-based sulfonamides demonstrated activity in infected murine J774 macrophages, causing log reductions similar to those seen with rifampin. However, some compounds caused toxicity in uninfected macrophages. In conclusion, the classes of 3-nitrotriazole-based amides and sulfonamides merit further investigation as potential antitubercular agents.

Postoperative pain relief after total hip arthroplasty: a randomized, double-blind comparison between intrathecal morphine and local infiltration analgesia.

BACKGROUND: Postoperative pain after total hip arthroplasty (THA) can delay mobilization. This was assessed after intrathecal morphine (ITM) compared with local infiltration analgesia (LIA) using a non-inferiority design. METHODS: Eighty patients were recruited in this randomized, double-blind study. ITM 0.1 mg (Group ITM) or periarticular local anaesthetic (ropivacaine 300 mg)+ketorolac 30 mg+ epinephrine 0.5 mg (total volume 151.5 ml) (Group LIA) were compared. After 24 h, 22 ml of saline (Group ITM) or ropivacaine (150 mg)+ketorolac (30 mg)+epinephrine (0.1 mg) (Group LIA) were injected via a catheter. After operation, rescue analgesic consumption, pain intensity, and home-readiness were measured. RESULTS: Morphine consumption was equivalent, median difference 0 mg (95% confidence interval -4 to 4.5) between the groups at 0-24 h. During 24-48 h, it was lower in Group LIA (3 mg, 0-60 mg, median, range) compared with Group ITM (10 mg, 0-81 mg) (P=0.01). Lower pain scores were recorded at rest at 8 h in Group ITM (P<0.01), but in Group LIA on standing and mobilization, at 24-48 h (P<0.01). Paracetamol and tramadol consumption was lower in Group LIA (P=0.05 and 0.05, respectively) as was pruritus, nausea, and vomiting (P<0.05). CONCLUSION: Lower pain intensity was recorded early after surgery in ITM group but later, analgesic consumption, pain intensity on mobilization, and side-effects were lower in patients receiving LIA. LIA is a good alternative to ITM in patients undergoing THA.

The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide in the treatment of hypertension.

INTRODUCTION: Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects. AREAS COVERED: This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions. EXPERT OPINION: Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin-angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.