Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinson disease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100 mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P < .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

A Phase I/II Clinical Trial of Intradermal, Controllable Self-Replicating Ribonucleic Acid Vaccine EXG-5003 against SARS-CoV-2.

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNPs). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG-5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG-5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG-5003 showed higher cellular responses compared with equivalently vaccinated participants in the placebo group. The findings suggest a priming effect of EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

Bone marrow-derived NCS-01 cells for ischemic stroke.

Stroke stands as one of the most common causes of death among adults worldwide. Currently, tissue plasminogen activator serves as the only approved drug by the Food and Drug Administration for the treatment of acute ischemic stroke. Stem cell therapy serves as a viable treatment option and has been deemed as a safe and effective treatment for stroke patients. Adult human bone marrow-derived NCS-01 cells serve as a potential treatment for stroke given their ability to reduce stroke-induced pathological deficits by increasing cell viability and mitochondrial activity. Recently, we demonstrated the use of adult bone marrow-derived NCS-01 cells both on both in vitro and in vivo models. Using NCS-01 cells in rat stroke models subjected to middle cerebral artery occlusion, an effective dosage of 7.5 × 106 cells/ml, administered through the intracarotid artery within 3 days poststroke, was shown to display significant improvements in motor and neurological behaviors, reductions in infarct area, and peri-infarct cell loss. NCS-01 cells, in comparison with other lines of stem cells (Li cells), are shown to produce greater therapeutic effects, most likely due to the observed filopodia formation that allows the stem cells to extend and target the ischemic cells. Given these findings, NCS-01 stem cells serve as a potential treatment for stroke through the demonstration of profound efficacy and further research that favors their filopodia-mediated mechanism of action.

[Sodium intake from seasonings by dish category and age group: An analysis of the 2014 Yamanashi Prefecture Nutrition Survey results].

Objective　To elucidate information on people's consumption of seasonings with a higher sodium content than those of other food groups.Methods　This study used the data of 503 persons aged≥20 years who participated in the 2014 Yamanashi Prefecture Nutrition Survey; survey responses connected with the consumption of seasonings were analyzed. Using the Japanese Standard Tables of Food Composition, the amount of salt intake per person was calculated based on the total household intake and apportioning. Dishes were classified into eight categories: rice, noodle, soup, grilled, deep-fried, simmered, marinated, and other. The proportion of participants who consumed salt-containing seasonings for breakfast, lunch, and dinner was first calculated. Then, the proportion of those who consumed salt-containing seasonings was calculated according to dish category. Finally, the proportion of those who consumed salt-containing seasonings was calculated according to dish category and age group.Results　The following seasonings were identified to have been the most frequently consumed by the participants: soy sauce, salt, miso (fermented soybean paste), noodle sauces, ketchup, sauces, mayonnaise, Japanese soup stock granules, soup broth cubes, Chinese soup stock, dressings, and curry or stew blocks. The proportion of participants who consumed seasonings in daily meals was 86.3 % for soy sauce, 84.5% for salt, 73.4% for miso, and 69.6% for Japanese soup stock granules. Moreover, most of the participants consumed seasonings in marinated dishes (84.5%), followed by soup (74.2%), grilled (67.0%), and simmered (67.0%) dishes. An analysis of the proportion of people who consumed salt-containing seasonings according to dish category and age group showed that the proportion of people who consumed soups and marinated dishes increased significantly with increasing age (P<0.001), whereas the proportion of those who consumed deep-fried and grilled dishes decreased significantly (P=0.028, P<0.001). Meanwhile, an analysis of the relationship between age group and dish category according to salt intake showed that while salt intake from marinated dishes increased significantly with increasing age (P=0.008), that from deep-fried dishes decreased significantly (P<0.001).Conclusion　Through analyzing the proportion of people of whom seasonings were their main source of salt intake according to age in the Yamanashi Prefecture, it was shown that the consumption of soups and marinated dishes increased significantly with increasing age; in contrast, young people often consumed grilled and deep-fried dishes.

Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke.

Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells' ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials.

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.

Clonazepam for chemotherapy-induced nausea and vomiting (CINV).

BACKGROUND: A 51-year-old woman experienced refractory chemotherapy-induced nausea and vomiting (CINV) in spite of extensive antiemetic therapy, including 5-HT3 antagonists, corticosteroids, dopamine antagonists and antihistamines. CASE REPORT: We administered the patient clonazepam. After taking clonazepam, the patient fully recovered from the nausea and vomiting and never experienced them again. CONCLUSION: Clonazepam may be useful in the control of CINV. We believe that clonazepam contributed to the favorable outcome by expressing an anxiolytic and an anticonvulsant effect on myoclonus. The efficacy of clonazepam in this indication of prevention of CINV warrants further investigation.

Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.

BACKGROUND: The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia (HGF-STAT trial) determined the effect of hepatocyte growth factor (HGF) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension (TcPo(2)) in patients with critical limb ischemia (CLI). METHODS AND RESULTS: Randomized patients with rest pain or ischemic ulcers and TcPo(2) <40 mm Hg and/or toe pressure <50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows: 0.4 mg at days 0, 14, and 28 (low dose); 4.0 mg at days 0 and 28 (middle dose); or 4.0 mg at days 0, 14, and 28 (high dose). Patients were evaluated for safety, changes in TcPo(2) and ankle and toe pressure, amputation, and wound healing. Ninety-three of 104 treated patients were evaluated for safety (mean age 70 years, 63% male, 53% diabetic, 64% with tissue loss, mean ankle-brachial index 0.41, and mean toe pressure 26 mm Hg). Adverse events occurred in 86% of the patients, most of which were related to CLI or comorbid conditions and were not different between groups. TcPo(2) (mean+/-SE) increased at 6 months in the high-dose group (24.0+/-4.2 mm Hg, 95% CI 15.5 to 32.4 mm Hg) compared with the placebo (9.4+/-4.2 mm Hg, 95% CI 0.9 to 17.8), low-dose (11.1+/-3.7 mm Hg, CI 3.7 to 18.7 mm Hg), and middle-dose (7.3+/-4.8 mm Hg, CI -2.2 to 17.0 mm Hg) groups (ANCOVA P=0.0015). There was no difference between groups in secondary end points, including ankle-brachial index, toe-brachial index, pain relief, wound healing, or major amputation. CONCLUSIONS: Intramuscular injection of HGF plasmid was safe and well tolerated. Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted.

[Clinical factors related to gains in body mass index (BMI) among patients under long-term antipsychotic treatment].

OBJECTIVE: Weight gain and obesity are often seen among patients taking antipsychotic drugs, the incidence being higher in this group than among the general adult population. They constitute risk factors for other diseases, such as hyperlipidemia, type 2 diabetes mellitus and hypertension, and may also adversely affect a patient's compliance. Thus the control of weight gain and obesity is significantly related to the quality of life for those who are under long-term antipsychotic treatment. We therefore conducted a retrospective investigation on the process of BMI increase in patients treated with antipsychotic agents over an extended period. The BMI of these patients was compared with measurements in the general adult population and the clinically relevant factors contributing to weight gain were identified. METHOD: The subjects were 66 outpatients (35 males, 31 females; mean age 37.5 +/- 11.9 y.o., range 15-65 years) who satisfied the F2 category of the ICD-10 diagnostic criteria, and who were on antipsychotic drugs for more than 2 years and less than 15 years. The study was conducted at two psychiatric clinics between May 1, 2000 and June 1, 2001. The results of the survey were analyzed as follows: 1) The BMI of the subjects was compared against that of the controls who visited the Health Center, the Jikei Hospital from 1999 to 2002 to observe time-related trends over the study period; and 2) The odds ratio was computed using a logistic regression model with the mean of the changes in BMI during treatment as a dependent variable and clinically related factors, gender, age, diagnosis, clinical outcome, duration of treatment, baseline BMI, and type and dose of antipsychotic drugs as independent variables, to determine those factors contributing to the gain in BMI. RESULTS: 1) When the patients' ages were stratified, there were no significant differences between the male patients and the corresponding standard, either for the baseline or recent BMI at each age level, with the exception of the 15-39 age level. Among female patients, there were no significant differences for the baseline BMI at any age level. However, the recent BMI for them was significantly higher at all age levels. 2) In the study of factors related to increase in BMI, 3 factors--gender, age, and complete remission in clinical outcome--were found to have significant difference. The odds ratio was significantly higher in the female subjects (4.94; 95% CI: 1.42-17.27) and significantly lower in older subjects (0.93; 95% CI: 0.88-0.99), and in those subjects who were in complete remission (0.081; 95% CI: 0.007-0.954). No other factors produced statistically significant differences. DISCUSSION: 1) Gender, age, and clinical outcome were the independent factors that contributed to the increase in BMI for those patients under long-term antipsychotic treatment. 2) The gain in BMI was greater in female patients than in male patients. 3) Age was inversely related to the gain in BMI, therefore special care must be taken after administering antipsychotic drugs because younger patients may gain excessive weight and develop weight-related complications at an earlier stage. 4) The increase in BMI was minimal for patients in complete remission, suggesting that these patients were better adapted socially and aware of maintaining an optimum BMI. In planning antipsychotic treatment for each patient, not only its efficacy on psychiatric symptoms but also the risks--such as an increase in BMI--should be taken into consideration.

[Relationships between infant lifestyle and adolescent obesity. The Enzan maternal-and-child health longitudinal study].

OBJECTIVE: A longitudinal study was analyzed to clarify relationships between infant lifestyle, obesity, features of family life and adolescent obesity. SUBJECTS AND METHODS: Subjects in the present study were born between April 1987 and March 1991, in Enzan City, Yamanashi prefecture. Infant height and weight were measured and questionnaires were collected at medical check-ups at 1.5- and 3-year-of age. Adolescent height and weight were measured in April 2000. Obese adolescents were defined as those with on obesity index > or = 20%. RESULTS: At 1.5-years-of age, 883 responses to the questionnaire were obtained, and 737 subjects were followed to adolescence (83.5%). Mean follow-up period was 10 years 11 months. A high Kaup index at 1.5-years-of age (odds ratio (OR) 2.61; 95% confidence interval (CI) 1.11-6.12) and when 3-years-of age (OR 5.34; CI 2.54-11.23), as well as maternal obesity (OR 5.32; CI 2.67-10.60) represented risk factors for adolescent obesity. Of the lifestyle items, "playing alone inside" at 1.5-years-of age (adjusted OR 3.01; CI 1.01-8.99) and "taking snacks without time constraints" at 3-years-of age (adjusted OR 2.12; CI 1.25-3.61) were additional risk factors. In food items, only low intake of cow's milk displayed a significant relationship with adolescent obesity, the link being negative with an adjusted OR of 0.63 (CI 0.41-0.95). Covariance structural analysis was performed and a causal model was constructed. Maternal obesity, obesity at 3-years-of age, playing alone inside, taking snacks without time constraints, and low intake of cow's milk were all associated with obesity in infancy. Maternal obesity affected methods of answering child demands, in turn affecting snacking habits. CONCLUSIONS: Adolescent obesity displays relationships with maternal obesity, a high Kaup index in infancy, play activity, snacking habits, and intake of cow's milk. Although genetic factors exert a strong influence, these components of infant lifestyle all play a role in the development of adolescent obesity.