First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E.

Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 days for the 0.330-mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).

Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect?

INTRODUCTION: Although antifibrinolytic agents are used to prevent and treat hemorrhage, there are concerns about a potential increased risk for peripartum venous thromboembolism. We sought to determine the impact of tranexamic acid and ɛ-aminocaproic acid on in vitro clotting properties in pregnancy. METHODS: Blood samples were obtained from healthy pregnant, obese, and preeclamptic pregnant women (n = 10 in each group) prior to delivery as well as from healthy non-pregnant controls (n = 10). Maximum clot firmness (MCF) and clotting time (CT) were measured using rotation thromboelastometry in the presence of tranexamic acid (3, 30, or 300 µg/mL) or ɛ-aminocaproic acid (30, 300, or 3000 µg/mL). ANOVA and regression analyses were performed. RESULTS: Mean whole blood MCF was significantly higher in healthy pregnant vs. non-pregnant women (66.5 vs. 57.5 mm, p < 0.001). Among healthy pregnant women, there was no significant difference between mean MCF (whole blood alone, and with increasing tranexamic acid doses = 66.5, 66.1, 66.4, 66.3 mm, respectively; p = 0.25) or mean CT (409, 412, 420, 424 sec; p = 0.30) after addition of tranexamic acid. Similar results were found using ɛ-aminocaproic acid. Preeclamptic women had a higher mean MCF after the addition of ɛ-aminocaproic acid and tranexamic acid (p = 0.05 and p = 0.04, respectively) compared to whole blood alone. CONCLUSIONS: Pregnancy is a hypercoagulable state, as reflected by an increased MCF compared to non-pregnant women. Addition of antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant, pregnant, and obese women. Whether antifibrinolytics are safe in preeclampsia may require further study.

Cervical dilation as a predictor of pregnancy outcome following emergency cerclage.

OBJECTIVE: To determine whether cervical dilation at the time of physical examination indicated cerclage placement can predicts latency and gestational age at delivery. METHODS: A retrospective cohort study of all women who underwent physical examination indicated cerclage placement from 1996 to 2011 at Duke University Hospital (DUH) was performed. Physical examination indicated cerclage was defined as cerclage placement after 16 weeks in women with a cervical length of less than 2.5 cm and/or cervical dilation greater than or equal to 1 cm at time of procedure. Subjects were divided into two groups depending on cervical dilation at time of procedure (2 cm, <2 cm) for comparison. A multivariate linear regression model for the outcome gestational age of delivery was constructed, controlling for confounding variables. RESULTS: A total of 110 women with complete data were available for analysis. Median gestational age at cerclage placement was similar between the two groups (20.3 vs. 20.3 weeks, p = 0.8). Women with cervical dilatation ≥ 2 cm dilation delivered at an earlier median gestational age than women with cervical dilation <2 cm (27.0 vs. 35.6 weeks, p < 0.001). Cervical dilation at the time of cerclage placement independently predicted gestational age at delivery while controlling for use of intracervical Foley balloon catheter for membrane reduction, cerclage suture type, history of prior preterm birth, race, insurance status, and tobacco use. CONCLUSIONS: Women who receive a rescue cerclage are more likely to deliver at an earlier gestational age when cervical dilation is ≥ 2 cm at the time of procedure.

Religiosity is an important part of coping with grief in pregnancy after a traumatic second trimester loss.

Women (n = 15) who were pregnant after a traumatic late pregnancy loss (termination because of fetal death or serious anomalies) completed psychometric screening tests and scales, including the Perinatal Grief Scale (PGS), the Impact of Event Scale (IES), the Duke Depression Inventory (DDI), the Generalized Anxiety Disorder-7 (GAD), and the Hoge Scale for Intrinsic Religiosity (IR). Despite a mean elapsed time since the prior loss of 27 (range, 7-47) months, half (7/15, 47%) of the combined groups had high levels of grief on the PGS. Multiple positive scores on psychometric tests were frequent: Sixty percent (9/15) had high scores on the PGS Active Grief subscale or on the IES. Forty percent (6/15) had a high score on the DDI, and 17% (3/15) on the GAD. IR scores significantly and negatively correlated with scores on the Despair subscale of the PGS. The results from this pilot study suggest that high levels of grief and PTS symptoms are significant problems for pregnant women who have suffered late loss of a wanted pregnancy. Religiosity may play an important part in maternal coping during these stressful pregnancies.

Pregnancy outcomes associated with viral hepatitis.

The aim of this study was to examine the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to pregnancy-related complications including gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), pre-eclampsia, antepartum haemorrhage and cholestasis. The Nationwide Inpatient Sample was queried for all pregnancy-related discharges, pregnancy complications and viral hepatitis from 1995 to 2005. Logistic regression was used to examine the association between HBV, HCV, HBV + HCV and pregnancy-related complications including GDM, PTB, IUGR, pre-eclampsia, antepartum haemorrhage, cholestasis and caesarean delivery. Model covariates included maternal age, race, insurance status, substance use and medical complications including liver complication, hypertension, HIV, anaemia, thrombocytopenia and sexually transmitted infections. Of 297 664 pregnant women data available for analysis, 1446 had a coded diagnosis of HBV, HCV or both. High-risk behaviours, such as smoking, alcohol and substance use were higher in women with either HBV or HCV. Women with HBV had an increased risk for PTB (aOR 1.65, CI [1.3, 2.0]) but a decreased risk for caesarean delivery (aOR 0.686, CI [0.53, 0.88]). Individuals with HCV had an increased risk for GDM (aOR 1.6, CI [1.0, 2.6]). Individuals with both HBV and HCV co-infection had an increased risk for antepartum haemorrhage (aOR 2.82, CI [1.1, 7.2]). There was no association of viral hepatitis with IUGR or pre-eclampsia. Women with hepatitis have an increased risk for complications during pregnancy. Research to determine the efficacy and cost-effectiveness of counselling patients about potential risks for adverse outcomes is warranted.

Bleeding per vaginam is associated with funisitis in women with preterm prelabour rupture of the fetal membranes.

OBJECTIVE: To evaluate the risk of funisitis among women with preterm prelabour rupture of the membranes (PPROM) and subsequent bleeding per vaginam. DESIGN: Prospective cohort study. SETTING: A University Hospital in the USA. POPULATION: A total of 157 women with PPROM, divided into those with bleeding per vaginam during the hospital admission (n = 46) and those without bleeding per vaginam (n = 111). METHODS: Pathologist blinded to bleeding status assessed placental pathology for funisitis. MAIN OUTCOME MEASURES: Funisitis. RESULTS: Women with bleeding per vaginam were more likely to have funisitis (67.4% versus 36%, P < 0.001) compared with those without bleeding. Logistic regression demonstrated that bleeding per vaginam predicted funisitis after controlling for gestational age at admission, latency period and gestational age at delivery. CONCLUSIONS: Among women with PPROM, those with bleeding per vaginam are more likely to have funisitis than those without bleeding per vaginam.

Severe factor V deficiency presenting with intracranial haemorrhage during gestation.

We present a case of intracranial haemorrhage detected by ultrasound at 36 weeks gestation in a foetus who was ultimately diagnosed with severe factor V deficiency. An abnormality of the foetal heart rate, auscultated at a routine antenatal visit, prompted an investigation that led to an ultrasound examination and detection of an intracranial haemorrhage and low amniotic fluid volume. An intrauterine foetal demise was averted. The clinical scenario in this case raises the issue of how often a stillbirth with intracranial haemorrhage may result from unrecognized factor deficiency.

Vrksayurveda of parasara--an ancient treatise on plant science.

Vrksayurveda of Parasara is a great contribution to the Botany in ancient India. N.N. Sircar and Roma sarkar edited this text with English translation. Notes with comparative references of modern botany were added. This book can be placed in all probability in between 1st century B.C to 4th century A.D by its linguistic style. Many scientific branches of Botany including origin of life, ecology, distribution of forests, morphology, classification, nomenclature, histology and physiology were dealt in this ancient work. Though it is presumed that this book was written by Parasara to teach Botany to preparatory to Ayurveda studies to ancient Ayurveda students, it is true to the Ayurveda personals and other disciplines related to Botany of present day as well. Aim of this article is to attract the attention of all scholars who are related to Ayurveda and Botany and to feel the depth of the knowledge of ancient Indian botany.

Vandhyatva--a medico historical study.

As per Ayurveda, important factors for conception are considered as rtu (fertile period), Ksetra (uterus and reproductive organs), Ambu (Proper nutrient fluid) and Bija (sukra-sonita) and also normalcy of Hrdaya (Psychology). Abnormality of properly functioning Vayu and Satbhavas (matrja, pitrja, atma, satva, satmaya and Rasa), any one of these causes infertility (Vandhyatva). From the time immemorial the phenomenon of infertility was prevalent through out the world and this may persist till the human race exists. Every human being has inherent, intense desire to continue his (one's) own race; to become a mother is one of the most cherished desires of every woman. Failure to achieve conception by a couple of mature age, having normal coitus during appropriate period of menstrual cycle regularly, at least for one year of their conjugal is termed as infertility. The historical importance of stri vandhyatva and a comparative study regarding its Nidana, Samprapti, Laksana, Chikitsa etc compiled from various Granthas are being presented in this paper.

Historical evidences on medicolegal autopsy and toxicological descriptions in Kautilya's Arthasastra.

Kautilya's Arthasastra deals mainly the art of government, duties of Kings, ministers, officials and methods of diplomacy. It also deals with branches of internal and foreign policies, civil, military, commercial, fiscal, judicial etc. By name and popularity of the book, scholars believe this as seed of political science and Economics. Surprisingly, it also has the descriptions of many Ayurveda herbs, metals, herbomineral preparations and poisonous substances. This book also deals with medico legal autopsy and Toxicology. The main aim of this article is to highlight the descriptions of forensic medicines and toxicology.

A contemporary scientific support on role of ancient ayurvedic diet and concepts in diabetes mellitus (madhumeha).

Diabetes Mellitus (Madhumeha) is a well-known clinical syndrome since antiquity. First time the role of Diet in the prevention, etiology and treatment of Diabetes was mentioned in Ayurveda under the heading of Prameha and Madumeha. Caraka Samhita, Susruta Samhita and other Ayurvedic classics have appropriate descriptions on the role of diet, habits and life style in Prameha and Madhumeha, which is akin to Diabetes. Recent modern (contemporary) Researches and statistics support these descriptions. Aim of this article is to alarm people regarding role of diet and lifestyle in Diabetes through Ayurvedic approach and contemporary scientific correlation with support of clinical and statistical data.

Contribution of kautilya arthasashtra towards dravyaguna, rasasastra and bhaishajyakalpana branches of ayurvedic medicine.

It is believed Kautilya, whose name was Vishnugupta and is popular as Chanakya (The son of Chanaka) wrote Arthasastra. This article is mainly based on Kautilya's Arthasastra, translated by R. Shamasastry. In the preface of 1(st) to 5(th) edition of this text, the translator Dr. R. Shamasastry tried to clarify the uncertainty regarding the name of the author and the time of the text. Kamandaka and Dandi quotation support the time of this treatise somewhere between 321 and 300 B.C. These quotations also support the authorship of Vishnugupta. According to Kadambari, the author of Arthasastra was Kautilya and according to Manu and Dharmasastras, Chanakya had written this Arthasastra. Though there are some controversies regarding the name of the author and time of this text, translator R. Shamasastry tried his level best in providing proper support for naming this text as Kautilya'sArthasastra as the original available manuscript contains the name of Kautilya at the end of each of the hundred and fifty chapters of the work. Still there is controversy regarding the exact time of this text. If views of many scholars is considered, time of the text can be placed between 3(rd) century B.C. to 3(rd) century A.D. This translated original text contains 15 books (Basic discussions of the text), 150 chapters, 180 sections and 6000 Slokas (Thirty two syllables are considered as one Sloka).

A literary review of Arsas (haemorrhoids).

The disease Arsas (hemorrhoids), an ano-rectal disorder is as old as mankind. Susrta farther of surgery described the Arsas under heading of 'Mahagadas' (eight major diseases). Due to inconsistency of human diet and social obligations, a large proportion of the population is suffering from hemorrhoids. As per Ayurveda, the etiological factors are broadly classified as Samanya (Non-specific) and Visesa (Specific). Visesa again sub divided in to Sahaja and Janmottara. Susrta classified this disease on the basis of clinical manifestations in to six types, where as Caraka and Vagbhata classified in to two according to discharging nature and causative factors respectively.