Pharmacokinetics and Excretion Studies on CDRI-85/92, an Antiulcer Proton Pump Inhibitor

CDRI 85/92 is an antiulcer pharmacophore and a proton pump inhibitor, which is in an advanced stage of preclinical trials. In view of its importance, pharmacokinetic and excretion were studied in Sprague Dawley rats after administering 20 mg/kg oral and intravenous doses. The compound was detectable in the serum samples as early as 5 min post-oral administration. The compound was eliminated slowly from serum with an elimination half-life of 2.1 h. Following the 20 mg/kg oral dose, maximum serum concentration (Cmax) was found to be 469.28 ± 45.52 ng/ml after 1.0 h. Based on AUC values, the absolute bioavailability of the CDRI 85/92 was 70.5% after oral administration. It was found to be excreted in urine (~15% of the dose) in intravenously treated (bile duct cannulated as well as noncannulated) rats, whereas bile and feces depicted insignificant levels of the compound

Mass Spectrometry as a Workhorse for Preclinical Drug Discovery: Special Emphasis on Drug Metabolism and Pharmacokinetics

Mass spectrometry as an instrument is popular, given its sensitivity, selectivity, speed and robustness. In this chapter, we have briefly deliberated on various mass spec platforms, their hardware components and specific applications in preclinical drug discovery with a special emphasis on drug metabolism and pharmacokinetic assays. Basic principle of operation of mass spectrometer and various ionization techniques/mass analyzers was explicitly discussed. Compatibility of mass spectrometers with ultrafast LC and various throughput techniques, enabled evaluation of thousands of compounds with quick turnaround times. Faster generation of results corresponding to in vitro ADME and in vivo pharmacokinetic assays, aid medicinal chemists to refine their combinatorial synthetic chemistry efforts and expedite the lead optimization and identification phases of drug discovery. Mass spectrometer is a powerful tool for both qualitative and quantitative applications. While quantitative applications include measurement of absolute/relative concentrations, qualitative features assist in identification of molecular structures of metabolites and putative biotransformation pathways. Qualitative inputs are more precise and accurate, with the advent of high-resolution mass spectrometry technology. Although, mass spectrometry has many built-in advantages, it also suffers from matrix effects, as the samples analyzed are mostly of biological origin and are complex in nature. In this chapter, we have defined the nature of matrix effects and various approaches by which these matrix effects can be mitigated

A self assembled monolayer based microfluidic sensor for urea detection

Urease (Urs) and glutamate dehydrogenase (GLDH) have been covalently co-immobilized onto a self-assembled monolayer (SAM) comprising of 10-carboxy-1-decanthiol (CDT) via EDC–NHS chemistry deposited onto one of the two patterned gold (Au) electrodes for estimation of urea using poly(dimethylsiloxane) based microfluidic channels (2 cm × 200 μm × 200 μm). The CDT/Au and Urs-GLDH/CDT/Au electrodes have been characterized using Fourier transform infrared (FTIR) spectroscopy, contact angle (CA), atomic force microscopy (AFM) and electrochemical cyclic voltammetry (CV) techniques. The electrochemical response measurement of a Urs-GLDH/CDT/Au bioelectrode obtained as a function of urea concentration using CV yield linearity as 10 to 100 mg dl−1, detection limit as 9 mg dl−1 and high sensitivity as 7.5 μA mM−1 cm−2

Highly sensitive biofunctionalized nickel oxide nanowires for nanobiosensing applications

We report results of the studies relating to the fabrication of nickel oxide nanowires (NwNiOs) with an enhanced aspect ratio of similar to 100 for biosensing applications. Anti Vibrio cholerae monoclonal antibodies were used to functionalize the nickel oxide nanowire (20-80 nm) surfaces fabricated on indium tin oxide coated glass plate for Vibrio cholerae detection. The results of the impedance response studies conducted using this immunoelectrode as a function of the Vibrio cholerae concentration revealed a detection range of 37-350 ng ml(-1) and a low detection limit of 0.553 ng ml(-1) using the 3 sigma(b)/m criteria. The high sensitivity (11.12 Omega (ng ml(-1))(-1) cm(-2)) of this fabricated sensor is attributed to the excellent electronic properties of NiO nanowires which facilitate the efficient transfer of electrons between the electrode and the antibody molecules through electron channeling effects. Besides this, the nanostructured NiO nanowire based immunosensor exhibits interesting supercapacitive behaviour towards the detection of CT. This immunosensor showed values of association constant (K-a) of 4.5 x 10(7) ng ml(-1) and dissociation constant (K-d) of 2.22 x 10(-6) ng ml(-1)

SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A

Introduction SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full‐length recombinant (r) FVIII (anti‐haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer. Aim To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25‐75 IU/kg in patients with severe haemophilia A (FVIII activity <1%). Methods Multinational, phase 1, prospective, open‐label, two‐period, fixed‐sequence, dose‐escalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3). Results Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatment‐related adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatment‐related changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5‐fold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25‐75 IU/kg dose range

Synergistic effect of intrathecal fentanyl and bupivacaine in spinal anesthesia for cesarean section

BACKGROUND: Potentiating the effect of intrathecal local anesthetics by addition of intrathecal opiods for intra-abdominal surgeries is known. In this study by addition of fentanyl we tried to minimize the dose of bupivacaine, thereby reducing the side effects caused by higher doses of intrathecal bupivacaine in cesarean section. METHODS: Study was performed on 120 cesarean section parturients divided into six groups, identified as B(8), B(10 )and B (12.5 )8.10 and 12.5 mg of bupivacaine mg and FB(8), FB(10 )and FB (12.5 )received a combination of 12.5 μg intrathecal fentanyl respectively. The parameters taken into consideration were visceral pain, hemodynamic stability, intraoperative sedation, intraoperative and postoperative shivering, and postoperative pain. RESULTS: Onset of sensory block to T6 occurred faster with increasing bupivacaine doses in bupivacaine only groups and bupivacaine -fentanyl combination groups. Alone lower concentrations of bupivacaine could not complete removed the visceral pain. Blood pressure declined with the increasing concentration of Bupivacaine and Fentanyl. Incidence of nausea and shivering reduces significantly whereas, the postoperative pain relief and hemodynamics increased by adding fentanyl. Pruritis, maternal respiratory depression and changes in Apgar score of babies do not occur with fentanyl. CONCLUSION: Spinal anesthesia among the neuraxial blocks in obstetric patients needs strict dose calculations because minimal dose changes, complications and side effects arise, providing impetus for this study. Here the synergistic, potentiating effect of fentanyl (an opiod) on bupivacaine (a local anesthetic) in spinal anesthesia for cesarian section is presented, fentanyl is able to reduce the dose of bupivacaine and therefore its harmful effects

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression

A self assembled monolayer based microfluidic sensor for urea detection

Urease (Urs) and glutamate dehydrogenase (GLDH) have been covalently co-immobilized onto a self-assembled monolayer (SAM) comprising of 10-carboxy-1-decanthiol (CDT) via EDC–NHS chemistry deposited onto one of the two patterned gold (Au) electrodes for estimation of urea using poly(dimethylsiloxane) based microfluidic channels (2 cm × 200 μm × 200 μm). The CDT/Au and Urs-GLDH/CDT/Au electrodes have been characterized using Fourier transform infrared (FTIR) spectroscopy, contact angle (CA), atomic force microscopy (AFM) and electrochemical cyclic voltammetry (CV) techniques. The electrochemical response measurement of a Urs-GLDH/CDT/Au bioelectrode obtained as a function of urea concentration using CV yield linearity as 10 to 100 mg dl−1, detection limit as 9 mg dl−1 and high sensitivity as 7.5 μA mM−1 cm−2

Gabapentin for chronic pelvic pain in women (GaPP2):a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundChronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology.MethodsWe performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762.FindingsParticipants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group.InterpretationThis study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology.FundingNational Institute for Health Research

Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B

NIHR (RP-PG-0310-1001), the Medical Research Council, the Katharine Dormandy Trust, the U.K. Department of Health, NHS Blood and Transplant, the NIHR Biomedical Research Centers (to University College London Hospital and University College London), the ASSISI Foundation of Memphis, the American Lebanese Syrian Associated Charities, the Howard Hughes Medical Institute, the National Heart, Lung, and Blood Institute (HL094396), the Royal Free Hospital Charity Special Trustees Fund 35, the Royal Free Hospital NHS Trust, and St. Jude Children’s Research Hospita