Preliminary Safety Evaluation Research Articles

Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols

Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock – MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as RM0, was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S-(E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1) and R,S-(E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (3) exhibited the best anticonvulsant activity. Compound 1, when administered to mice by intraperitoneal (i.p.) injection, showed the ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p.). The distances measured in crystals of compound 1 were: 7.99 Å – from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 Å – from the phenyl ring to the amide group, and 3.112 Å – from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2).

Abstract CT309: Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects

Abstract Inhibiting cMet has potential therapeutic value in oncology. The Janssen WAVE Early Development unit, a team focused on efficient proof-of-concept evaluations, sought to rapidly assess the safety, pharmacokinetics, and pharmacodynamics of a novel, highly selective small molecule cMet TK inhibitor with a favorable preclinical safety profile. We conducted a placebo-controlled, randomized, double blind single ascending dose and multiple dose trial in 84 healthy males at Quotient Clinical LTD (UK). The trial design was adaptive in several respects: to expedite determination of an optimal formulation and to maintain sufficient systemic exposure to sustain target inhibition. In the single ascending dose phase, doses ranged from 6-350 mg, with early transition from a solution to capsule formulation at 18 mg. Two multiple dose cohorts received 60 mg twice daily for 7 days (inter-dose intervals of 4.5 and 12 hours). Target engagement biomarkers were plasma hepatocyte growth factor and soluble cMet. Evaluation of renal safety was of particular interest. Clinical evaluation, including both single ascending and multiple dose phases, was completed in only 6 months. All doses were safe and well tolerated. Pharmacokinetic analysis revealed dose-proportional increases in exposure. Dose escalation was limited by concentrations of a major metabolite that approached the ceiling established in preclinical toxicology studies. Renal toxicity was not identified. Initial evaluation of this oncology drug in healthy subjects offered the advantages of rapid trial enrollment and completion, robust placebo comparison data, absence of concomitant illness or laboratory abnormalities, rapid dose escalation in a carefully-monitored, controlled setting, a thorough preliminary safety evaluation, and reduced costs. This approach, enabled by the acceptable preclinical safety profile of the compound, efficiently produced high quality clinical safety and pharmacokinetic data to support compound progression decisions. Citation Format: A Dawn Millington, Sandra R. Chaplan, Zuleima Aguilar, Dennis M. Fisher, Jo Collier, Marielena Mata, Geert Mannens, Nico Goyvaerts, Vijay Peddareddigari, Chris Takimoto. Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT309. doi:10.1158/1538-7445.AM2015-CT309

A Novel Method for Real-Time Audio Recording With Intraoperative Video

Although laparoscopic surgery has become widespread, effective and efficient education in laparoscopic surgery is difficult. Instructive laparoscopy videos with appropriate annotations are ideal for initial training in laparoscopic surgery; however, the method we use at our institution for creating laparoscopy videos with audio is not generalized, and there have been no detailed explanations of any such method. Our objectives were to demonstrate the feasibility of low-cost simple methods for recording surgical videos with audio and to perform a preliminary safety evaluation when obtaining these recordings during operations. We devised a method for the synchronous recording of surgical video with real-time audio in which we connected an amplifier and a wireless microphone to an existing endoscopy system and its equipped video-recording device. We tested this system in 209 cases of laparoscopic surgery in operating rooms between August 2010 and July 2011 and prospectively investigated the results of the audiovisual recording method and examined intraoperative problems. Numazu City Hospital in Numazu city, Japan. Surgeons, instrument nurses, and medical engineers. In all cases, the synchronous input of audio and video was possible. The recording system did not cause any inconvenience to the surgeon, assistants, instrument nurse, sterilized equipment, or electrical medical equipment. Statistically significant differences were not observed between the audiovisual group and control group regarding the operating time, which had been divided into 2 slots-performed by the instructors or by trainees (p > 0.05). This recording method is feasible and considerably safe while posing minimal difficulty in terms of technology, time, and expense. We recommend this method for both surgical trainees who wish to acquire surgical skills effectively and medical instructors who wish to teach surgical skills effectively.

A preliminary safety evaluation of polyhexamethylene guanidine hydrochloride.

Polyhexamethylene guanidine hydrochloride (PHMGH) is used worldwide as an antimicrobial agent with broad spectra of activity and also for treating pool water. This non-GLP preliminary study aims at investigating in a subchronic toxicity study possible effects at supra-optimal doses of this biocide. Both acute and subchronic toxicity studies were conducted. LD(50) for PHMGH was estimated to be 600 mg/kg (ie LC(50) 2 ml of 7.5% solution) when administered as a single dose by gavage via a stomach tube in accordance with the expected route of administration. The acute studies showed that the median lethal dose (LD(50)) of 600 mg/kg was accompanied by signs of neurotoxicity. Haematological and biochemical parameters of subchronic toxicity studies were non-significant. Subchronic doses of 0.006 mg/kg, 0.012 mg/kg and 0.036 mg/kg were administered. 20% of the animals at a dose of 0.006 mg/kg and 0.036 mg/kg showed mild degrees of hydropic changes in proximal tubules while 10% of animals at all the doses had their liver tissues showing local areas of mild pericentral hepatocytes degeneration. PHMGH did not produce any major organ defect with regard to the kidney, heart, and liver. The LD(50) was much higher than the recommended dosage by a factor of about 50,000. The recommended residual concentration is far less than the median lethal dose using rats as test subjects. These results could serve as a basis for investigating the full toxicological profile if it is to be used for the treatment of raw water to make it potable.

Preliminary Safety Evaluation and Biochemical Efficacy of a Carum carvi Extract: Results from a Randomized, Triple‐Blind, and Placebo‐Controlled Clinical Trial

Carum carvi L. (Apiaceae) is known as caraway, and its derivatives find wide medicinal use for health purposes, including for gastrointestinal problems and obesity. Since there is inconsistency among the reports on the safety of this plant in humans, this research was aimed at assessing the safety of a characterized caraway aqueous extract (CAE) in a randomized, triple-blind, placebo-controlled study. Seventy, overweight and obese, healthy women were randomly assigned into placebo (n = 35) and plant extract (n = 35) groups. Participants received either 30 ml/day of CAE or placebo. Subjects were examined at baseline and after 12 weeks for changes in heart rate, blood pressure, urine test, 25-item blood chemistries, and general health status. No significant changes of blood pressure, heart rate, urine specific gravity, and serum blood tests were observed between the two groups before and after treatment. However, in the complete blood count test, red blood cell levels were significantly (p < 0.01) increased, and platelet distribution width was significantly decreased after the dietary CAE treatment, as compared with placebo. No negative changes were observed in the general health status of the two groups. This preliminary study suggests that the oral intake of CAE appears to be without any adverse effects at a dosage of 30 ml daily for a period of 12 weeks.

Effects of fluid–structure interaction modeling assumptions on seismic floor acceleration demands within gravity dams

This paper presents an original investigation of the sensitivity of floor acceleration demands in gravity dams to various modeling assumptions of the impounded reservoir. Such floor acceleration demands are crucial for the assessment of the seismic performance or vulnerability of dam-supported appurtenant structures. Two approaches are proposed to obtain floor acceleration demands: analytical and coupled dam–reservoir finite element models. Both techniques are applied to typical dam–reservoir systems with different geometries. The dam–reservoir systems are subjected to ground motions with various frequency contents and the resulting floor acceleration demands are examined to investigate the effects of reservoir geometry, water compressibility, reservoir bottom wave absorption and dam higher vibration modes. A new approach based on proposed floor frequency response functions is also developed to assess floor acceleration demands at the stage of preliminary seismic design or safety evaluation of dam-supported appurtenant structures. Examples are given to illustrate how the proposed approach can be effectively used to compare floor acceleration demands within different dams or within the same dam considering various modeling assumptions of the reservoir.

Adsorption and Preliminary Safety Evaluation of Activated Carbons Refined from Charcoals

The objectives of this study were to investigate the absorption and preliminary safety of activated carbon (AC) refined from Makino bamboo, Moso bamboo and Japanese cedar charcoals with carbon dioxide (CO2) at an 800 and 900°C activation temperature with 90, 120 and 150 min of activation time. The yield of AC was from 47.5 to 90.4%. The benzene absorption (10.8–37.4%) of AC was also higher than that (1.3–9.4%) of charcoals. The iodine value (562–1088 mg/g) of AC was higher than that (141–628 mg/g) of charcoals. The true density (2.11–2.17 g/cm 3 ) and BET surface area (791.22–829.78 m 2 /g) of AC were obviously higher than those (1.68–1.86 g/cm 3 and 58.95–356.62 m 2 /g) of charcoals. The AC belongs to a mesopore structure because the results of average pore diameters were from 2.22 to 2.69 nm. No matter what the relative humidity (RH) was in high/low RH at either 90 or 40% with a constant temperature of 25˚C, the hygroscopic ability of AC was better than that for charcoals, and the water activity of AC was from 0.45 to 0.46. The heavy metal content as the Pb (Plumbum) ppm base of AC was below 40 ppm and met the Sanitation Standard of Edible Natural Colorants from the announcement by the Department of Health’s Executive Yuan, in Taiwan. The preliminary safety evaluation using the Ames test for the charcoals and AC had no cytotoxicity and mutagenicity toward Salmonella typhimurium TA98 and TA100. It is suggested that the AC, refined from the charcoals, can be expected to be a natural moisture–proof material.

Preliminary safety evaluation of a taurocholate‐conjugated low‐molecular‐weight heparin derivative (LHT7): a potent angiogenesis inhibitor

In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight heparin derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg(-1) doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg(-1) doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg(-1) did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg(-1) repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material.

Preliminary Safety Evaluation of Photodynamic Therapy for Blood Purification: An Animal Study

Photodynamic therapy (PDT) has been shown to inactivate blood-borne pathogenic microorganisms in vitro. The method may be used to purify blood in the body, kill pathogenic microorganisms, and treat difficult diseases. Our aim was to investigate the safety of photodynamic blood purification (PBP) therapy using an in vivo blood circulation experiment in an animal model. Twenty-four New Zealand rabbits were used as experimental subjects; 12 received PDT and 12 served as negative controls. Extracorporeal blood bypass was established using the femoral artery and vein. A sterile disposable irradiation chamber was connected in the bypass pathway. Hematoporphyrin monomethyl ether was injected intravenously as a photosensitizer with an initial bolus of 3.7 mg, followed by a continuous infusion at 24 mg/h during PDT administration. Five minutes after initial injection, a laser beam was vertically focused on the irradiation chamber side wall, with a 9.5 cm(2) spot area, 1 h exposure time, and 20 mW/cm(2) power density. Six animals received a single PDT application, and six received PDT every other day for three applications. The 12 control group animals underwent extracorporeal blood circulation but did not receive the photosensitizer or light treatment. Blood samples were taken 20 min, 1 day, 4 days, and 7 days after PDT treatment for analysis of cell counts, coagulation, liver and renal function, and other biochemical changes. On the 7th day, animals were sacrificed, and parenchymal organs were evaluated for morphological changes. There were no significant differences in white blood cells, red blood cells, or destroyingplatelets after PDT compared with the control group. There was a little significant difference in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, uric acid, blood urea nitrogen, and creatinine in the PDT group compared with the control group, except at individual time points. We found no significant damage in the heart, liver, spleen, lungs, kidneys, or other organs after PDT. This short-duration, fixed-strength PBP method did not cause changes in blood parameters or in the structure or function of major organs in an animal model. These findings suggest that PBP is safe in vivo and has potential as a new therapy for inactivating blood-borne microorganisms.

One-year follow-up of a series of 100 patients treated for lumbar spinal canal stenosis by means of HeliFix interspinous process decompression device.

Purpose. New interspinous process decompression devices (IPDs) provide an alternative to conservative treatment and decompressive surgery for patients with neurogenic intermittent claudication (NIC) due to degenerative lumbar spinal stenosis (DLSS). HeliFix is a minimally invasive IPD that can be implanted percutaneously. This is a preliminary evaluation of safety and effectiveness of this IPD up to 12 months after implantation. Methods. After percutaneous implantation in 100 patients with NIC due to DLSS, data on symptoms, quality of life, pain, and use of pain medication were obtained for up to 12 months. Results. Early symptoms and physical function improvements were maintained for up to 12 months. Leg, buttock/groin, and back pain were eased throughout, and the use and strength of related pain medication were reduced. Devices were removed from 2% of patients due to lack of effectiveness. Conclusions. Overall, in a period of up to 12-month follow-up, the safety and effectiveness of the HeliFix offered a minimally invasive option for the relief of NIC complaints in a high proportion of patients. Further studies are undertaken in order to provide insight on outcomes and effectiveness compared to other decompression methods and to develop guidance on optimal patient selection.

Gamma knife surgery in management of secretory pituitary adenoma preliminary evaluation of role, efficacy and safety

Historically the treatment armamentarium for secretory pituitary adenomas included neurosurgery, medical management, fractionated radiotherapy and recently gamma knife surgery (GKS), the goal of this study is to evaluate the efficacy, safety and role of gamma knife surgery for treatment of secretory pituitary adenomas regarding hormonal and adenoma size control, between mid of 2005 and 2012 a retrospective analysis of 54 consecutive patients with secretory pituitary adenomas underwent GKS at the International Medical Center (IMC) Cairo-Egypt, 10 patients with adrenocorticotrophic hormone secreting adenoma, 24 prolactin secreting adenoma and 20 with growth hormone secreting adenoma, in 25 patients GKS was the secondary to a prior surgery with failure of hormonal control even in addition of medical treatment, in the other 29 the secretory pituitary adenomas not controlled with medical treatment alone, the median follow up period was 28 months(12-84 months), achieving hormonal control was either normalization or marked decline of abnormal hormone level >50%, radiological tumour size control was either tumour size stabilization or reduction, among the 54 patients 31 had microadenoma of 1cc volume or less, over all 34 patients (63%) had hormonal control and 51 patients (94%) had tumor size control after GKS, there was a direct correlation between tumor size, prescription radiation dose and post-gamma knife hormonal and size control, 29 out of the treated 31 microadenomas cases showed both hormonal and size control, inconclusions gamma knife surgery is safe and effective treatment for secretory pituitary adenomas failed to respond to medical treatment alone or with postsurgical residual or recurrence especially microadenomas.

Abstract P2-16-04: A phase 2 study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer

Abstract Background: Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents. The dose limiting toxicity was stomatitis, similar to RIDA monotherapy. Preliminary signals of anti-tumor activity, including partial responses and prolonged progression free survival (PFS), were observed in ER+ advanced breast cancer (ABC), especially in high proliferation tumors (Ki67 ≥15%). Methods: The trial was a multi-center, international randomized study with PFS as the primary endpoint. Key eligibility included ABC with prior treatment with a non-steroidal aromatase inhibitor. The original phase 2 study design was a two-part, adaptive design intended to first test the combination of RIDA (30 mg by mouth daily for 5 out of every 7 days), -DALO (10 mg/kg IV weekly) against a standard agent, exemestane in Part A. Patients were stratified into high and low proliferation strata based on baseline Ki67. Following a demonstration of PFS benefit of the combination in Part A, Part B was intended to show the PFS benefit of the combination over each single agents by comparing RIDA-DALO to RIDA and DALO. Results: The study was initiated in October 2011. Accrual was suspended after the first 66 patients were randomized due to a higher than expected rate of stomatitis in the RIDA-DALO arm. Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively. Although the incidence of overall stomatitis in the 10 mg cohort remained high, 88% (22/25 pts), grade 3 stomatitis was dramatically reduced to 8% (2/25 pts). Conclusion: Preliminary evaluation of safety from this phase 2 study demonstrates that the previously recommended phase 2 dose of RIDA-DALO was not tolerable. However lower doses of RIDA (10 mg) in combination with DALO appeared to be tolerable with markedly reduced rates of grade 3 stomatitis. Final results of efficacy, safety and RNA profiling analysis from the two RIDA-DALO dose cohorts as well as from the randomized portion of the study will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-04.

Preliminary safety evaluation for CSR1000 with passive safety system

This paper describes the preliminary safety analysis of the Chinese Supercritical water cooled Reactor (CSR1000), which is proposed by Nuclear Power Institute of China (NPIC). The two-pass core design applied to CSR1000 decreases the fuel cladding temperature and flattens the power distribution of the core at normal operation condition. Each fuel assembly is made up of four sub-assemblies with downward-flow water rods, which is favorable to the core cooling during abnormal conditions due to the large water inventory of the water rods. Additionally, a passive safety system is proposed for CSR1000 to increase the safety reliability at abnormal conditions. In this paper, accidents of “pump seizure”, “loss of coolant flow accidents (LOFA)”, “core depressurization”, as well as some typical transients are analysed with code SCTRAN, which is a one-dimensional safety analysis code for SCWRs. The results indicate that the maximum cladding surface temperatures (MCST), which is the most important safety criterion, of the both passes in the mentioned incidents are all below the safety criterion by a large margin. The sensitivity analyses of the delay time of RCPs trip in “loss of offsite power” and the delay time of RMT actuation in “loss of coolant flowrate” were also included in this paper. The analyses have shown that the core design of CSR1000 is feasible and the proposed passive safety system is capable of mitigating the consequences of the selected abnormalities.

Preliminary evaluation of safety of conditionally replication adenovirus M4

Conditionally replication adenovirus M4, which was constructed in our lab, was proved to have good clinical application prospect for its good anti-tumor and anti-metastasis effect. However, clinically applying M4 faces many problems. One of the most important is the safety of M4. In this study, we investigated the safety of M4 by comparing with Adv-TK, which was proved to be safe in I-III phase clinical trials. M4 and Adv-TK were injected into mice via the tail vein separately, and the mice were sacrificed at the indicated time. Blood was collected for biochemical tests, the liver was harvested for hematoxylin and eosin (H&E) staining and viral quantification, and splenic lymphocytes were separated for adenovirus specific cellular immune response. Our results showed that M4 had no obvious effect on mouse general symptoms. A transient reversible infiltration of inflammatory cells in collect abbacy was only observed in M4 group, and a transient slight increase in Cr level was detected both after M4 and Adv-TK injection. The adenovirus specific cellular immune response induced by M4 was similar to that by Adv-TK, and the distribution and metabolism of M4 in the mouse liver were also similar to those of Adv-TK. It was concluded that conditionally replication adenovirus M4 had the same safety as Adv-TK. The study provides safety basis for the coming clinical trials of M4.

Clinical evaluation of the preliminary safety and effectiveness of a minimally invasive interspinous process device APERIUS® in degenerative lumbar spinal stenosis with symptomatic neurogenic intermittent claudication

New interspinous process decompression devices (IPDs) provide an alternative to conservative treatment and decompressive surgery for patients with neurogenic intermittent claudication (NIC) due to degenerative lumbar spinal stenosis (DLSS). APERIUS(®) is a minimally invasive IPD that can be implanted percutaneously. This multicentre prospective study was designed to make a preliminary evaluation of safety and effectiveness of this IPD up to 12 months post-implantation. After percutaneous implantation in 156 patients with NIC due to DLSS, data on symptoms, quality of life, pain, and use of pain medication were obtained for up to 12 months. Early symptom and physical function improvements were maintained for up to 12 months, when 60 and 58 % of patients maintained an improvement higher than the Minimum Clinically Important Difference for Zurich Claudication Questionnaire (ZCQ) symptom severity and physical function, respectively. Leg, buttock/groin, and back pain were eased throughout, and the use and strength of related pain medication were reduced. Devices were removed from 9 % of patients due to complications or lack of effectiveness. Overall, in a period of up to 12 months follow-up, the safety and effectiveness of the APERIUS(®) offered a minimally invasive option for the relief of NIC complaints in a high proportion of patients. Further studies are underway to provide insight on outcomes and effectiveness compared to other decompression methods, and to develop guidance on optimal patient selection.

The co-drug of conjugated hydroquinone and azelaic acid to enhance topical skin targeting and decrease penetration through the skin

A co-drug of hydroquinone (HQ) and azelaic acid (AA), bis(4-hydroxyphenyl)nonanedioate (BHN), was synthesized and investigated as a topical prodrug with the aim of improving the dermal delivery of the parent drugs. Physicochemical parameters were ascertained, and the enzymatic hydrolysis was examined. Skin permeation of HQ, AA, and BHN was studied by determining the skin deposition and flux across nude mouse skin under equivalent doses with the same thermodynamic activity. The partition coefficient (log P) of the co-drug increased by up to 5.0 with HQ and AA conjugation, which had respective log P values of 0.5 and 1.4. In the skin absorption experiment, BHN in ethanol/pH 7 buffer resulted in a 2-fold enhancement of skin deposition compared to both HQ and AA. With permeation using polyethylene glycol 400/pH 7 buffer as the vehicle, the co-drug, respectively, exhibited 8.1- and 1.4-fold enhancements of skin uptake compared to HQ and AA alone. The transdermal flux from BHN was negligible compared to those with HQ and AA treatments. The results of a preliminary safety evaluation showed no signs of stratum corneum disruption or erythema by BHN application within 24h. The co-drug approach provides a viable option for the treatment of skin hyperpigmentation of HQ and AA.

Preliminary evaluation of clinical outcome and safety of ketamine as an anesthetic for electroconvulsive therapy in schizophrenia

Objectives. Electroconvulsive therapy (ECT) is an effective and safe option in the treatment of affective disorders and schizophrenia. One parameter known to influence ECT treatment efficacy is the choice of narcotic, and ketamine has emerged as an interesting alternative to conventional anaesthetics like barbiturates since it does not negatively influence seizure threshold. However, due to the potential to provoke dissociative symptoms, ketamine anaesthesia is rather hesitantly used in schizophrenia patients for fear of causing disease exacerbation. Methods. We retrospectively investigated clinical outcome and safety in patients treated with ECT for schizophrenia and receiving ketamine anaesthesia, either exclusively or as switch from another narcotic and compared seizure parameters to a group of ECT-treated schizophrenia patients with thiopental anaesthesia. Results. In none of the six patients undergoing ECT with ketamine did we observe disease exacerbation, and except for one patient, all patients responded or remitted under ECT. A preliminary analysis of seizure parameters shows an association with longer seizures in patients exclusively receiving ketamine. Conclusions. While the small sample size and retrospective character are limitations of our study, our preliminary results nonetheless challenge wide-spread preconceptions about the use of ketamine in schizophrenia patients and encourage further research into the option of using ketamine anaesthesia for ECT.

Patient-Controlled Sedation and Analgesia with Propofol and Alfentanil: A Preliminary Safety Evaluation Prior to Use of Non-Anaesthesiology Doctors

Background: The aim was to evaluate safety aspects of patient-controlled sedation and analgesia (PCS) for extracorporeal shockwave lithotripsy (ESWL) and PCS to be handled by non-anaesthesiology doctors. Methods: Thirty-four ASA I-III patients used PCS with propofol and alfentanil for ESWL in this interventional study. Strict safety limits were defined regarding respiratory rate (RR), heart rate (HR), mean arterial blood pressure (MAP), oxygen saturation from pulse oximetry (SpO2), and transcutaneous partial pressures of oxygen (PtcO2) and carbon dioxide (PtcCO2). The patients' levels of consciousness was graded on a five-point scale and monitored with Bispectral Index (BIS). A nurse anaesthetist was supervising the procedure but was instructed to intervene only if safety limits were breached. No supplementary oxygen was given. Results: All patients responded to verbal stimuli during treatment. Cardiovascular stability was maintained, but respiratory variables were affected. Two patients with SpO2 2 ≥ 6.5 kPa). In 18 patients hypoxaemia was indicated as PtcO2 ≤ 8.0 kPa. All these 18 patients were given supplementary oxygen. There was no correlation between dose of drugs, age, weight or any vital variable. The 34 patients would use PCS again in the case of future treatment. Conclusions: During ESWL treatment PCS can be used with good patients’ satisfaction, and maintained cardiovascular stability, but PCS had an indisputable effect on pulmonary function with hypoxemia (resulting in need for supplementary oxygen) or hypercarbia. The person in charge of PCS must therefore be trained to perform according to the guidelines for sedation and/or analgesia by non-anaesthesiology doctors.

Phytochemical, Antioxidant and Toxicological Investigation ofMorinda citrifoliaL. Blossoms

Noni blossoms have a long history of medicinal uses in tropical areas. This study was conducted to investigate the major phytochemical components, toxicological properties, and antioxidant activity of noni blossoms. An HPLC-PDA method was developed and validated for the identification and quantification of major components. The major phytochemicals were iridoid glycosides, deacetylasperulosidic acid and asperulosidic acid, and flavonoids, quercetin-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside and kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside, each present at 3.764, 3.576, 1.513, and 3.096 mg/g, respectively. The aqueous extract of noni blossoms, at 500 μg/mL, exhibited greater antioxidant activity in the 2,2-diphenylpicrylhydrazyl radical scavenging assay than green tea (88.11 ± 0.01% versus 76.60 ± 0.05%). A primary DNA damage test inE. coliPQ37 (SOS-chromotest) and a twenty-four hour brine shrimp toxicity test did not reveal any genotoxic or cytotoxic activity. These results provide a useful reference for the identification of noni blossoms as well as preliminary evaluation of safety and efficacy. Further evaluation of the potential applications of noni blossoms is warranted.

Pharmacokinetics and preliminary safety evaluation of azithromycin in adult horses

Azithromycin is widely used in foals but has not been studied in adult horses. The goals of this study were to determine the pharmacokinetic profile and to make a preliminary assessment of the safety of azithromycin in adult horses. Azithromycin was administered intravenously (5 mg/kg) and intragastrically (10 mg/kg) to six healthy mares in a crossover design. Serial plasma samples, blood neutrophils, and pulmonary macrophages were collected for the measurement of azithromycin concentrations. Azithromycin was also administered orally (10 mg/kg) once a day for 5 days to five healthy mares for preliminary evaluation of safety in adult horses. The bioavailability of azithromycin following intragastric administration was 45 ± 12%. Concentrations within peripheral neutrophils and bronchoalveolar macrophages were several fold higher than that of plasma. Mild decreases in appetite (n = 3) and alterations in fecal consistency (n = 3) were noted following repeated oral administration. The pharmacokinetic profiles of azithromycin in adult horses, especially the slow elimination rate and intraneutrophil and intrapulmonary macrophage accumulation, demonstrate that it is conducive to use in this age group. Because of the gastrointestinal alterations noted, further studies are warranted before azithromycin can be recommended for use in adult horses.