A Pilot Study of the Pharmacogenetics of Ketamine-Induced Emergence Phenomena: A Dissertation

Background: Up to 55% of patients administered ketamine, experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury. While genetics accounts for about 50% of severe adverse drug reactions, no studies have investigated genetic association of ketamine-induced EP in healthy patients. Ketamine is metabolized by CYP 2B6 enzymes and CYP 2B^8^ allele significantly alter ketamine metabolism. In addition, ketamine exerts most of its effects by inhibiting the N-methyl-D-aspartate receptor (NMADR), and NMDAR genes (GRIN2B) are associated with learning and memory impairment and schizophrenia. Purpose: To investigate the relationship between CYP2B6*6 and GRIN2B single nucleotide polymorphisms (SNPs) and ketamine-induced emergence phenomena (EP). Methods: This cross-sectional pharmacogenetic study recruited 75 patients having minor orthopedic, hand, foot, anorectal surgeries from two outpatient surgical centers. EP was measured with the Clinician Administered Dissociative State Scale (CADSS). DNA was genotyped using standard Taqman assays and protocols. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 & rs1806191) SNPs and ketamine induced EP occurrence and severity were tested using multivariate logistic and linear regression, adjusting for age, ketamine dose, duration of anesthesia, and time since ketamine administration. Results: Forty-seven patients (63%) received ketamine and were genotyped. Nineteen EP cases were identified (CADSS \u3e 4), leaving 28 non-EP controls. For our population, CADSS has an internal consistency reliability Cronbach’s alpha of 0.82, and could reliably distinguish ketamine from non-ketamine cases. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p \u3e 0.1). Models removing genotype and containing age, ketamine dose, duration of v anesthesia, and time since ketamine administration significantly predicted EP occurrence (p = 0.001) and severity (p = 0.007). Presence and severity of EP did not affect patient satisfaction with care. Discussion: Younger age, higher dose and longer duration of anesthesia significantly predicted EP occurrence and severity among our sample. This study provides effect size estimates useful for the design of adequately powered future genetic association studies. The feasibility of recruitment from patients undergoing elective, outpatient surgeries and ease of post-operative EP assessment with CADSS supports our approach. However, the small sample size may have limited about ability to determine significant differences. Conclusion: Fully powered studies are needed to investigate this important phenomena. Determining factors for anesthesia-related EP symptoms may reduce risks and costs associated with this adverse medication effect

Fourier Transform Infrared Spectroscopy and Scanning Electron Microscopy Characterization of Adhesive Produced From Polystyrene Waste

In this study, the optimized adhesive formulated from polystyrene waste was characterized for Fourier transform infrared (FTIR) spectra, Scanning Electron Microscopy (SEM) / Energy Dispersive X-ray (EDX) spectroscopy, solubility, density and water absorption for identification of existing functional group(s), morphology, elemental compositions, etc. The results revealed that polystyrene, unsaturated hydrocarbon has been degraded to form a new product containing aromatic compounds. SEM morphology showed well mixed blended adhesive with silver-like appearance due to additives and EDX revealed 12 existing elemental compositions with their corresponding percentage atomic weights as follows; carbon 93.14 %, hafnium 1.44 %, vanadium 1.66 %, chromium 1.40 %, bromine 0.47 %, palladium 0.26 %, copper 0.43 %, nickel 0.31 %, cobalt 0.29 %, potassium 0.38 %, iron 0.15 % and manganese 0.08 %. The produced polystyrene adhesive was sparsely soluble in water after 30 minutes; it has a density of 1041 kg/m3 and does not absorb moisture. Because of these results, the adhesive from polystyrene waste could serve as green adhesive, since there are no threats of toxic substance emission from the spectral analysis since most of the elements are used as a supplement in pharmaceuticals and catalyst in process industries

Instrumental Characterization of Unmodified and HDTMA-Br Modified Kaolinite Clay: SEM-EDX, Quantachrome and TGA-DTA

Kaolinite clay from Alkaleri Northeast Nigeria was pre-treated and beneficiated using physical process. The treated clay of cation exchange capacity (CEC) 9.5 meq/100 g was modified with cationic surfactant hexadecyltrimethylammonium bromide (HDTMA-Br) with amount equivalent to and doubled the CEC. The unmodified kaolinite clay (UKC) and the resultant organo-kaolinite clays: monolayer modified clay (MMC) and bilayer modified clay (BMC) were characterized using the following instruments: Energy Dispersive X-ray spectrometer (EDX), Scanning Electron Microscopy (SEM), Quantachrome and Thermogravimetric-Differential Thermal Analysis (TG-DTA). EDX profile analysis shows 22.41 % C, 56.17 % O & 10.56 % Al in UKC; 21.06 % C, 55.49 % O & 11.66 % Al in MMC and 18.98 % C, 54.59 % O & 12.14 % Al in BMC respectively; with Fe and K found in MMC. The SEM morphology shows UKC has high porosity and large particles, while MMC and BMC showed fine particles and darker than UKC with textural non-uniformity. TGA curve shows that UKC attains equilibrium decomposition at 997.20oC with 15.32 % weight loss, MMC 997.30 oC with 32.67 % weight loss and BMC 998.90 oC with 37.23 % weight loss. The revealed weight loss indicates water of hydration and dehydroxylation. The DTA curves show endothermic at 510 oC, 250 oC and 520 oC for UKC, MMC and BMC respectively. The single point surface area was 11.9754 m2/g, 3.0132 m2/g and 3.8225 m2/g for UKC, MMC and BMC with corresponding adsorption average pore width 355.0050 Å, 478.6275 Å and 752.8364 Å respectively. Clay materials being promising minerals when modified can achieve desired surface properties for best performance in adsorption applications

Optimised Condition Catalytic Upgrading of Agbabu Bitumen in the Presence of Rice Husks

In this study, the optimisation of bitumen collected from Agbabu Ondo State, Nigeria, was upgraded in the presence of rice husks in a nitrogen environment using a 100 ml autoclave batch reactor with the aid of the design expert software. Response surface methodology (RSM) was used to determine the optimum conditions for the bitumen upgrading in the presence of rice husks using the Box-Behnken Designed Experiment (BBD). Three mesoporous aluminosilicate catalysts (NiMo/ZSM-5, CoMo/HZSM-5 and Mo/HZSM-5) were used to upgrade the bitumen at the obtained optimised point. The bitumen sample was characterised by saturates (53.48 wt.%), aromatics (12.84 wt.%), resins (15.37 wt.%), asphaltenes (8.86 wt.%) and an initial viscosity of 86.78 Pa.s, API gravity of 7.87 o and density of 1.0153 kg/l. The GC-MS result revealed that there were 42 chemical compounds present in the raw bitumen. The XRF result for the rice husks revealed that the silica to Alumina (SiO2/Al2O3) ratio was 11.89:1. RSM optimisation of the experimental runs with the autoclave reactor gave an optimum condition (Temperature of 345.716 oC, Reaction time of 30 min, and Rice husks of 1.0 wt.%) without employing any of the three mesoporous aluminosilicate catalysts. The responses obtained for the upgraded oil were viscosity 8.34 Pa.s, API gravity 24.520 o, residue yield 22.39 w/w% and light oil yield 50.064 w/w%. The experimental run with NiMo/ZSM-5 catalyst at the optimum conditions was observed to be more effective in the catalytic thermal cracking of the bitumen upgrading process, as the light oil yield was 70.42 w/w%, viscosity of 2.060 Pa.s, API gravity of 29.826o and residue yield of 10.66 w/w% compared to what was obtained from CoMo/HZSM-5 and Mo/HZSM-5 mesoporous aluminosilicate catalysts. The FT-IR and GC-MS of the upgraded Agbabu bitumen testified that the level of upgrade of the bituminous oil was satisfactory as the raw Agbabu bitumen had an initial viscosity of 86.780 Pa.s, API gravity of 7.87 o and density of 1.0153 kg/l in which all the initial core properties of the bitumen have shifted satisfactorily after the bitumen upgrade to produce light oil that fell within the acceptable range of refinery feedstock specifications for refining processes in the vacuum distillation unit (VDU)

Multi-Metal Adsorption of Lead (II), Cadmium (II), and Manganese (II) Ions from Simulated Solution onto HDTMA-Br Modified Dijah-Monkin Bentonite Clay

In this study, Dijah-Monkin bentonite clay was modified with a cationic surfactant hexadecyltrimethylammonium bromide (HDTMA-Br) at the level of twice the cation exchange capacity (CEC) and applied in adsorption to obtain the optimal conditions for the removal of lead (II), cadmium (II) and manganese (II) from a solution. The Box-Behnken design matrix comprised particle size of clay, initial metal ion concentration, and contact time as the independent variables, with the heavy metals' adsorption capacities and percentage removals as the responses. The experimental results fit linear models for the adsorption capacity and quadratic models for the percentage removal. Also, only the particle size and initial concentration significantly affected the responses. However, the effect of contact time was significant for cadmium removal, suggesting that the adsorption of cadmium ion on the adsorbent increases with increased contact time; this is due to high cadmium cation hydration energy of -1807 kJ/mol-1 compared to lead and manganese with -1481 kJmol-1, -1760 kJmol-1 respectively. Furthermore, the model equations for the responses were developed, and the optimum adsorption condition for the multi-metal adsorption that maximised the adsorption capacity and the percentage removal was obtained to be 150 µm particle size, 50 mg/l initial concentration over 171 minutes

Biological activities of extracts and isolated compounds from Bauhinia galpinii (Fabaceae) and Combretum vendae (Combretaceae) as potential antidiarrhoeal agents

Diarrhoea is one of the killer diseases resulting from the dehydration and loss of electrolytes through profuse and excessive excretion of loose stool. The pathoaetiologies include infections, intestinal inflammation, imbalanced intestinal oxidative homeostasis and altered motility. Treatment with oral rehydration therapy (ORT) is a key intervention especially in secretory diarrhoea as supportive therapy. Symptomatic and non-symptomatic therapies directed at treating the intestinal tissues are available. However, these conventional treatments are still not sufficient in curing diarrhoea due to their associated hazards such as the development and spread of drugresistant pathogens, changes in normal intestinal bacteria flora and potential chronic toxicity. Therapies targeted at intestinal tissue include antimotility and antisecretory agents have adverse effects such as addictiveness, constipation and fatal ischaemic colitis. Many ethnopharmacological and ethnobotanical therapies for treating diarrhoea exist among different cultures. The aims of this study were to evaluate the biological activities of plant extracts against some diarrhoeal pathophysiologies. A literature search in English of published articles and books that discussed ethnobotanical uses of medicinal plants in southern Africa was conducted. A list of 230 medicinal plants used in South African traditional medicines for treating diarrhoea and associated complications was created. The list included family, genus, species, biological activities and bioactive isolates as well as the remedies for diarrhoea. Twenty seven species were selected to evaluate for antimicrobial, antioxidant and anti-inflammatory activities. Safety of the plants was determined by determining the cytotoxicity of the crude extracts against Vero African green monkey kidney cell lines using a standard method. Motility effects of Bauhinia galpinii (BGE) and 2500 μg/ml. In general the non-polar fractions had a higher antimicrobial activity. The crude extracts contained wide range phenolic compounds with a total phenolic (7 4.91 ±1.26 to 467.04±15.82 mg GAE/g plant material), and total flavonoids (11.27±3.37 to 176±5.96 mg EQ/g plant material). The antioxidant activities were concentrated and potentiated in the polar fractions. The non-polar fractions had poor antioxidant activities with EC50 values ranging from 0.21 ±0.03 to 303.65±3.84 μg/ml for DPPH radical scavenging and 0.43±0.03 to 1709±91.44 μg/ml for ABTS radical scavenging. The crude extracts had selective COX-1 inhibitory activities ranging between 41.70 to 84.61% and had no COX-2 inhibitory activity. All the extracts tested had 15-LOX inhibitory capacity with LC50 values ranging between 0.86±0.27 and 111.44±37.28 1-μg/ml. The cytotoxicity results indicated a wide variation in toxic potential of the crude extracts with LC50 values ranging from 3.51 to 741.901-μg/ml. The BGE extracts had dual activities as spasmolytic by stimulating the spontaneous contractility and also agonised contractions induced by spasmogens but it inhibited K+ induced contraction. CVE had spasmodic activities through a multiple mechanisms inhibiting contractions induced by spasmogens and K+ in a dosedependent manner. Several bioactive xompoundswere isolated from the <i<Combretum vendae leaves, There were triterpenoids (ursol-12-en-28-oic acid, mixtures of corosolic acid and maslinic acid, and asiatic acid and arjunolic acid) as well as bibenzyls combretastatin 85-0-2'-β-D-glucopyranoside, combretastatin 81-0-2'-β-Dglucopyranoside and a flavonoid (apigenin) .. From Bauhinia galpinii the following bioactive compounds were isolated and characterized: β-3 ethoxy sitosterol, one new flavone (5, 7, 4' 5' tetrahydroxy-2'-methoxyflavone (isoetin 2'-methyl ether) or 5, 7, 2' 5' tetrahydroxy-4'-methoxyflavone (isoetin 4'-methyl ether)), 3, 5, 7, 3', 4'-pentahydroxyflavone and 3, 5, 7, 3', 4', 5'hexahydroxyflavone, quercetin-3-0-β-galactopyranoside and myriceti n-3-0-β-galactopyranoside The extraction protocol used in this work potentiated the antimicrobial activities in the non-polar fractions while antioxidant activities were potentiated in the polar fractions. This indicated that using polar solvents as extractant for treating infectious diarrhoea may not be quite effective unless some other antidiarrhoeal mechanisms are involved. Therefore, mixture of organic solvent (ethanol) and water can be recommended for broad-based activity. Bauhinia galpinii extracts had a dual- mechanism of action (prokinetic and relaxant) on gastro-intestinal motility, depending on the prevalent patho-physiological condition and Combretum vendae mediated spasmolytic effects on isolated rat ileum through multiple inhibitions of a wide range of contractile stimuli. Hence, the presence of multiple acting spasmolytic activities in the plant extract might be contributing towards its effectiveness in treating diarrhoea and abdominal spasm. The uses of these plants in traditional medicine need to be monitored closely because of the selective inhibition of COX-1 and its associated GIT injury, and the high toxicity potential of some of the extracts. Further work evaluating the antidiarrhoea mechanisms, identification and isolation of bioactive compounds, sub-acute and acute toxicity of the plant extracts is recommended.Thesis (PhD)--University of Pretoria, 2013.Paraclinical Sciencesunrestricte

Biological activities of extracts and isolated compounds from Bauhinia galpinii (Fabaceae) and Combretum vendae (Combretaceae) as potential antidiarrhoeal agents

Diarrhoea is one of the killer diseases resulting from the dehydration and loss of electrolytes through profuse and excessive excretion of loose stool. The pathoaetiologies include infections, intestinal inflammation, imbalanced intestinal oxidative homeostasis and altered motility. Treatment with oral rehydration therapy (ORT) is a key intervention especially in secretory diarrhoea as supportive therapy. Symptomatic and non-symptomatic therapies directed at treating the intestinal tissues are available. However, these conventional treatments are still not sufficient in curing diarrhoea due to their associated hazards such as the development and spread of drugresistant pathogens, changes in normal intestinal bacteria flora and potential chronic toxicity. Therapies targeted at intestinal tissue include antimotility and antisecretory agents have adverse effects such as addictiveness, constipation and fatal ischaemic colitis. Many ethnopharmacological and ethnobotanical therapies for treating diarrhoea exist among different cultures. The aims of this study were to evaluate the biological activities of plant extracts against some diarrhoeal pathophysiologies. A literature search in English of published articles and books that discussed ethnobotanical uses of medicinal plants in southern Africa was conducted. A list of 230 medicinal plants used in South African traditional medicines for treating diarrhoea and associated complications was created. The list included family, genus, species, biological activities and bioactive isolates as well as the remedies for diarrhoea. Twenty seven species were selected to evaluate for antimicrobial, antioxidant and anti-inflammatory activities. Safety of the plants was determined by determining the cytotoxicity of the crude extracts against Vero African green monkey kidney cell lines using a standard method. Motility effects of Bauhinia galpinii (BGE) and Combretum vendae (CVE) were determined by modulation of the contractility process of the isolated rat ileum induced by spasmogens. Phenolic compositions of the crude extract were determined using various standard methods and finally bioactivity guided isolation of antimicrobial and antioxidant compounds from BGE and CVE were carried out using open column chromatography. Identification and characterization of the isolated compounds was achieved by NMR, EI-MS and UV spectroscopy. The non-polar fractions had good antimicrobial activities with MIC ranged between 19 – 1250 μg/ml while the polar fraction had moderate antimicrobial activities with MIC ranged between 39 - >2500 μg/ml. In general the non-polar fractions had a higher antimicrobial activity. The crude extracts contained wide range phenolic compounds with a total phenolic (74.91±1.26 to 467.04±15.82 mg GAE/g plant material), and total flavonoids (11.27±3.37 to 176±5.96 mg EQ/g plant material). The antioxidant activities were concentrated and potentiated in the polar fractions. The non-polar fractions had poor antioxidant activities with EC50 values ranging from 0.21±0.03 to 303.65±3.84 μg/ml for DPPH radical scavenging and 0.43±0.03 to 1709±91.44 μg/ml for ABTS radical scavenging. The crude extracts had selective COX-1 inhibitory activities ranging between 41.70 to 84.61% and had no COX-2 inhibitory activity. All the extracts tested had 15-LOX inhibitory capacity with LC50 values ranging between 0.86±0.27 and 111.44±37.28 μg/ml. The cytotoxicity results indicated a wide variation in toxic potential of the crude extracts with LC50 values ranging from 3.51 to 741.90μg/ml. The BGE extracts had dual activities as spasmolytic by stimulating the spontaneous contractility and also agonised contractions induced by spasmogens but it inhibited K+ induced contraction. CVE had spasmodic activities through a multiple mechanisms inhibiting contractions induced by spasmogens and K+ in a dosedependent manner. Several bioactive xompoundswere isolated from the Combretum vendee leaves, There were triterpenoids (ursol-12-en-28-oic acid, mixtures of corosolic acid and maslinic acid, and asiatic acid and arjunolic acid) as well as bibenzyls combretastatin B5-O-2’-β-D-glucopyranoside, combretastatin B1-O-2’-β-D glucopyranoside and a flavonoid (apigenin). From Bauhinia galpinii the following bioactive compounds were isolated and characterized: P-3 ethoxy sitosterol, one new flavone (5, 7, 4’ 5’ tetrahydroxy-2’-methoxyflavone (isoetin 2’-methyl ether) or 5, 7, 2’ 5’ tetrahydroxy-4’-methoxyflavone (isoetin 4’-methyl ether)), 3, 5, 7, 3’, 4’-pentahydroxyflavone and 3, 5, 7, 3’, 4’, 5’- hexahydroxyflavone, quercetin-3-O-β-galactopyranoside and myricetin-3-O-β-galactopyranoside. The extraction protocol used in this work potentiated the antimicrobial activities in the non-polar fractions while antioxidant activities were potentiated in the polar fractions. This indicated that using polar solvents as extractant for treating infectious diarrhoea may not be quite effective unless some other antidiarrhoeal mechanisms are involved. Therefore, mixture of organic solvent (ethanol) and water can be recommended for broad-based activity. Bauhinia galpinii extracts had a dual- mechanism of action (prokinetic and relaxant) on gastro-intestinal motility, depending on the prevalent patho-physiological condition and Combretum vendee mediated spasmolytic effects on isolated rat ileum through multiple inhibitions of a wide range of contractile stimuli. Hence, the presence of multiple acting spasmolytic activities in the plant extract might be contributing towards its effectiveness in treating diarrhoea and abdominal spasm. The uses of these plants in traditional medicine need to be monitored closely because of the selective inhibition of COX-1 and its associated GIT injury, and the high toxicity potential of some of the extracts. Further work evaluating the antidiarrhoea mechanisms, identification and isolation of bioactive compounds, sub-acute and acute toxicity of the plant extracts is recommended.Thesis (PhD)--University of Pretoria, 2012.Paraclinical Sciencesunrestricte

Estimating the Direct Costs of Outpatient Opioid Prescriptions: A Retrospective Analysis of Data from the Rhode Island Prescription Drug Monitoring Program

Background: Overuse and misuse of prescription opioids is associated with increased morbidity and mortality, and places a significant cost burden on health systems. Objective: To estimate annual state-wide spending for prescription opioids in Rhode Island. Methods: A cross-sectional study of opioids dispensed from retail pharmacies using data from the Rhode Island (R.I.) Prescription Drug Monitoring Program (PDMP) was performed. The study sample consisted of 651,227 opioid prescriptions dispensed to 197,062 patients between January 1, 2015 to December 31, 2015. The mean, median and total cost of opioid utilization was estimated using both prescription dispensings and patients as units of analysis. A generalized linear model with gamma distribution with an identity link function and separately with a log link function were used to estimate the annual adjusted average prescription opioid cost and to examine potential predictors of total annual expenditure, respectively. Results: The estimated annual expenditure for opioid prescriptions in R.I. for 2015 was $44,271,827. The average and median cost of an opioid prescription were$67.98 (standard deviation [SD] $210.91) and$21.08 (interquartile range [IQR]: $7.65,$47.51), respectively. Prescriptions for branded opioid products accounted for $17,380,279.05, which was about 39.3% of overall spending, although only 6% of all opioids dispensed were for brand-name drugs. On average, patients aged 45-54 and 55-64 years had overall adjusted spending for opioids that were 1.53 (95% confidence interval [CI]: 1.49, 1.57) and 1.75 (95% CI: 1.71, 1.80) times higher than patients age 65 years and older, respectively. Per patient Medicaid and Medicare average annual spending for opioid prescriptions were 1.19 (95% CI: 1.16, 1.22) and 2.01 (95% CI: 1.96, 2.06) times higher than commercial insurance spending, respectively. Annual opioid prescription spending was 2.01 (95% CI: 1.98, 2.04) and 1.50 (95% CI: 1.45, 1.55) times higher among patients who also had at least one benzodiazepine or sympathomimetic stimulant dispensing, respectively. Average total spending for prescription opioids per patient increased with the average daily dosage; from 3-fold for patients using 50-90 MME daily to 22-fold for those receiving 90 or more MME daily compared to those receiving less than 50 MME daily. Conclusion: This study provides the first estimate of the state-wide direct cost burden of prescription opioid use using PDMP data and standardized pricing benchmarks. Total annual cost increased with age up to 65 years, mean daily dose, and concurrent use of benzodiazepines or stimulants. Commercial insurance bears the majority of the cost of prescription opioid use but cost per patient is highest among Medicare beneficiaries. In addition to reducing harms associated with opioid overuse and misuse, substantial cost savings could be realized by reducing unnecessary opioid utilization especially among middle aged adults

Prevalence of Psychotropic Polypharmacy and Associated Healthcare Resource Utilization during Initial Phase of Care among Adults with Cancer in USA

Background: The use of psychotropic medications is not uncommon among patients with newly diagnosed cancer. However, the impact of psychotropic polypharmacy on healthcare utilization during the initial phase of cancer care is largely unknown. Methods: We used a claims database to identify adults with incident breast, prostate, lung, and colorectal cancers diagnosed during 2011–12. Psychotropic polypharmacy was defined as concurrent use of two or more psychotropic medication classes for at least 90 days. A multivariable logistic regression was performed to identify significant predictors of psychotropic polypharmacy. Multivariable Poisson and negative binomial regressions were used to assess the associations between psychotropic polypharmacy and healthcare utilization. Results: Among 5604 patients included in the study, 52.6% had breast cancer, 30.6% had prostate cancer, 11.4% had colorectal cancer, and 5.5% had lung cancer. During the year following incident cancer diagnosis, psychotropic polypharmacy was reported in 7.4% of patients, with the highest prevalence among patients with lung cancer (14.4%). Compared with patients without psychotropic polypharmacy during the initial phase of care, patients with newly diagnosed cancer with psychotropic polypharmacy had a 30% higher rate of physician office visits, an 18% higher rate of hospitalization, and a 30% higher rate of outpatient visits. The rate of emergency room visits was similar between the two groups. Conclusion: Psychotropic polypharmacy during the initial phase of cancer care was associated with significantly increased healthcare resource utilization, and the proportion of patients receiving psychotropic polypharmacy differed by type of cancer. Impact: Findings emphasize the importance of evidence-based psychotropic prescribing and close surveillance of events causing increased healthcare utilization among patients with cancer receiving psychotropic polypharmacy