Pyrolysis of solid waste residues from Lemon Myrtle essential oils extraction for bio-oil production.

Solid waste residues from the extraction of essential oils are projected to increase and need to be treated appropriately. Valorization of waste via pyrolysis can generate value-added products, such as chemicals and energy. The characterization of lemon myrtle residues (LMR) highlights their suitability for pyrolysis, with high volatile matter and low ash content. Thermogravimetric analysis/derivative thermogravimetric revealed the maximum pyrolytic degradation of LMR at 335 °C. The pyrolysis of LMR for bio-oil production was conducted in a fixed-bed reactor within a temperature range of 350-550 °C. Gas chromatography-mass spectrometry showed that the bio-oil contained abundant amounts of acetic acid, phenol, 3-methyl-1,2-cyclopentanedione, 1,2-benzenediol, guaiacol, 2-furanmethanol, and methyl dodecanoate. An increase in pyrolysis temperature led to a decrease in organic acid and ketones from 18.09% to 8.95% and 11.99% to 8.75%, respectively. In contrast, guaiacols and anhydrosugars increased from 24.23% to 30.05% and from 3.57% to 7.98%, respectively.

Identification and Development of an Irreversible Monoacylglycerol Lipase (MAGL) Positron Emission Tomography (PET) Radioligand with High Specificity.

Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed throughout the brain, serves as a key gatekeeper regulating the tone of endocannabinoid signaling. Preclinically, inhibition of MAGL is known to provide therapeutic benefits for a number of neurological disorders. The availability of a MAGL-specific positron emission tomography (PET) ligand would considerably facilitate the development and clinical characterization of MAGL inhibitors via noninvasive and quantitative PET imaging. Herein, we report the identification of the potent and selective irreversible MAGL inhibitor 7 (PF-06809247) as a suitable radioligand lead, which upon radiolabeling was found to exhibit a high level of MAGL specificity; this enabled cross-species measurement of MAGL brain expression (Bmax), assessment of in vivo binding in the rat, and nonhuman primate PET imaging.

Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.

Clinical investigation of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 resulted in serious adverse neurological events. Structurally unrelated FAAH inhibitors tested in humans have not presented safety concerns, suggesting that BIA 10-2474 has off-target activities. A recent activity-based protein profiling (ABPP) study revealed that BIA 10-2474 and one of its major metabolites inhibit multiple members of the serine hydrolase class to which FAAH belongs. Here, we extend these studies by performing a proteome-wide analysis of covalent targets of BIA 10-2474 metabolites. Using alkynylated probes for click chemistry-ABPP in human cells, we show that des-methylated metabolites of BIA 10-2474 covalently modify the conserved catalytic cysteine in aldehyde dehydrogenases, including ALDH2, which has been implicated in protecting the brain from oxidative stress-related damage. These findings indicate that BIA 10-2474 and its metabolites have the potential to inhibit multiple mechanistically distinct enzyme classes involved in nervous system function.

Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log  D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.

Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects.

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

Design and optimization of selective azaindole amide M1 positive allosteric modulators.

Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.

Measurement of atropisomer racemization kinetics using segmented flow technology.

When stable atropisomers are encountered by drug discovery teams, they can have important implications due to potential differences in their biological activity, pharmacokinetics, and toxicity. Knowledge of an atropisomer's activation parameters for interconversion is required to facilitate informed decisions on how to proceed. Herein, we communicate the development of a new method for the rapid measurement of atropisomer racemization kinetics utilizing segmented flow technology. This method leverages the speed, accuracy, low sample requirement, safety, and semiautomated nature of flow instrumentation to facilitate the acquisition of kinetics data required for experimentally probing atropisomer activation parameters. Measured kinetics data obtained for the atropo isomerization of AMPA antagonist CP-465021 using segmented flow and traditional thermal methods were compared to validate the method.

Oral premalignant lesions induce immune reactivity to both premalignant oral lesions and head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, and despite advances in treatments, the 5-year survival has remained at less than 50%. One treatment strategy is to focus on patients with premalignant oral lesions that carry a high-risk for developing recurrent premalignant lesions and HNSCC disease. As an initial attempt to determine if immune therapy has the potential to be protective in these patients, studies determined if premalignant lesions express tumor antigens that have previously been shown to be expressed on HNSCC. Immunohistochemical analyses showed prominent expression of epidermal growth factor receptor in premalignant lesions, even in lesions with mild dysplasia. MUC-1 and carcinoembryonic antigen were expressed in most patient samples, while NY-ESO-1 was less frequently expressed. Each of these antigens was expressed on HNSCC. This provided the rationale for determining if premalignant oral lesions could be used to stimulate autologous peripheral blood mononuclear leukocytes (PBML) to react against heterologous premalignant lesions and HNSCC. Following sensitization with autologous premalignant lesions, PBML responded to a challenge with either heterologous premalignant oral lesion cells or HNSCC by releasing IFN-gamma. In addition, sensitization with autologous premalignant lesion lysates generated cytolytic activity by both PBML and T cells against allogeneic premalignant lesion cells and HNSCC. These studies show the feasibility of using premalignant oral lesions to stimulate immune reactivity against both premalignant oral lesions as well as HNSCC.

Substituted 6-phenyl-pyridin-2-ylamines: selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.

Swallowing dysfunction in infants less than 1 year of age.

BACKGROUND: Gastroesophageal reflux (GER) occurs frequently in infants and children and is implicated as a trigger for reactive airways disease. While evaluating patients for GER by upper gastrointestinal studies (UGI), we frequently noticed laryngeal penetration or tracheal aspiration in infants < 1 year of age. We conducted this prospective study to assess the incidence of swallowing dysfunction in infants with vomiting or respiratory symptoms. METHODS: Between February 1994 and August 1997, 1,003 UGI in infants < 1 year of age were performed by two experienced pediatric radiologists. Fluoroscopy of swallowing using an appropriate image intensifier was observed as part of the UGI in all patients. In addition to evaluating premature infants, former premature infants, and infants with underlying conditions such as bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), esophageal atresia and/or tracheoesophageal fistula (EA), and neurologic disorders, we assessed swallowing in 472 full-term infants in the general population who had respiratory symptoms or suspected GER, but no other apparent abnormalities. Swallowing was not assessed in patients with congenital bowel obstruction. The presence of normal swallowing or swallowing dysfunction was recorded immediately following the study. Chest radiographs obtained on the same day as the UGI were evaluated in the study. Forty-four videotaped modified barium-swallow studies (MBSS) were obtained in 25 general-population infants and reviewed frame-by-frame to determine the length of time that barium could be visualized in the subglottic trachea. RESULTS: The incidence of swallowing dysfunction is significant in premature and former premature infants, those with BPD, CHD, EA, various syndromes, and neurologic abnormality. In the general population of full-term infants referred for evaluation of vomiting or respiratory symptoms, 63 (13.4 % of 472) had swallowing dysfunction. Forty-four had tracheal aspiration (TA) and 19 had laryngeal penetration (LP). Gastroesophageal reflux was found in 79.5 % with TA and in 68.4 % with LP. The MBSS confirmed swallowing dysfunction in all patients shown to have vocal cord penetration or tracheal aspiration by UGI. CONCLUSIONS: Careful evaluation of swallowing during an UGI can identify swallowing dysfunction in full-term infants who have respiratory problems, as well as in infants with an abnormality that predisposes the patient to aspiration. Episodes of tracheal aspiration may be fleeting and overlooked if swallowing is not assessed carefully. An MBSS can confirm the observation of swallowing dysfunction found during an UGI and assist in planning appropriate dietary therapy that minimizes the likelihood of tracheal aspiration during feeding.

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation.

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Systematic review of laparoscopic surgery for colorectal malignancy.

BACKGROUND: We set out to evaluate the current literature on the use of laparoscopic surgery for malignant colorectal disease and identify its place in current practice. METHODS: We performed a systematic review of the literature that included papers published from January 1991 to March 1997. Inclusion criteria were used to select the most robust studies. The quality of each study was assessed against predefined criteria and weighted according to hierarchy of evidence and sample size. RESULTS: The published literature was found to be low in the hierarchy of evidence. Of the 157 studies located, only 42 papers were found to be of sufficiently high quality to be included in the review. Only 13 of these 42 papers concentrated specifically on malignant colorectal disease. We noted the following findings: The average age of patients was 63.2 years. The most frequently reported contraindication to laparoscopic surgery was obesity. Conversion rate to open procedure varied between 1.5% and 48%. The most common postoperative complication was wound infection. Thirty-day mortality varied between 0 and 5.1%. Disease stage and pathology were poorly reported. Patient recovery benefits varied. It was not possible to identify the effectiveness, safety, survival outcome, or cost of laparoscopic surgery for colorectal malignancy in comparison to open surgery. CONCLUSIONS: Six years after the first report of laparoscopic surgery, studies low in the hierarchy of evidence continue to be reported. This reflects a lack of control following the introduction of this new technology. The majority of reports continue to be feasibility studies. The variable nature and content of the literature demonstrate the lack of standardization and the absence of an agreed core minimum data set. The benefit of laparoscopic surgery for malignant colorectal disease remains unclear. Until the mechanisms of port site recurrences are elucidated and long-term data on survival outcomes become available, laparoscopic surgery for malignant disease should be carried out only in the context of a large, multicenter randomized controlled trial.

Comparing outcomes of major models of police responses to mental health emergencies.

OBJECTIVE: The study compared three models of police responses to incidents involving people thought to have mental illnesses to determine how often specialized professionals responded and how often they were able to resolve cases without arrest. METHODS: Three study sites representing distinct approaches to police handling of incidents involving persons with mental illness were examined-Birmingham, Alabama; and Knoxville and Memphis, Tennessee. At each site, records were examined for approximately 100 police dispatch calls for "emotionally disturbed persons" to examine the extent to which the specially trained professionals responded. To determine differences in case dispositions, records were also examined for 100 incidents at each site that involved a specialized response. RESULTS: Large differences were found across sites in the proportion of calls that resulted in a specialized response-28 percent for Birmingham, 40 percent for Knoxville, and 95 percent for Memphis. One reason for the differences was the availability in Memphis of a crisis drop-off center for persons with mental illness that had a no-refusal policy for police cases. All three programs had relatively low arrest rates when a specialized response was made, 13 percent for Birmingham, 5 percent for Knoxville, and 2 percent for Memphis. Birmingham's program was most likely to resolve an incident on the scene, whereas Knoxville's program predominantly referred individuals to mental health specialists. CONCLUSIONS: Our data strongly suggest that collaborations between the criminal justice system, the mental health system, and the advocacy community plus essential services reduce the inappropriate use of U.S. jails to house persons with acute symptoms of mental illness.

A SAMHSA research initiative assessing the effectiveness of jail diversion programs for mentally ill persons.

For nearly 30 years jail diversion programs have had wide support as a way to prevent people with mental illnesses and substance use disorders from unnecessarily entering the criminal justice system by providing more appropriate community-based treatment. Although these programs have had wide support, very few systematic outcomes studies have examined their effectiveness. This paper discusses findings on rates of incarceration of persons with serious mental illness and co-occurring substance use disorders in U.S. jails, summarizes recently completed research on jail diversion programs, and describes a three-year research initiative begun in 1997 by the Substance Abuse and Mental Health Services Administration that uses a standardized protocol to examine the characteristics and outcomes of various types of jail diversion programs in nine sites throughout the U.S.

Emerging partnerships between mental health and law enforcement.

Police departments in the 194 U.S. cities with a population of 100,000 or more were surveyed in 1996 to identify strategies they used to obtain input from the mental health system about dealing with mentally ill persons. A total of 174 departments responded (90 percent). Ninety-six departments had no specialized response for dealing with mentally ill persons. Among the 78 departments with special programs, three basic strategies were found: a police-based specialized police response, a police-based specialized mental health response, and a mental-health-based specialized mental health response. At least two-thirds of all departments, even those with no specialized response program, rated themselves as moderately or very effective in dealing with mentally ill persons in crisis.

Locality commissioning: how much influence have general practitioners really had?

This paper investigates the various models of locality commissioning in relation to the participation of general practitioners (GPs), and explores the perceived successes of locality commissioning in the 15 health boards in Scotland and 13 health authorities in the Northern and Yorkshire Region of England. A postal questionnaire was sent to 190 individuals involved in commissioning, and semi-structured interviews with GPs (n = 31) and health authority managers (n = 41) were undertaken in each of the 28 health authorities. Seventy-five per cent of the health authorities had introduced some form of locality commissioning. Five types of locality commissioning organization were identified on the basis of the level of GP influence over decisions. All GP responders identified benefits resulting from their involvement in the process but only 27% of health authority responders did so. Most benefits related to improved professional relationships, not to service changes. On the whole, locality commissioning does not appear to have resulted in major changes to contracts or services.

Police perspectives on responding to mentally ill people in crisis: perceptions of program effectiveness.

In this study, we sampled sworn police officers from three law enforcement agencies (n = 452), each of which had different system responses to mentally ill people in crisis. One department relies on field assistance from a mobile mental health crisis team, a second has a team of officers specially trained in crisis intervention and management of mentally ill people in crisis, and a third has a team of in-house social workers to assist in responding to calls. Calls involving mentally ill people in crisis appear to be frequent and are perceived by most of the officers to pose a significant problem for the department; however, most officers reported feeling well prepared to handle these calls. Generally, officers from the jurisdiction with a specialized team of officers rated their program as being highly effective in meeting the needs of mentally ill people in crisis, keeping mentally ill people out of jail, minimizing the amount of time officers spend on these calls, and maintaining community safety. Officers from departments relying on a mobile crisis unit (MCU) and on police-based social workers both rated their programs as being moderately effective on each of these dimensions except for minimizing officer time on these calls where the MCU had significantly lower ratings.