Primary amebic meningoencephalitis: a review of Naegleria fowleri and analysis of successfully treated cases.

Primary amebic meningoencephalitis (PAM) is a necrotizing and hemorrhagic inflammation of the brain and meninges caused by Naegleria fowleri, a free-living thermophilic ameba of freshwater systems. PAM remains a neglected disease that disproportionately affects children in tropical and subtropical climates, with an estimated mortality rate of 95-98%. Due to anthropogenic climate change, the average temperature in the USA has increased by 0.72 to 1.06 °C in the last century, promoting the poleward spread of N. fowleri. PAM is often misdiagnosed as bacterial meningitis or viral encephalitis, which shortens the window for potentially life-saving treatment. Diagnosis relies on the patient's history of freshwater exposure and the physician's high index of suspicion, supported by cerebrospinal fluid studies. While no experimental trials have been conducted to assess the relative efficacy of treatment regimens, anti-amebic therapy with adjunctive neuroprotection is standard treatment in the USA. We performed a literature review and identified five patients from North America between 1962 and 2022 who survived PAM with various degrees of sequelae.

Direct analysis in real time high resolution mass spectrometry as a tool for rapid characterization of mind-altering plant materials and revelation of supplement adulteration--The case of Kanna.

We demonstrate the utility of direct analysis in real time ionization coupled with high resolution time-of-flight mass spectrometry (DART-HRTOFMS) in revealing the adulteration of commercially available Sceletium tortuosum, a mind-altering plant-based drug commonly known as Kanna. Accurate masses consistent with alkaloids previously isolated from S. tortuosum plant material enabled identification of the products as Kanna, and in-source collision-induced dissociation (CID) confirmed the presence of one of these alkaloids, hordenine, while simultaneously revealing the presence of an adulterant. The stimulant ephedrine, which has been banned in herbal products and supplements, was confirmed to be present in a sample through the use of in-source CID. High-throughput DART-HRTOFMS was shown to be a powerful tool to not only screen plant-based drugs of abuse for psychotropic alkaloids, but also to reveal the presence of scheduled substances and adulterants.

Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: the case of Mitragyna speciosa aka "Kratom".

Mitragyna speciosa, also known commonly as "Kratom" or "Ketum", is a plant with psychoactive properties that have been attributed to the presence of various indole alkaloids such as mitragynine and 7-hydroxymitragynine. M. speciosa use is gaining popularity internationally as a natural and legal alternative to narcotics. As a drug of abuse, its detection and identification are not straightforward, since M. speciosa plant material is not particularly distinctive. Here, we show that direct analysis in real time-mass spectrometry (DART-MS) can be used not only to rapidly identify M. speciosa plant material and distinguish it from other plants, but also to distinguish between M. speciosa plant varieties, based on differences between their chemical profiles. The method is rapid and the analysis expeditious. Plant material such as that found at a crime scene can be analyzed directly with no sample pre-preparation steps. Furthermore, we show that the basis set of principal components that permit characterization of the plant material can be used to positively identify M. speciosa.

DART-MS as a preliminary screening method for "herbal incense": chemical analysis of synthetic cannabinoids.

Direct analysis in real time mass spectrometry (DART-MS) served as a method for rapid high-throughput screening of six commercially available "Spice" products, detecting various combinations of five synthetic cannabinoids. Direct analysis in real time is an ambient ionization process that, along with high mass accuracy time-of-flight (TOF)-MS to 0.0001 Da, was employed to establish the presence of cannabinoids. Mass spectra were acquired by simply suspending a small portion of sample between the ion source and the mass spectrometer inlet. The ability to test minute amounts of sample is a major advantage when very limited amounts of evidentiary material are available. In addition, reports are widespread regarding the testing backlogs that now exist because of the large influx of designer drugs. This method circumvents time-consuming sample extraction, derivatization, chromatographic, and other sample preparative steps required for analysis by more conventional mass spectrometric methods. Accordingly, the synthetic cannabinoids AM-2201, JWH-122, JWH-203, JWH-210, and RCS-4 were identified in commercially available herbal Spice products, singly and in tandem, at concentrations within the range of 4-141 mg/g of material. Direct analysis in real time mass spectrometry decreases the time necessary to triage analytical evidence, and therefore, it has the potential to contribute to backlog reduction and more timely criminal prosecution.

DART-MS for rapid, preliminary screening of urine for DMAA.

Dimethylamylamine (DMAA) is a sympathomimetic amine found in weight-loss/workout supplements or used as an appetite suppressant. DMAA is a stimulant that is banned by the World Anti-Doping Agency (WADA). Adverse health effects as well as fatalities have been implicated with its use. Direct analysis in real time mass spectrometry (DART-MS) is an ambient ionization method that was employed to rapidly identify the presence of DMAA in various samples without any extraction or preparations whatsoever. DMAA was first identified in supplements, sampled directly in their solid forms. Furthermore, DMAA was detected directly in urine over 48 h as a means of indicating recent abuse of the substance. DART-MS analysis is instantaneous, and coupled with the high mass accuracy associated with the time-of-flight mass analyzer, results in unequivocal identification of the presence of DMAA. These features demonstrate DART-MS as an attractive potential alternative screening method for the presence of drugs and medications or for toxicological investigations.

Direct analysis in real time mass spectrometry with collision-induced dissociation for structural analysis of synthetic cannabinoids.

RATIONALE: The emergence of numerous cannabinoid designer drugs has been tied to large spikes in emergency room visits and overdoses. Identifying these substances is difficult for the following reasons: (1) the compounds are novel, closely structurally related, and do not usually test positive in drug screens; (2) novel analogs rapidly appear on the market; (3) no standard protocols exist for their identification; and (4) customized and extensive sample preparation/extraction and analysis procedures are required to demonstrate their presence. METHODS: Direct analysis in real time mass spectrometry (DART-MS) employing collision-induced dissociation (CID) provided confirmatory structural information that was useful in characterizing the various cannabinoid analogs, including those contained in mixtures. CID analysis illustrated that, although closely related compounds fragment in a similar fashion, their structural differences still resulted in multiple diagnostic peaks that provided additional confidence towards structural identification. RESULTS: DART-MS spectra were acquired under CID conditions to rapidly differentiate among five synthetic cannabinoids contained within 'herbal' products purchased locally in New York State (USA). The spectra exhibited [M+H](+) ions and product ions unique to each cannabinoid that corresponded to major structural features. Five different cannabinoid analogs, alone and as mixtures of at least two cannabinoids, were identified in six herbal products and differentiated by their CID product ion patterns. CONCLUSIONS: Illicit synthetic cannabinoid products continue to be readily available despite national and international restrictions. These products contain a wide range of active components, and, in many cases, multiple active ingredients. DART-MS allows rapid analyses of these synthetic cannabinoids based on the exact masses of their [M+H](+) ions and product ion peaks generated using CID.

Preclinical assessment of the feasibility of applying controlled release oral drug delivery to a lead series of atypical antipsychotics.

In this paper, we present a preclinical approach for evaluating the feasibility of applying controlled-release (CR) oral drug delivery to increase the duration of exposure and lower the C(max) of compounds in a lead series of short half-life atypical antipsychotics. Three lead compounds in the series had demonstrated potential pharmacological benefits for the treatment of psychosis, in preclinical studies. However, the compounds showed evidence of insufficient half-lives to enable a once-a-day (QD) product using immediate-release (IR) oral delivery. To evaluate and compare the potential for oral CR delivery to extend the duration of action and thereby enable QD administration, the in vitro solubility and permeability, and the duodenal and colonic absorption of three compounds in the series were measured. Based on the results, one candidate was selected for advancement that showed moderate in vitro solubility, but had the highest in vitro permeability and ratio of colonic to duodenal bioavailability (0.9) in the rat. The results from this study provided evidence that a CR drug delivery system could be used to extend the duration of exposure of the compounds in the series and a scientific basis for selecting one of the three compounds as a candidate.

Safety, health or the environment--which comes first?

This paper describes the development and application of two integrated models which can be used for assessing the life cycle risk (to life) and environmental impact of a number of possible concept options for new offshore oil and gas developments. The two models can also be used for ranking the designs in terms of lowest human risk and environmental impact. The paper also gives values/criteria for both risks to safety, health and the environment by which the total safety, health and environmental assessment/impact may be balanced as a whole. The paper illustrates the use of the models and shows that the pragmatic or cosmetic improvement to safety, health or the environment may not be advantageous to the overall safety, health and environmental objectives. While the models were developed originally for offshore installations, the basic framework can be readily adapted for use on onshore petrochemical processes.

"Calcium entry blockers" as cerebral protecting agents: comparative activity in tests of hypoxia and hyperexcitability.

The group of drugs described as "Ca2+-entry blockers" is chemically and pharmacologically heterogeneous. It is believed now that these drugs are useful in the treatment of ischemic disease. In an effort to define which drugs could offer the best therapeutic alternative, a comparative pharmacological study was made. Nine drugs (D-600, diltiazem, flunarizine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, tiapamil) were tested in experimental screening models of brain hypoxia, ischemia, cellular intoxication and against bicuculline-induced seizures. Three types of activity were found. Verapamil, D-600, tiapamil and diltiazem were almost inactive, possibly due to their poor brain penetration. The dihydropyridines had a broad spectrum of activity, but considerable differences between these compounds exist. They all were active against hypoxia and less active against ischemia. Out of this subgroup, only nicardipine protected against metabolic intoxication and nifedipine and nicardipine could block seizure components at very high doses. Flunarizine was the only compound with a dose-related effect in all the tests. These results suggested that this combination of screening tests could be used to find compounds with an interesting activity in the field of cerebral protection.