The safety of lookalikes: a new THC beverage enhancer and a non-THC counterpart.

A new tetrahydrocannabinol (THC) beverage enhancer is available to medical and recreational cannabis consumers across the US. Beverage enhancers that do not contain THC, but instead contain flavored concentrates and/or other additives such as caffeine, are used by squirting the contents of a bottle into water, or other beverage of choice, ad libitum and can be used in a titratable manner according to the user's preference or taste. The THC beverage enhancer described herein has an important safety feature: a mechanism that allows users to measure out a 5-mg dose of THC before they add it to their beverage. This mechanism, however, can be easily bypassed if a user attempts to use the product exactly the same way that its non-THC counterparts are used, by turning the bottle upside down and squirting the contents of the bottle into a beverage ad libitum. The THC beverage enhancer described herein would benefit from additional safety features such as a mechanism that prevents the contents of the bottle from leaving the device when turned upside down and a THC warning label.

A preliminary evaluation of N-acetylcysteine's effects on patient adherence to treatment for cocaine use disorder.

Introduction: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment. Methods: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale. Results: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 ± 26; control 30 ± 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 ± 30; control 78 ± 26, (P = .04). Discussion: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.

Radiolytic degradation of dodecane substituted with common energetic functional groups.

Explosives exist in and are expected to withstand a variety of harsh environments up to and including ionizing radiation, though little is known about the chemical consequences of exposing explosives to an ionizing radiation field. This study focused on the radiation-induced chemical changes to a variety of common energetic functional groups by utilizing a consistent molecular backbone. Dodecane was substituted with azide, nitro, nitrate ester, and nitramine functional groups and γ-irradiated with 60Co in order to study how the functional group degraded along with what the relative stability to ionizing radiation was. Chemical changes were assessed using a combination of analysis techniques including: nuclear magnetic resonance (NMR) spectroscopy, gas chromatography of both the condensed and gas phases, Raman spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Results revealed that much of the damage to the molecules was on the energetic functional group and often concentrated on the trigger linkage, also known as the weakest bond in the molecule. The general trend from most to least susceptible to radiolytic damage was found to be D-ONO2 → D-N3 → D-NHNO2 → D-NO2. These results also appear to be in line with the relative stability of these functional groups to things such as photolysis, thermolysis, and explosive insults.

Chemical Descriptors for a Large-Scale Study on Drop-Weight Impact Sensitivity of High Explosives.

The drop-weight impact test is an experiment that has been used for nearly 80 years to evaluate handling sensitivity of high explosives. Although the results of this test are known to have large statistical uncertainties, it is one of the most common tests due to its accessibility and modest material requirements. In this paper, we compile a large data set of drop-weight impact sensitivity test results (mainly performed at Los Alamos National Laboratory), along with a compendium of molecular and chemical descriptors for the explosives under test. These data consist of over 500 unique explosives, over 1000 repeat tests, and over 100 descriptors, for a total of about 1500 observations. We use random forest methods to estimate a model of explosive handling sensitivity as a function of chemical and molecular properties of the explosives under test. Our model predicts well across a wide range of explosive types, spanning a broad range of explosive performance and sensitivity. We find that properties related to explosive performance, such as heat of explosion, oxygen balance, and functional group, are highly predictive of explosive handling sensitivity. Yet, models that omit many of these properties still perform well. Our results suggest that there is not one or even several factors that explain explosive handling sensitivity, but that there are many complex, interrelated effects at play.

Description of collaborative, fee-for-service, office-based, pharmacist-directed medical cannabis therapy management service for patients with chronic pain.

BACKGROUND: Treatment with medical cannabis (MC) in the United States tends to be patient-driven in nature despite evidence that suggests that patients have remarkably poor knowledge on the medical use of this treatment modality. OBJECTIVE: To develop and pilot a collaborative, fee-for-service (FFS), office-based, pharmacist-directed MC therapy management (MCTM) service for patients suffering chronic pain. PRACTICE DESCRIPTION: A collaborative, FFS, office-based, pharmacist-directed MCTM service where patients are seen after a physician deems them suitable for treatment with MC. The pharmacist designs the initial treatment regimen by selecting a formulation, dose, route, and frequency of administration and then manages ongoing therapy by making regimen changes based on the patient's response, adverse effects, and financial concerns. PRACTICE INNOVATION: The creation of a specialized service where a registered MC pharmacist is positioned in a collaborating provider's office and sees patients face-to-face for the provision of MCTM services. EVALUATION METHODS: Patient retention, revenue generated, and ability to replicate the service were evaluated. Patient satisfaction was assessed by collecting subjective feedback on the service. RESULTS: The pilot site that developed the service has seen 133 patients from 2016 to 2021 and has retained 89% of patients after 5 years of quarterly appointments. Patients appear willing to pay out of pocket for the service, and the revenue generated covers the pharmacist's and collaborating physician's time as well as additional overhead. The service has been replicated at 2 additional sites, and patient feedback has been positive. CONCLUSIONS: MCTM is another useful pharmacist service that patients are willing to pay for. MCTM services decrease the collaborating provider's workload while still allowing them to offer their patients personalized treatment with MC. In our experience, the service retains patients, generates enough revenue to cover costs, can be replicated, and is well received by patients.

Chemical Evaluation and Performance Characterization of Pentaerythritol Tetranitrate (PETN) under Melt Conditions.

Pentaerythritol tetranitrate (PETN) is a nitrate ester explosive commonly used in commercial detonators. Although its degradation properties have been studied extensively, very little information has been collected on its thermal stability in the molten state due to the fact that its melting point is only ∼20 °C below its onset of decomposition. Furthermore, studies that have been performed on PETN thermal degradation often do not fully characterize or quantify the decomposition products. In this study, we heat PETN to melt temperatures and identify thermal decomposition products, morphology changes, and mass loss by ultrahigh-pressure liquid chromatography coupled to quadrupole time of flight mass spectrometry, scanning electron microscopy, nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. For the first time, we quantify several decomposition products using independently prepared standards and establish the resulting melting point depression after the first melt. We also estimate the amount of decomposition relative to sublimation that we measure through gas evolution and evaluate the performance behavior of the molten material in commercial detonator configurations.

Δ-9-tetrahydrocannabinol dose increase leads to warfarin drug interaction and elevated INR.

OBJECTIVE: We have reported a case of a drug-drug interaction (DDI) involving warfarin and Δ-9-tetrahydrocannabinol (THC) that resulted in a supratherapeutic international normalized ratio (INR) level. The purpose of this case report is to highlight the possibility of a pharmacokinetic DDI between THC and warfarin. CASE SUMMARY: A 67-year-old Caucasian man suffering from chronic pain presented to a dispensary in Buffalo, NY, for a refill of his medical cannabis (MC). The patient asked to speak with the pharmacist, and during their discussion the patient stated that he had a supratherapeutic INR level of 5.2 measured at home with a self-test device. The patient had no evidence of bleeding, and administration of warfarin was held for 2 days before the INR level returned to a normal range. The supratherapeutic level occurred when the patient was self-titrating his dose of THC and scored an 8, or "probable," on the Naranjo Adverse Drug Effect Probability Scale. PRACTICE IMPLICATIONS: Warfarin and cannabinoids such as THC are both metabolized by cytochrome P450 (CYP) isozymes present in the liver and gastrointestinal tract. In the case described, a dose increase of 7.35 mg THC preceded an INR elevation of 5.2, but did not result in any bleeding. These observations are suggestive of a DDI involving warfarin and THC. Clinicians involved with MC should have adequate knowledge of the drugs that act as substrates, inhibitors, and inducers of CYP enzymes, including the major cannabinoids.

Synthesis of Erythritol Tetranitrate Derivatives: Functional Group Tuning of Explosive Sensitivity.

Understanding the factors that affect explosive sensitivity is paramount to the safe handling and development of new explosives molecules. Erythritol tetranitrate (ETN) is an explosive that recently has attracted significant attention in the explosives community because of its ease of synthesis and physical properties. Herein, we report the synthesis of ETN derivatives using azide, nitramine, and nitrate ester functional groups. Impact, spark, and friction sensitivity measurements, computationally calculated explosive properties, and the crystal structure analysis of the ETN derivatives are reported. Mixing explosive functional groups led to changes in the explosive sensitivity, explosive performance as well as physical properties including melting point and physical state at room temperature. Overall, we have demonstrated that combining functional groups can enable the tuning of explosive and physical properties of a molecule. This tunability can potentially aid in the development of new explosives in which characteristics are varied to meet certain specifications.

Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis.

INTRODUCTION: Medical cannabis (MC) is commonly claimed to be an effective treatment for chronic or refractory pain. With interest in MC in the United States growing, as evidenced by the 29 states and 3 US districts that now have public MC programs, the need for clinical evidence supporting this claim has never been greater. METHODS: This was a retrospective, mirror-image study that investigated MC's effectiveness in patients suffering from chronic pain associated with qualifying conditions for MC in New York State. The primary outcome was to compare European Quality of Life 5 Dimension Questionnaire (EQ-5D) and Pain Quality Assessment Scale (PQAS) scores at baseline and 3 months post-therapy. The secondary outcomes included comparisons of monthly analgesic prescription costs and opioid consumption pre- and post-therapy. Tolerability was assessed by side effect incidence. RESULTS: This investigation included 29 subjects. Quality of life and pain improved, measured by change in EQ-5D (Pre 36 - Post 64, P < .0001) and change in PQAS paroxysmal (Pre 6.76 - Post 2.04, P < .0001), surface (Pre 4.20 - Post 1.30, P < .0001), deep (Pre 5.87 - Post 2.03, P < .0001), unpleasant (Pre "miserable" - Post "annoying", P < .0001). Adverse effects were reported in 10% of subjects. DISCUSSION: After 3 months treatment, MC improved quality of life, reduced pain and opioid use, and lead to cost savings. Large randomized clinical trials are warranted to further evaluate the role of MC in the treatment of chronic pain.

Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia.

OBJECTIVE: We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). METHODS: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003-December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter-individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. FINDINGS: Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl ≥25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl ≥65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). CONCLUSION: PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk.

The insecticidal spider toxin SFI1 is a knottin peptide that blocks the pore of insect voltage-gated sodium channels via a large ß-hairpin loop.

Spider venoms contain a plethora of insecticidal peptides that act on neuronal ion channels and receptors. Because of their high specificity, potency and stability, these peptides have attracted much attention as potential environmentally friendly insecticides. Although many insecticidal spider venom peptides have been isolated, the molecular target, mode of action and structure of only a small minority have been explored. Sf1a, a 46-residue peptide isolated from the venom of the tube-web spider Segesteria florentina, is insecticidal to a wide range of insects, but nontoxic to vertebrates. In order to investigate its structure and mode of action, we developed an efficient bacterial expression system for the production of Sf1a. We determined a high-resolution solution structure of Sf1a using multidimensional 3D/4D NMR spectroscopy. This revealed that Sf1a is a knottin peptide with an unusually large ß-hairpin loop that accounts for a third of the peptide length. This loop is delimited by a fourth disulfide bond that is not commonly found in knottin peptides. We showed, through mutagenesis, that this large loop is functionally critical for insecticidal activity. Sf1a was further shown to be a selective inhibitor of insect voltage-gated sodium channels, consistent with its 'depressant' paralytic phenotype in insects. However, in contrast to the majority of spider-derived sodium channel toxins that function as gating modifiers via interaction with one or more of the voltage-sensor domains, Sf1a appears to act as a pore blocker.

Analysis of epigenetic stability and conversions in Saccharomyces cerevisiae reveals a novel role of CAF-I in position-effect variegation.

Position-effect variegation (PEV) phenotypes are characterized by the robust multigenerational repression of a gene located at a certain locus (often called gene silencing) and occasional conversions to fully active state. Consequently, the active state then persists with occasional conversions to the repressed state. These effects are mediated by the establishment and maintenance of heterochromatin or euchromatin structures, respectively. In this study, we have addressed an important but often neglected aspect of PEV: the frequency of conversions at such loci. We have developed a model and have projected various PEV scenarios based on various rates of conversions. We have also enhanced two existing assays for gene silencing in Saccharomyces cerevisiae to measure the rate of switches from repressed to active state and vice versa. We tested the validity of our methodology in Δsir1 cells and in several mutants with defects in gene silencing. The assays have revealed that the histone chaperone Chromatin Assembly Factor I is involved in the control of epigenetic conversions. Together, our model and assays provide a comprehensive methodology for further investigation of epigenetic stability and position effects.

Cuticular hydrocarbons of buffalo fly, Haematobia exigua, and chemotaxonomic differentiation from horn fly, H. irritans.

We determined the quantity and chemical composition of cuticular hydrocarbons of different strains, sexes, and ages of buffalo flies, Haematobia exigua. The quantity of cuticular hydrocarbons increased from less than 1 microg/fly for newly emerged flies to over 11 microg/fly in 13-d-old flies. The hydrocarbon chain length varied from C(21) to C(29), with unbranched alkanes and monounsaturated alkenes the major components. Newly emerged flies contained almost exclusively C(27) hydrocarbons. Increasing age was accompanied by the appearance of hydrocarbons with shorter carbon chains and an increase in the proportion of alkenes. 11-Tricosene and 7-tricosene were the most abundant hydrocarbons in mature H. exigua. Cuticular hydrocarbons of H. exigua are distinctly different from those of horn flies, Haematobia irritans. The most noticeable differences were in the C(23) alkenes, with the major isomers 11- and 7-tricosene in H. exigua and (Z)-9- and (Z)-5-tricosene in H. irritans, respectively. Cuticular hydrocarbon analysis provides a reliable method to differentiate the two species, which are morphologically difficult to separate. The differences in cuticular hydrocarbons also support their recognition as separate species, H. exigua and H. irritans, rather than as subspecies.

Composition of chemical attractants affects trap catches of the Australian sheep blowfly, Lucilia cuprina, and other blowflies.

Numbers of Lucilia cuprina (Australian sheep blowfly), Chrysomya spp., and Calliphora spp. blowflies caught on sticky traps baited with various synthetic attractants or a standard liver/sodium sulfide attractant in western Queensland were recorded. Numbers of each genus collected were influenced by the composition of the chemical attractants. Attractant mixtures based on 2-mercaptoethanol, indole, butanoic/pentanoic acid, and a sodium sulfide solution gave 5- to 20-fold higher L. cuprina catches than the liver standard. These blends attracted similar numbers of Chrysomya spp. (0.85-2.7x) and fewer Calliphora spp. (0.02-0.2x) compared to the liver standard. These synthetic attractants were more effective and selective for L. cuprina than the standard liver/sodium sulfide attractant, and they can be packaged in controlled-release dispensers to generate constant, prolonged release of the attractant.