Using a Bioactive Eremophila-Derived Serrulatane Scaffold to Generate a Unique Carbamate Library for Anti-infective Evaluations.

The known Eremophila microtheca-derived diterpenoid 3,7,8-trihydroxyserrulat-14-en-19-oic acid (1) was targeted for large-scale purification, as this bioactive plant compound has proven to be an attractive scaffold for semisynthetic studies and subsequent library generation. Compound 1 was converted to a selectively protected trimethyl derivative, 3-hydroxy-7,8-dimethoxyserrulat-14-en-19-oic acid methyl ester (2), using simple and rapid methylation conditions. The resulting scaffold 2 was reacted with a diverse series of commercially available isocyanates to generate an 11-membered carbamate-based library. The chemical structures of the 11 new semisynthetic analogues were fully characterized by spectroscopic and spectrometric analysis. All natural products and semisynthetic compounds were evaluated for their anthelmintic, antimalarial, and anti-HIV activities. Compound 3 was shown to elicit the greatest antiplasmodial activity of all compounds tested, with IC50 values of 4.6 and 11.6 µM against Plasmodium falciparum 3D7 and Dd2, respectively. Compound 11 showed the greatest inhibition of development to fourth-stage Haemonchus contortus larvae (L4) and induction of a skinny (Ski) phenotype (67.5% of nematodes) at 50 µM. Compound 7, which inhibited 59.0% of HIV production at 100 µg/mL, was the carbamate analogue that displayed the best antiviral activity.

Identification of Anthelmintic Bishomoscalarane Sesterterpenes from the Australian Marine Sponge Phyllospongia bergquistae and Structure Revision of Phyllolactones A-D.

High-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract derived from the Australian marine sponge Phyllospongia bergquistae with activity against Hemonchus contortus (barber's pole worm), an economically important parasitic nematode. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from P. bergquistae led to the purification of four known bishomoscalarane sesterterpenes, phyllolactones A-D (1-4). The absolute configurations of phyllolactones B (2) and C (3) were determined by single-crystal X-ray diffraction analysis; literature and data analyses revealed the need for these chemical structures to be revised. Compounds 2-4 induced a lethal, skinny (Ski) phenotype in larvae of H. contortus at concentrations between 5.3 and 10.1 µM. These data indicate that the bishomoscalarane sesterterpene structure class warrants further investigation for nematocidal or nematostatic activity.

Practical High-Throughput Method to Screen Compounds for Anthelmintic Activity against Caenorhabditis elegans.

In the present study, we established a practical and cost-effective high throughput screening assay, which relies on the measurement of the motility of Caenorhabditis elegans by infrared light-interference. Using this assay, we screened 14,400 small molecules from the "HitFinder" library (Maybridge), achieving a hit rate of 0.3%. We identified small molecules that reproducibly inhibited the motility of C. elegans (young adults) and assessed dose relationships for a subset of compounds. Future work will critically evaluate the potential of some of these hits as candidates for subsequent optimisation or repurposing as nematocides or nematostats. This high throughput screening assay has the advantage over many previous assays in that it is cost- and time-effective to carry out and achieves a markedly higher throughput (~10,000 compounds per week); therefore, it is suited to the screening of libraries of tens to hundreds of thousands of compounds for subsequent evaluation and development. The present phenotypic whole-worm assay should be readily adaptable to a range of socioeconomically important parasitic nematodes of humans and animals, depending on their dimensions and motility characteristics in vitro, for the discovery of new anthelmintic candidates. This focus is particularly important, given the widespread problems associated with drug resistance in many parasitic worms of livestock animals globally.

Use of in-chamber transcutaneous oxygen measurement to determine optimal treatment pressure in patients undergoing hyperbaric oxygen therapy.

INTRODUCTION: Hyperbaric oxygen (HBO2) therapy is used to promote healing in select problem wounds. Transcutaneous oxygen measurement (TCOM) can be used to predict the response of these wounds to HBO2, with in-chamber TCOM values shown to be the most predictive. We evaluated the use of in-chamber TCOM values to determine optimal treatment pressure. METHODS: A retrospective review was completed of patients undergoing HBO2 therapy for a lower-extremity wound and who had in-chamber TCOM. Data collected included TCOM values, treatment profile, and patient outcome. RESULTS: A total of 142 patients were identified. The overall results demonstrated healing in 59%, minor amputation (below ankle) in 11.3%, and major amputation (above ankle) in 16.2% of patients. 79.3% of patients at 2 atmospheres absolute (ATA) and 86.6% of patients at 2.4 ATA had transcutaneous oxygen pressure (TcPO2) values ≥250 mmHg. Among those with TcPO2 ⟨250 mmHg at 2 ATA, 41% attained TcPO2 ⟩250 mmHg at 2.4 ATA. Among those treated at 2 ATA the healing rate was 70.6% if TcPO2 ⟩250 mmHg, and 11.8% if TcPO2 ⟨250 mmHg (P⟨0.001). Among those treated at 2.4 ATA the healing rate was 33.3% if TcPO2 ⟩250 mmHg and 14.3% if TcPO2 ⟨250 mmHg (P⟨0.001). DISCUSSION: Determining optimal therapeutic pressure for patients undergoing HBO2 is important to maximize benefit and minimize risk. This study indicates that in-chamber TCOM can be used to select an individualized optimal treatment pressure in patients undergoing HBO2 for lower-extremity wounds, including diabetic foot ulcers. This may result in better utilization of HBO2 and better outcomes.

Hyperbaric oxygen for the treatment of nonhealing arterial insufficiency ulcers.

There is limited data regarding hyperbaric oxygen's effectiveness in the treatment of nonhealing arterial insufficiency ulcers. This study was designed to analyze healing rates and amputation rates in patients who underwent adjunctive hyperbaric oxygen for a nonhealing arterial insufficiency ulcer. A retrospective chart review was completed on patients who underwent hyperbaric oxygen for arterial insufficiency ulcers that failed to heal despite standard treatment. Information collected included complete ulcer healing, amputation, and patient characteristics. There were 82 patients identified. A majority did not have diabetes (84.1%). The overall rate of healing was 43.9%. The overall major amputation rate was 17.1%. The amputation rate among those who healed was 0% compared to 42.4% among those not healed (p < 0.0001). Dialysis was predictive of major amputation (p = 0.03). Our findings suggest hyperbaric oxygen can play a role in management of arterial insufficiency ulcers that have failed standard treatment. The overwhelming majority of these patients did not have diabetes, which allows this study to be translated to patients with a primary arterial insufficiency ulcer. These results support the use of hyperbaric oxygen for select nonhealing arterial insufficiency ulcers that have failed standard therapy and the need for a prospective pilot study.

Seizure incidence by treatment pressure in patients undergoing hyperbaric oxygen therapy.

INTRODUCTION: Hyperbaric oxygen (HBO2) therapy uses different maximum treatment pressures. A side effect of HBO2 is oxygen toxicity seizure. The purpose of this study was to determine the overall incidence of oxygen toxicity seizure and assess risk at different treatment pressures. METHOD: A retrospective chart review was performed on patients who underwent HBO2 at a university hospital and at an outpatient center. Statistical analysis was performed to determine overall incidence of seizure and identify risk factors including maximum treatment pressure. RESULTS: A total of 931 patients were identified representing a total of 23,328 treatments. The overall incidence of seizure was one in 2,121 treatments (five per 10,000). There were zero per 10,000 at 2.0 atmospheres absolute/atm abs (0/16,430), 15 per 10,000 at 2.4/2.5 atm abs (1/669) and 51 per 10,000 at 2.8 atm abs (1/197). There was a statistically significant difference for seizure between the different pressures (χ2 (2, 23,540) = 31.38, p < .001). DISCUSSION: The overall incidence of oxygen toxicity seizure in this study is consistent with recent reports. This study demonstrated a statistically significant increased risk of seizure with increasing treatment pressure. Treatment at higher pressure should be chosen based on demonstrable benefit with a clear understanding of increased risk with higher pressure.