Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice.

Platensimycin (PTM) is a promising natural product drug lead against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), while the clinical development was hampered by problems related to its poor solubility and pharmacokinetic properties. In this study, we used liposomes and micelles as carriers of PTM to prepare PTM nanoformulations for the treatment of MRSA infection in mice. PTM-loaded nanoparticles could effectively reduce residual bacteria in the MRSA-infected macrophage cell model, comparing to free PTM. More importantly, in vivo studies showed that encapsulation of PTM by liposomes or micelles effectively improved the pharmacokinetic properties of PTM in Sprague-Dawley rats and the survival rate of MRSA-infected C57BL/6J mice. Our study has thus suggested that the clinically used nanocarriers, such as liposome and micelle, might also be useful to improve the efficacy of other natural product drug leads to accelerate their in vivo evaluation and preclinical development.

2-PHENOXYETHANOL (2-PE) AND TRICAINE METHANESULFONATE (MS-222) IMMERSION ANESTHESIA OF AMERICAN HORSESHOE CRABS (LIMULUS POLYPHEMUS).

Despite extensive literature examining American horseshoe crab physiology, there are comparatively few publications addressing their medical care. Establishing anesthesia protocols for horseshoe crabs is integral to limiting the potential stress and pain associated with invasive procedures and for advancing euthanasia techniques. The objective of this study was to compare the effects of two immersion anesthetics, tricaine methanesulfonate (MS-222) at 1 g/L (buffered with sodium carbonate) and 2-phenoxyethanol (2-PE) at 2 mL/L, on horseshoe crabs. Twenty horseshoe crabs were assigned to one of two anesthetic treatment groups and individually anesthetized in natural seawater. Water quality, cardiac contractility, and hemolymph gas analytes were measured prior to anesthesia and at 30 min Animals were monitored via heart rate, gilling rate, and sedation score every 5 min until recovered. Transcarapacial ultrasonography was used to obtain heart rate, gilling rate, and percent fractional shortening. Light or surgical anesthesia was produced in 10/10 animals in the 2-PE group and 8/10 animals in the MS-222 group. There was no significant difference in sedation scores, induction time (median 15 min), or recovery time (median 20.5 min). Gilling rate and cardiac contractility decreased during anesthesia, whereas heart rate did not. Hemolymph pH and pO2 were not different among treatment groups or time points. Baseline pCO2 was higher than pCO2 at 30 min for both groups but significantly elevated only in the MS-222 group. This is attributed to increased activity during the handling of awake animals. Invasive blood pressure obtained via cardiac catheterization in two animals was markedly decreased during surgical anesthesia. In conclusion, 2-PE and MS-222 provided effective anesthesia with clinically useful induction and recovery times. 2-PE provided a subjectively more reliable and smoother anesthesia compared to MS-222.

Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.

BACKGROUND: Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. METHODS: In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. RESULTS: Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. CONCLUSIONS: The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.

Retinal toxicity associated with occupational exposure to the fish anesthetic MS-222.

PURPOSE: To report a case of retinopathy associated with chronic occupational exposure to ethyl-m-aminobenzoic acid methanesulfonate (MS-222), a retinotoxic fish anesthetic. METHOD: Case report with electroretinograms to document changes in visual electrophysiology. RESULTS: An ichthyologist with a long history of skin exposure to MS-222 was initially examined for decreased vision, photophobia, and photopsia. His electroretinogram abnormalities were similar to those seen in animal models of acute MS-222 toxicity. After terminating MS-222 contact for 7 months, his vision returned to normal, and his electroretinogram improved. CONCLUSION: Individuals with occupational exposure to MS-222 should exercise caution to avoid systemic absorption of this retinotoxic compound.

Symptomatic methemoglobinemia with a commonly used topical anesthetic, cetacaine.

Severe cyanosis resulting from acquired methemoglobinemia after application of a topical anesthetic, Cetacaine spray, occurred in a 37-year-old patient following bronchoscopy for postoperative atelectasis. Response to methylene blue therapy was dramatic and complete. Attention is drawn to a dangerous adverse effect of this commonly used topical anesthetic agent.

Influence of Alvogyl on the healing of extraction wound in man.

Eight volunteer patients free of any systamic disease underwent extraction of two teeth on the same day. One extraction socket was packed with Alvogyl, the other served as a control wound. Biopsies for histological assessment were taken from both sockets 1 and 2 weeks after extraction. Histological study revealed the normal sequence of wound healing in the sockets allowed to heal spontaneously. On the other hand, the signs of retarded wound healing (acute inflammatory infiltrate, persistent granulation tissue, failure to form connective tissue scar and frequent foreign bodies/foreign body giant cells) were encountered in the sockets packed with Alvogyl. On the basis of these preliminary results, it seems warranted to state that the systematic use of Alvogyl as a preventive and curative treatment for postextraction alveolar infections cannot be advocated.

Photocontact dermatitis from P-aminobenzoic acid.

A 6-year-old girl with xeroderma pigmentosum was contact and photocontact sensitized to PABA which had been used as a sunscreening agent. The activating wavelengths for photocontact dermatitis were in long-wave ultraviolet light. The experimental photocontact sensitization was not induced in guinea pigs. Although PABA is the most effective and harmless sunscreening agent for normal skin, it could induce photocontact sensitivity especially in diseased or damaged skin.

Methemoglobinemia induced by a topical anesthetic spray (cetacaine).

In two seriously ill patients, cyanosis developed shortly after a topical anesthetic spray (Cetacaine) was used. In both cases the presence of methemoglobinemia was suggested by a discrepancy between the arterial oxygen tension and the oxygen saturation of hemoglobin, as measured spectrophotometrically. The characteristic responses of the spectrophotometric oximeter to blood containing different concentrations of methemoglobin are described. Physicians administering this topical anesthetic spray (Cetacaine) should be aware of the possible development of methemoglobinemia.