Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys.

Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.

Rapid response to a conjunctivitis outbreak: the use of technology to leverage information.

When an outbreak of conjunctivitis was identified at a rural New England college early in 2002, the college health center medical staff used various information management and communication systems to alert the community to the situation. They called upon the state Department of Human Services and the Centers for Disease Control and Prevention to help them understand and manage the outbreak. Technological systems already in place at the college allowed for rapid collection of data by means of a survey delivered over the Internet and a carriage study facilitated by a Web-based appointment and communication system. Within days, the data were collected and analyzed and an immediate response to contain the outbreak was launched.

Early containment of severe acute respiratory syndrome (SARS); experience from Bamrasnaradura Institute, Thailand.

BACKGROUND: On March 11, 2003, a World Health Organization (WHO) physician was admitted to Bamrasnaradura Institute, after alerting the world to the dangers of severe acute respiratory syndrome (SARS) in Vietnam and developing a fever himself. Specimens from the first day of his admission were among the first to demonstrate the novel coronavirus, by culture, reverse transcription-polymerase chain reaction (RT-PCR), and rising of specific antibody, but proper protective measures remained unknown. The authors instituted airborne, droplet and contact precautions from the time of admission, and reviewed the efficacy of these measures. MATERIAL AND METHOD: A specific unit was set up to care for the physician, beginning by roping off an isolated room and using a window fan to create negative pressure, and later by constructing a glass-walled antechamber, designated changing and decontamination areas, and adding high-efficiency particulate air (HEPA) filters. The use of personal protective equipment (PPE) was consistently enforced by nurse managers for all the staff and visitors, including a minimum of N95 respirators, goggles or face shields, double gowns, double gloves, full head and shoe covering, and full Powered Air Purifying Respirator (PAPR) for intubation. To assess the adherence to PPE and the possibility of transmission to exposed staff a structured questionnaire was administered and serum samples tested for SARS coronavirus by enzyme-linked immunosorbent assay (ELISA). Exposure was defined as presence on the SARS ward or contact with laboratory specimens, and close contact was presence in the patient's room. RESULTS: The WHO physician died from respiratory failure on day 19. 112 of 129 exposed staff completed questionnaires, and the 70 who entered the patient's room reported a mean of 42 minutes of exposure (range 6 minutes-23.5 hours). 100% reported consistent handwashing after exposure, 95% consistently used a fit-tested N95 or greater respirator, and 80% were fully compliant with strict institutional PPE protocol. No staff developed an illness consistent with SARS. Serum samples from 35 close contacts obtained after day 28 had a negative result for SARS coronavirus antibody. CONCLUSIONS: Hospitalization of one of the earliest SARS patients with documented coronavirus shedding provided multiple opportunities for spread to the hospital staff, but strict enforcement of conservative infection control recommendations throughout the hospitalization was associated with no transmission.