CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats.

BACKGROUND AND PURPOSE: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats. EXPERIMENTAL APPROACH: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats. KEY RESULTS: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia. CONCLUSIONS AND IMPLICATIONS: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.

Maintenance of weight loss in overweight middle-aged women through the Internet.

OBJECTIVE: The purpose of this study was to compare weight regain in a group of perimenopausal women (48.0+/-4.4 years old), randomized to a 12-month weight maintenance Internet intervention or to self-directed weight maintenance after a 4-month weight loss treatment. METHODS AND PROCEDURES: After a 4-month behavioral weight loss program, 135 women were randomized to either Internet or self-directed groups. The Internet group (n=66) used a website to gain information and complete logs concerning their weight, diet, and exercise progress over a 12-month follow-up. The 69 self-directed women had no contact with study staff. All women were measured for weight and body composition, and diet intake, and were interviewed using the 7-day physical activity questionnaires at baseline, 4 months, and 16 months. RESULTS: At the end of the 12-month follow-up, the Internet and self-directed groups had regained on average 0.4+/-5.0 kg and 0.6+/-4.0 kg, respectively (P=0.5). In within-group analyses, Internet diet-log entries were correlated with follow-up weight change (r=-0.29; P<0.05) and moderately with change in exercise energy expenditure (EEE; r=0.44; P<0.01). Follow-up weight change was not correlated with change in dietary intake. DISCUSSION: While significant weight loss was maintained over follow-up by both groups of women, Internet use did not surpass self-direction in helping to sustain weight loss. Among Internet users, Internet use was related to weight change and EEE.

Patterns of specific antimigraine drug use--a study based on the records of 18 community pharmacies.

The objective of this study was, first, to characterize the usage patterns of specific antimigraine drugs, and second, to compare these in patients with one type of drug with patients with two or more types of drug. Dispensing data on triptans and ergotamine were collected from community pharmacy records over a 1-year period. In a population of approximately 168,000 specific antimigraine medication has been dispensed to 2343 patients (1.4%). Oral dosage forms were prescribed in most prescriptions (77.1%), subcutaneous injections in 9.7%, rectal suppositories in 7.1% and nasal sprays in 6.1%. We identified 292 patients (12.5%) to whom more than one type of drug was dispensed. Multiple drugs patients showed significantly higher drug consumption and deviating patterns of specific antimigraine drug usage, receiving significantly more non-oral dosage forms (32.8% vs. 20.4%, P<0.001). Our data indicate substantially suboptimal treatment of migraine patients.

Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study.

Drugs which directly counteract nitric oxide (NO), such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers, may be effective in the acute treatment of migraine, but are also likely to be effective in migraine prophylaxis. In the underlying pilot study the prophylactic effect of the NO scavenger hydroxocobalamin after intranasal administration in migraine was evaluated. Twenty patients, with a history of migraine of > 1 year and with two to eight migraine attacks per month, were included in an open trial. A baseline period was followed by an active treatment period of 3 months with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete a diary in which details of each attack were described. A reduction in migraine attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds to 53% of the patients (responders). A reduction of > or = 30% was noted in 63% of the patients. The mean attack frequency in the total study population showed a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001). For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9 (baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/- 1.5 (P > 0.1). A reduction was also observed for the total duration of the migraine attacks per month, the total number of migraine days per month and the number of medication doses for acute treatment used per month. This is the first prospective, open study indicating that intranasal hydroxocobalamin may have a prophylactic effect in migraine. As a percentage of responders in prophylactic trials of > 35-40% is unlikely to be a placebo effect, a double-blind study is warranted.

A quantification of the placebo response in migraine prophylaxis.

To quantify the placebo response of prophylactic therapy in migraine, a meta-analysis of prophylactic, double-blind, placebo controlled migraine studies was performed. The total analysis included 22 studies testing 19 different products, including 2013 patients, of which 828 were treated with placebo. A reduction in migraine attacks of 50% or more (responders) was seen in 23.5%+/-8.0 (95% C.I. 18.3-28.8%) of the patients in the placebo groups and 45.5%+/-15.5 (95% C.I. 37.4-53.6%) in the active groups. A reduction in migraine attacks of 16.8%+/-12.7 (95% C.I. 10.9-22.6%) was observed in the placebo groups and 41.8%+/-11.7 (95% C.I. 36.9-46.6%) in the active groups. We propose that if the percentage of responders in an open-label prophylactic trial in migraine is above 35-40%, or if a reduction in migraine attack frequency is found of 40% or more, further studies are indicated to determine the prophylactic activity of the drug. In all studies included in this analysis, no placebo response was seen above these limits.

A medical center's experience with managing specialty bed usage.

The focus of this case study was the escalating use of specialty beds at a large military medical center. Members of a multidisciplinary task force looked at current use of specialty beds, clinical appropriateness of past decisions regarding use of these beds, and education of staff members. They concluded that specialty beds were being ordered randomly from multiple vendors without the benefit of sound clinical decision making. The task force narrowed the types of beds used from 16 to only 7, limited the number of primary bed vendors to two and placed them under contract, educated staff regarding proper selection of specialty beds, and established a protocol specifying WOC nurses and physicians as responsible personnel for ordering specialty beds. These efforts resulted in a marked decline in the use of specialty beds, better patient clinical outcomes, and a sizable cost reduction.

NMR studies of Ru(3)(CO)(10)(PMe(2)Ph)(2) and Ru(3)(CO)(10)(PPh(3))(2) and their H(2) addition products: detection of new isomers with complex dynamic behavior.

The clusters Ru(3)(CO)(10)L(2), where L = PMe(2)Ph or PPh(3), are shown by NMR spectroscopy to exist in solution in at least three isomeric forms, one with both phosphines in the equatorial plane on the same ruthenium center and the others with phosphines in the equatorial plane on different ruthenium centers. Isomer interconversion for Ru(3)(CO)(10)(PMe(2)Ph)(2) is highly solvent dependent, with DeltaH decreasing and DeltaS becoming more negative as the polarity of the solvent increases. The stabilities of the isomers and their rates of interconversion depend on the phosphine ligand. A mechanism that accounts for isomer interchange involving Ru-Ru bond heterolysis is suggested. The products of the reaction of Ru(3)(CO)(10)L(2) with hydrogen have been monitored by NMR spectroscopy via normal and para hydrogen-enhanced methods. Two hydrogen addition products are observed with each containing one bridging and one terminal hydride ligand. EXSY spectroscopy reveals that both intra- and interisomer hydride exchange occurs on the NMR time scale. On the basis of the evidence available, mechanisms for hydride interchange involving Ru-Ru bond heterolysis and CO loss are proposed.

Bioavailability of intranasal formulations of dihydroergotamine.

OBJECTIVE: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. METHODS: Two intranasal formulations of DHEM in combination with randomly methylated beta-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray (= two puffs of 100 microliters); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray (= four puffs of 125 microliters); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. RESULTS: No statistically significant differences were found in maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under plasma concentration-time curve (AUC0-8 h), Frel(t = 8 h) and Cmax/AUC(t = 8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. CONCLUSION: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers.

Absorption of clonazepam after intranasal and buccal administration.

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.

The vascular architecture of the fruit receptacle of red raspberry determined by 3D NMR microscopy and surface-rendering techniques.

The three-dimensional structure of the vascular system in tht fruit receptacle of red raspberry was determined using NMR microscopy in combination with computer techniques which highlight the surfaces of specific tissue types. The surface-rendering technique is particularly valuable in situations, where there are large differences in image characteristics between the tissue of interest and the rest of the specimen, and thus ideal for the delineation of ilic vascular tissue in the raspberry receptacle. This was shown to consist of a conical network of bundles with a spiral pattern of gaps; tht carpellury traces emereed from the proximal end of each gap. The inner xylem and outer phloem tissues each appeared as a pair of fused columns in the surface-rendered images, and each carpellary trace had a separate supply from the xyiern and phloem.

Antimicrobial prophylaxis in hysterectomies: a double-blind, randomized, comparative study of a single dose of piperacillin (2 g) versus a single dose of amoxicillin-clavulanic acid (2.2 g).

A double-blind, randomized comparative study of piperacillin (2 g) versus amoxicillin-clavulanic acid (2.2 g) as a single dose 30 minutes before the initiation of hysterectomy was performed. A total of 595 patients (of which 307 were in the piperacillin group) were evaluable for efficacy. Infectious complications were infrequent in both arms. One case of (mild) sepsis was observed in the piperacillin group and two cases of wound infection were observed in the amoxicillin-clavulanic acid group. Urinary tract infection was observed in 5.5% of the patients in the piperacillin group and in 2.4% of the amoxicillin-clavulanic acid group. A relatively high incidence of asymptomatic bacteriuria was seen in both groups: 11.8% in the piperacillin group and 8.7% with amoxicillin-clavulanic acid. A marked difference was seen between the two different hospital locations: a 15% incidence in the hospital where midstream urine was used for culture (Sittard), versus 5% in the hospital where catheter urine was used (Geleen). It is concluded that both antibiotics are associated with a low rate of infectious complications and that catheter urine must be used for sample collection.

Is Recormon less painful than Eprex after subcutaneous administration?

In this study, we examined the differences in pain score after subcutaneous injection of the epoetin preparations Eprex and Recormon. Patients (n = 30) received 5 injections Eprex and 5 injections Recormon in a randomized double-blind sequence. 10 Min after receiving the injection the patient was asked to complete a visual and a verbal analogue scale and two descriptive scales. The results of 25 patients were used for statistical evaluation. The overall results indicate that there are significantly more patients reporting pain after subcutaneous injection of Eprex than after Recormon (11 versus 2 patients, p less than 0.05; McNemar test). 12 Patients reported no differences in pain. 43 Out of 123 injections Eprex and 69 out of 125 injections Recormon caused no pain (p less than 0.01; chi 2 9.455). For 4 patients Recormon was significantly (p less than 0.05) less painful than Eprex. It can be concluded that Recormon may be a less painful alternative for individual patients reporting pain after subcutaneous injection of Eprex.

Ofloxacin intravenous. Compatibility with other antibacterial agents.

The physical and chemical compatibility of ofloxacin (infusion solution 100 ml = 200 mg) with amoxicillin, amoxicillin + clavulanic acid, flucloxacillin, tobramycin, gentamicin, clindamycin, vancomycin, ceftazidime and piperacillin was investigated. Upon admixture with flucloxacillin a precipitate formed between 7 and 24 hours. No other physical or chemical incompatibilities were observed with any of the other combinations. Ofloxacin may be safely combined with the tested antimicrobial drugs, except for flucloxacillin.

Comparison of clonazepam sorption to polyvinyl chloride-coated and polyethylene-coated tubings.

The sorption of clonazepam to polyvinyl chloride tubing, polyethylene-coated tubing and to a polyethylene syringe was determined. Pumping of clonazepam (5 mg/48 ml) through the polyvinyl chloride tubing with flow rates of 2 ml/h and 4 ml/h resulted in a reduction of the clonazepam concentration to about 40% and 55% of the original strength after 0.6 h, respectively. This value was 55% at a flow rate of 2 ml/h and a clonazepam concentration of 10 mg/48 ml. The effluent clonazepam concentration increased gradually after an infusion period of 1 h. Sorption of clonazepam to the polyethylene syringe and to the tubing coated on the inside with polyethylene does not occur. The use of polyethylene-coated administration sets is recommended for intravenous administration of clonazepam.

Stability of amphotericin B in CAPD fluid.

Amphotericin B is the drug of choice in continuous ambulatory peritoneal dialysis (CAPD) associated fungal peritonitis and is usually administered intraperitoneally. The drug is stated to be incompatible with anions. All CAPD fluids contain chloride and lactate anions. Therefore, the physical and chemical compatibility of amphotericin B with dextrose 5%, Dianeal 1.36% CAPD fluid, and Dianeal 1.36% peritoneal effluent was studied at amphotericin B concentrations of 1, 2, and 5 mg/L. Amphotericin B was most stable in Dianeal CAPD fluid. The rate of degradation was concentration dependent in dextrose 5% and peritoneal effluent. The higher the concentration, the lower the rate of degradation. After an incubation of 6 h at 37 degrees C, no significant decomposition was found at all concentrations studied in Dianeal CAPD fluid whereas 12-18% decomposition was found in effluent. No physical incompatibility with any solution was observed.