Primary Prevention of Sudden Cardiac Death: Can We Afford the Cost of Cardioverter-Defibrillators? Data from the Search-MI Registry-Italian Sub-study

Background: Large randomized trials show that in appropriately selected patients with left ventricular dysfunction, implantable cardioverter-defibrillators (ICDs) can improve overall survival at 2–5 years. Since direct implementation of the criteria used in the MADIT II and SCD-HeFT will lead to a marked rise in ICD implants, there is a growing fear that increased use of ICDs may cause a dramatic burden to health care systems. The ICD has traditionally been seen as an expensive form of treatment, which is difficult to accept at the first look. This is mainly due to the nonlinear character of the ICD investment, characterized by high initial expenditure, followed by a deferred pay-off in terms of clinical benefits. Cost-effectiveness analysis may help provide a different perspective on the problem of ICD cost, as may estimation of the daily cost of ICD treatment, assuming a time horizon of 5–7 years—a particularly interesting subject for further registry studies.
Methods and Results: Based on real expenditure data from 2002 to 2005, as recorded in the Search-MI Registry-Italian Sub-study of patients implanted on MADIT II indications, we estimated the daily costs associated with the device and leads. Over a 5–7 year time horizon, the average daily cost was estimated to be €4.60–€6.70. Translation of these figures into U.S. market conditions suggests a daily cost of around $7.90–$11.40.
Conclusions: These findings appear useful to help evaluate the affordability of ICD in comparison with other therapeutic options in a context of limited available economic resources.     

Biopharmaceutics: Effect of Ointment Bases on Topical and Transdermal Delivery of Salicylic Acid in Rats: Evaluation by Skin Microdialysis

Microdialysis has been used to determine the concentration of salicylic acid in skin tissue and plasma periodically for 4 h to evaluate the effect of ointment bases on topical and transdermal delivery of salicylic acid. The ointment bases examined were solbase (water-soluble), poloid and white petrolatum (oleaginous), hydrophilic poloid (water in oil (w/o) type emulsion lacking water) and absorptive ointment (w/o-type emulsion containing water). The ointments (0.1 g) containing 25 μmol salicylic acid were applied for 2 h to the surface of rat skin (1 cm²) with (intact) or without the stratum corneum. For intact skin, the extent of topical delivery from different ointments, evaluated by the area under the concentration-time curve (AUC) of salicylic acid in the skin tissue (AUCskin), increased in the order solbase. white petrolatum, poloid, hydrophilic poloid. absorptive ointment. The ratio of AUC_skin (topical delivery) to the AUC of salicylic acid in plasma (AUC_plasma, transdermal delivery) varied remarkably among the different bases, the greatest ratio being observed for absorptive ointment. When the ointments were applied to skin surface without stratum corneum, AUC_skin for solbase was much higher (about 45 times that for intact skin), whereas only a small (two-fold) increase was observed for poloid and hydrophilic poloid and the increase was negligible for white petrolatum and absorptive ointment. For skin without the stratum corneum, the ratio AUC_skin/AUC_plasma for the different ointments was comparable, although the magnitudes of AUC_skin and AUC_plasma still varied substantially. The variance of AUC values arises as a result of the different rates of release of salicylic acid from the bases. These results indicate that: the topical and transdermal delivery of salicylic acid in intact skin varies substantially among different ointment bases, and the greatest topical delivery is observed for absorptive ointment; use of absorptive ointment increases the retention of salicylic acid in the stratum corneum; and the stratum corneum functions strongly as a penetration barrier for solbase, moderately for poloid and hydrophilic poloid, and less for absorptive ointment and white petrolatum.     

Use of Blunt Scalp Hooks for Abdominal Procedure in Lumboperitoneal Shunt Placement: Technical Note

In obese patients, we often find difficulty in laparotomy for placing a lumboperitoneal shunt catheter. The authors introduced an easy technique to get a sufficiently wide and shallow operative field through small abdominal incision in obese people. Four blunt scalp hooks and rubber bands, commonly used in craniotomy, were prepared. The fat layer and the rectus abdominis muscle layer were retracted and pulled up using these hooks. Blunt scalp hooks were useful for safe and effective retraction of abdominal wall, which made a sufficient and shallow operative field.     

Pseudomyxoma Peritonei with High Carcinoembryonic Antigen (CEA) Level: Report of Two Cases

Two cases of pseudomyxoma peritonei with high serum carcinoembryonicantigen (CEA) are reported. CEA levels in serum increased incorrelation with the accumulation of ascites. Systemic chemotherapywith anticancer agents such as 5-fluorouraciI (5-FU), cyclophosphamide,mitomycin C (MMC) and chromomycin A_a showed no effect on reducingeither the production of mucinous materials or the CEA level,but repeated intraperi-toneal instillation of large amountsof MMC reduced them in one case. In the other case, the CEAlevel returned to normal after removal of the tumor. These resultssuggest that CEA may be a useful indicator of the effect oftreatment and of the prognosis of pseudomyxoma peritonei.     

Tolerance to Lower Body Negative Pressure Exposure: Comparison Between Patients with Neurocardiogenic Syncope and Controls

Lower body negative pressure exposure (LBNPE) produces hemodynamic modifications similar to those produced by head-up tilt test (HUT). Patients with vasovagal syncope are more susceptible to HUT than healthy persons. The supine position during LBNPE would facilitate the simultaneous performance of complementary methods. The aim of this study was to compare tolerance to LBNPE between a group of patients with vasovagal syncope and a group of healthy volunteers. Eleven patients with vasovagal syncope and positive HUT and 13 healthy volunteers without prior history of syncope and negative HUT were included. The following protocol was used: −10 mmHg, 1 minute; −20 mmHg, 1 minute; −30 mmHg, 3 minutes, and −40, −50, −60, and −70 mmHg, 5 minutes for each stage. Tolerance was expressed as: maximum tolerated negative pressure (Max NP), maximum tolerated time (Max T), and Σ P × T, where P = pressure and T = time. Syncope or presyncope during the test was considered positive LBNPE. LBNPE was positive at −50 or −60 mmHg in 8 of 11 patients (73%). One healthy volunteer had presyncope after 5 minutes at −70 mmHg. Tolerance, as expressed by any of the three parameters, was significantly higher for the healthy volunteers (Max NP: −59.1 ± 7.9 vs −70, P < 0.01; Max T: 19.1 ± 4.2 vs 24.4 ± 0.3, P < 0.01; Σ P × T: 836.3 ± 269.5 vs 1214.6 ± 18, P < 0.01). We conclude that patients with neurocardiogenic syncope have a significantly lower tolerance to LBNPE than subjects with no previous history of syncope.     

N-Acetyl-L-γ-glutamyl Derivatives of p-Nitroaniline,Sulphamethoxazole and Sulphamethizole for Kidney-specific Drug Delivery in Rats

Kidney-specific delivery of p-nitroaniline, sulphamethoxazole and sulphamethizole after either intravenous administration of the L-γ-glutamyl or N-acetyl-L-γ-glutamyl derivatives or the parent drugs has been examined in a rat model. All L-γ-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-γ-glutamyl derivatives were fairly stable in the systemic circulation after parenteral administration. Concentrations of p-nitroaniline and sulphamethoxazole 20 min after administration of the parent drugs were somewhat higher in the kidney than in the liver and lung. The concentration of sulphamethizole in the kidney was dramatically higher than those in the hepatic and pulmonary tissue. Kidney-specific delivery of the drugs of interest was evaluated by determining the tissue concentrations of the released parent drug and the total drug levels (i.e. drug levels after hydrolysis of all conjugate to the parent drug). For L-γ-glutamyl-p-nitroaniline released renal levels of p-nitroaniline and total p-nitroaniline concentrations were both higher than those obtained after p-nitroaniline dosing. Use of L-γ-glutamylsulphamethoxazole resulted in higher total sulphamethoxazole concentrations in the kidney, but did not lead to an increase in released (unconjugated) sulphamethoxazole levels. In contrast, no kidney-selective distribution was observed for L-γ-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-γ-glutamyl-p-nitroaniline and N-acetyl-L-γ-glutamylsulpha-methoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-γ-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-γ-glutamyl-p-nitroaniline. In conclusion, N-acetyl-L-γ-glutamyl derivatization of certain compounds seems to be useful for kidney-specific ***drug delivery and preliminary data suggests that lipophilic drugs are better substrates than hydrophilic compounds. Results related to the selectivity of tissue distribution of the derivatives and species differences are discussed.