The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Risk of death from acute pancreatitis

Summary Conclusions The analysis of all the data available in 192 patients at 24 h from admission shows that only serum glucose above 250 mg/dL (13.88 mmol/L) and serum creatinine above 2 mg/dL (176.8 μmol/L) are prognostic factors of death (P<0.0001). When, however, pathological chest X-rays are also considered in a subset of 149 patients, these and serum creatinine are prognostic factors of death with odds ratios of 2.9 (95% CL 1.3–6.3) and 9.4 (95% CL 2.2–40.7), respectively (P<0.0001). Background In patients suffering from acute pancreatitis, neither Ranson scores nor Glasgow criteria evaluation at 24 h yield a sufficiently reliable prognosis of the risk of death from the first acute attack. Methods After excluding posttraumatic, postsurgical, and post-ERCP acute pancreatitis, we selected 192 consecutive patients admitted in the first instance to our center for a first attack, distinguishing between patients who died and patients who survived. We used Cox's model to analyze the prognostic weight of variables available within 24 h of admission (sex, age, alcohol intake, smoking habits, 17 biochemical tests, body mass index, chest X-rays, body temperature, and shock status). Results Seventeen (8.8%) patients died; mortality showed a decreasing trend over the period of years considered and was correlated, among other things, with necrotizing type of pancreatitis, idiopathic etiology, and shock status on admission.     

Insulin-sperm interaction: effects on plasma membrane and binding to acrosome.

In in vitro studies, viable, intact human spermatozoa took up free radioinsulin with an apparently non-receptor-mediated mechanism. However, when a colloidal gold-insulin complex was substituted for the radiotracer, no surface binding was visualized at the ultrastructural level. Upon sperm incubation in the presence of free insulin, a dose-dependent release of phospholipid phosphorus occurred, with a concomitant derangement of head cell membrane. After head membrane removal, spermatozoa-bound radioinsulin in a time- and concentration-dependent manner, the binding was displaceable by unlabeled insulin, and an exclusive localization of the colloidal gold-insulin complex was visualized at the acrosome level. On the basis of this evidence, both the plasma membrane and the acrosome seem to represent cytological targets for insulin.     

The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta.

In patients with osteogenesis imperfecta (OI), a disease characterized by abnormal bone fragility, bone mineral density (BMD) was found to be relatively preserved. Quantitative computed tomography (QCT) is the only available method for directly measuring in vivo both volumetric density and the cross-sectional area. Here we report the data from dual-energy X-ray absorptiometry DXA (spine and hip) and peripheral (pQCT) (ultradistal and proximal radius) measurement of 27 adult patients affected by OI, mostly of type I, compared with a group of healthy persons. In the patients with OI, areal BMD values at both femoral neck and lumbar spine were considerably lower than in control subjects (-32 and -36%, respectively; p<0.001 for body weight and height adjusted values). pQCT volumetric density at the ultradistal radius was 19% lower than in control subjects and this difference rose to 32% for purely cancellous bone tissue. The whole bone cross-sectional area of ultradistal radius, as measured by pQCT, was superimposable to normal. At the proximal radius, both cross-sectional area and cortical area, together with Bending Breaking Resistance Index (BBRI), were significantly lower in OI (-23; -22; -32% respectively; p<0.001 for body weight and height adjusted values), but cortical volumetric density was even slightly higher in the OI group than in control subjects. In conclusion, it appears that the most obvious defect in adults with OI is the inability to acquire an adequate thickness of the cortices of long bone and to achieve or maintain normal trabecular density.     

Syndiospecific polymerization of styrene with the catalytic system [Ti2(OC2H5)8Cl]2Mg2(μ-Cl)2/methylaluminoxane compared with MgCl2-supported and unsupported Ti(OC2H5)4

As a part of our interest in the performance of [Ti₂(OC₂H₅)₈Cl]₂Mg₂(μ-Cl)₂ as Ziegler-Natta catalyst, the polymerization of styrene with a toluene solution of this compound and methyl-aluminoxane as cocatalyst was performed. It was found that the present catalytic system promotes the syndiospecific polymerization of styrene with high stereoregularity and the results were compared with those obtained with MgCl₂-supported or unsupported Ti(OC₂H₅)₄ catalysts. Determination of the titanium oxidation states and electron spin resonance (ESR) measurements both in the absence and in the presence of styrene were carried out for all the catalytic systems aimed at shedding some light on the nature of the active species.     

Administration of ciprofibrate to lactating mothers induces PPARα-signaling pathway in the liver and kidney of suckling rats

It is well known that the hypolipidemic drug ciprofibrate induces peroxisome proliferation in rodent liver, which in turn leads to the oxidative stress, and modifies some parameters related to cell proliferation and apoptosis. The administration of ciprofibrate to rats during the lactating period determined in their pups significant modifications in hepatic peroxisome enzyme activities, induction of the PPARalpha-target gene, Cyp4a10, and perturbation in cell proliferation and apoptosis, which affected the size of the liver. Moreover, this modification was associated to about two-fold induction of mRNA-PPARalpha. On the contrary, in the kidney, although a similar two-fold up-regulation of PPARalpha was detected, the induction of both peroxisomal enzyme activities and Cyp4a10 were weak, and no alterations were detected, neither in cell cycle nor in the size of the tissue. Our results indicate that the response to ciprofibrate is stronger in the liver than in the kidney of newborn rats.     

Different effects of the liver mitogens triiodo-thyronine and ciprofibrate on the development of rat hepatocellular carcinoma

Previous work has shown that treatment with thyroid hormone (T3) decreased the incidence of rat hepatocellular carcinoma (HCC). The present study was designed to determine whether the inhibitory effect of T3 on HCC development was limited to early steps of the carcinogenetic process or, whether a similar effect could also be exerted by starting T3 treatment at later stages. Hepatic nodules were induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3 groups: group 1 was maintained on basal diet: group 2 was fed a diet containing 4 mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA administration: group 3 was exposed to cycles of T3 starting 8 months after initiation. Results demonstrate that inhibition of HCC development was essentially similar in rats exposed to T3 starting either 9 weeks or 8 months after initiation (50% inhibition compared to control rats). We have previously shown that T3-induced nodule regression and HCC inhibition occurred in spite of its mitogenic effect. Therefore, we next wished to determine whether a similar antitumoral effect could be exerted by other liver mitogens, such as peroxisome proliferators. Rats exposed to the initiation-promotion protocol described previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented diet, each cycle consisting of 7 days/month: the incidence of HCC and lung metastases was determined 13.5 months after initiation. Results showed that although treatment with T3 strongly inhibited HCC development (only 31% of T3+ rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same number of HCC as T3-untreated rats. In conclusion, the results of this study showed that the anticarcinogenic effect of T3 is maintained also when treatment begins late in the process, and its antitumoral property appears to be specific and may not be shared by other liver mitogens.     

Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score

Liver transplantation (LT) for colorectal liver metastasis (CRLM) may provide excellent survival rates in patients with unresectable disease. High tumor load is a risk factor for recurrence and low overall survival (OS) after liver resection (LR). We tested the hypothesis that LT could offer better survival than LR in patients with high tumor load. LR performed at Padua University Hospital for CRLM was compared with LT for unresectable CRLM performed both at Oslo and Padua. High tumor load was defined as tumor burden score (TBS) ≥ 9, and inclusion criteria were as in the SECA-I transplant study. 184 patients were eligible: 128 LRs and 56 LTs. 5-year OS after LR and LT was 40.5% and 54.7% (P = 0.102). In the high TBS cohort, 5-year OS after LR and LT was 22.7% and 52.2% (P = 0.055). In patients with Oslo score ≤ 2 and TBS ≥ 9 (13 LR; 24 LT) the 5-year OS after LR and LT was 14.6% and 69.1% (P = 0.002). The corresponding disease-free survival (DFS) was 0% and 22.9% (P = 0.005). Selected CRLM patients with low Oslo score and high TBS could benefit from LT with survival outcomes that are far better than what is achieved by LR.     

Prognostic evaluation of patients submitted to surgery for malignant pleural mesothelioma

The role of surgical resection remains controversial in malignant pleural mesothelioma. The assessment of its impact on prognosis is complicated by a poor understanding of the prognostic factors in the disease. We therefore evaluated, through univariate and multivariate analysis, the role on prognosis of 24 variables in 57 patients submitted to surgery from 1985 to 1993. Sixteen patients had only exploratory thoracotomy and 12 minimal residual disease after surgery (no nodules >1 cm in diameter). Thirty-four cases had epithelial histotype, 6 sarcomatous and 17 mixed. Median survival for the whole group was 15.7 months. Multivariate analysis showed a highly significant influence on survival for minimal residual disease after surgery (p=0.0006), followed by TNM stage (p=0.01). Median survival for patients with TNM stage I disease was 36.3 months and for patients with minimal residual disease 33 months. In conclusion, these data suggest that patients with limited disease have a longer survival after surgery than those with extensive disease. At the same time, our results indicate that the achievement of significant disease reduction with surgery has a critical impact on the prognosis of pleural mesothelioma.