Pharmacodynamic differences between species exemplified by the novel anticancer agent CHS 828

When a candidate drug enters clinical trials, decisions regarding dosing are mainly based on animal data. Occasionally, toxicity problems are faced in the clinic because of unexpected species differences in pharmacokinetics or pharmacodynamics between humans and preclinical species. Fludarabine and topotecan are examples of such drugs. In the first clinical trials of the new agent CHS 828, the maximum tolerated dose was reached earlier than expected from animal data. This paper discusses the issue of species differences in the development of anticancer drugs, and preclinical models for detection and quantification of such differences. Pharmacokinetic and hematological toxicity data of CHS 828 from studies in rats and humans are presented. In vitro sensitivity to CHS 828 and some established cytotoxic agents was measured in lymphocytes from humans and rats and in a panel of human and rodent cell‐lines. 10–100 times higher CHS 828 exposure was tolerated by rats than by patients. In both in vitro cell systems, CHS 828 showed higher potency in human cells compared to rodent cells. A species difference was evident also for fludarabine, but not for doxorubicin and cisplatin. CHS 828 pharmacokinetics were similar across species. In conclusion, the lower tolerance of CHS 828 in humans than in rats could be detected in vitro in cultures of peripheral lymphocytes. Preclinical studies of species differences could help the interpretation of in vivo effect studies as well as the choice of starting dose for clinical trials. We suggest peripheral lymphocytes from different species as a potential model system for such studies. Drug Dev. Res. 61:218–226, 2004. © 2004 Wiley‐Liss, Inc.     

Patterns of clinical use of antipsychotics in hospitalized psychiatric patients

The ways of using antipsychotic drugs have greatly changed over the last 10 years. The aim of this study was to evaluate such changes in psychiatric patients admitted to the Psychiatric Department of Milan's Ospedale Maggiore in 1989 (n=350), 1999 (n=718) and 2002 (n=628). The medical records of the hospitalized patients were evaluated by analyzing the anamnestic and clinical data with particular reference to age, gender, diagnosis and medication use. In 2002, atypical antipsychotics were more frequently prescribed as monotherapy upon discharge than typical antipsychotics (32.64% vs. 30.10%). Combinations of two or more antipsychotic drugs were prescribed upon discharge for 20.63% of the patients in 1989, 31.24% in 1999 and 23.09% in 2002. The combinations of one typical and one atypical drug increased from 4.04% in 1999 to 13.06% in 2002. The mean (+/-S.D.) daily antipsychotic drug dose (expressed in chlorpromazine equivalents) was significantly higher in 2002 than in 1999 and 1989. The results of this study confirm the trend to use combinations of one typical and one atypical antipsychotic, and higher doses.     

Effect of oxprenolol and metoprolol on serum lipid concentration

Summary The aim of the present study was to evaluate whether a reduction in HDL-cholesterol is peculiar to non cardioselective beta blockers or whether it is also produced by cardioselective beta₁-blockers. 16 patients with primary arterial hypertension on a balanced isocaloric diet were given oxprenolol 120 to 240 mg/day or metoprolol 100 to 200 mg/day in a random cross-over study. No significant change was observed after either treatment in fasting blood glucose, serum total cholesterol and triglycerides. HDL-cholesterol concentration was significantly decreased on metoprolol, from 41 to 36 mg/dl (p<0.05), while oxprenolol did not affect it at all. The difference might depend on intrinsic sympathomimetic activity which is possessed by oxprenolol and which metoprolol lacks.     

The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets

OBJECTIVE: Data from prospective studies suggest a significant reduction in the risk of new diabetes from drug therapies containing angiotensin-converting enzyme (ACE) inhibitors. Since the renin-angiotensin system (RAS) has been found locally in several tissues and cells, including pancreatic islets, we hypothesized that the positive metabolic effects of ACE inhibitors may be due to a beneficial action of these compounds on insulin-secreting beta-cells. DESIGN AND METHODS: Isolated human pancreatic islets were studied after 24 h of incubation with 22.2 mmol/l glucose, with or without the presence in the incubation medium of 0.5-6.0 mmol/l zofenoprilat or enalaprilat, ACE inhibitor drugs which differ by the presence of a sulphydryl or a carboxyl group in their structural formula. Functional and molecular studies were then performed to assess insulin secretion, redox balance, mRNA and protein expression. RESULTS: Angiotensinogen, ACE and angiotensin type 1 receptor mRNA expression increased in islets cultured in high glucose; this was similarly prevented by the presence of either ACE inhibitor. As expected, preculture of human islets in high glucose determined a marked reduction in insulin secretion which was associated with enhanced oxidative stress, as shown by increased nitrotyrosine concentrations, and enhanced expression of protein kinase C beta and NADPH oxidase. The presence of either of the ACE inhibitors counteracted several of the deleterious effects of high glucose exposure, including reduction of insulin secretion and increased oxidative stress; zofenoprilat showed significantly more marked effects. CONCLUSIONS: These results showed that: (a) RAS molecules are present in human islets and their expression is sensitive to glucose concentration, (b) ACE inhibitors, and in particular zofenoprilat, protect human islets from glucotoxicity and (c) the effects of ACE inhibition are associated with decreased oxidative stress. Together, these findings provide evidence that the possible beneficial effects of ACE inhibitors in human diabetes are due, at least in part, to a protective action on pancreatic beta-cells.     

Health assessment for migrants and asylum seekers upon arrival and while hosted in reception centres: Italian guidelines

BackgroundDuring 2016–17, national guidelines were developed in order to provide evidence-based recommendations on health assessments for migrants and asylum seekers upon their arrival in Italy.MethodsScientific literature published between 2005 and 2016 was searched in different databases. A free search was also performed on international organizations’ websites in order to identify additional relevant documents. A multidisciplinary panel discussed the resulting evidence and formulated recommendations.ResultsEvidence-based recommendations were formulated: signs and symptoms of specific diseases should to be actively searched for active TB, malaria, STI, intestinal parasites, diabetes, anaemia. In case of other health conditions (latent TB, HIV, HBV, HCV, STI, strongyloides, schistosoma, diabetes), testing should be offered to asymptomatic subjects coming from endemic areas or exposed to risk factors. Mass screening is recommended for anaemia and hypertension; a pregnancy test should be considered, while inclusion in cervical cancer screening and vaccination programs is recommended.A modulated, progressive approach was developed, covering an initial evaluation during rescue operations, a full medical examination at first line reception stage and the referral to national health services during second line reception.ConclusionsIt is important to produce and periodically update guidelines on these issues and local peculiarities should be taken into account in their design and implementation. Guidelines can not only support economic sustainability, but also counteract stigmatization dynamics.     

Central adiposity and left ventricular mass in obese children

AimThe impact of central adiposity on left ventricular (LV) mass in childhood obesity has been little explored. This study evaluates whether central obesity influences LV mass and function in obese children.Methods and resultsBiochemical, anthropometric and echocardiographic measurements were taken in obese (n = 111, mean age 10.6 ± 2.5 years) and non-obese children (n = 30, mean age 10.8 ± 3.0 years). Left ventricular function was analyzed by conventional and tissue Doppler echocardiography. LV mass was calculated according to the Penn convention and indexed for height^2.7 (LVM_i). The obese group showed increased levels of LVM_i as compared to the non-obese group (35.7 ± 8.5 vs 23.5 ± 2.8 g/h^2.7, p < 0.0001). Among obese children, we observed a significant increase of LVM_i across tertile of waist–height ratio (WHtR). The subjects identified by the highest tertile of WHtR, as compared to subjects identified by the lowest tertile, showed higher levels of BMI (29.5 ± 5.4 vs 31.0 ± 5.0 kg/m², p < 0.0001) and LVM_i (32.1 ± 6.5 vs 37.1 ± 8.5 g/h^2.7, p < 0.01). Among obese children a positive correlation (standardized for age and gender) was found between LVM_i and BMI (r = 0.282, p < 0.01) and WHtR (r = 0.334, p < 0.0001). To analyze the independent predictors of LVM_i, a stepwise linear regression analysis was performed using age, gender, BMI, blood pressure, heart rate, HOMA-IR and WHtR as independent variables. LVM_i was independently associated only with WHtR (β = 0.309, t = 3.238, p = 0.002).ConclusionObese children show an increased LVM_i and a preserved LV function. Central adiposity is the major determinant of left ventricular mass.     

Effects of C-peptide on isolated human pancreatic islet cells

BACKGROUND: Recent data have demonstrated that pro-insulin-derived C-peptide can affect the function of several different cell types. We hypothesized that C-peptide might have an influence on the function and survival of isolated human islets. METHODS: Islets were prepared by combining enzymatic digestion and density gradient centrifugation, and the effects of human C-peptide were evaluated acutely and after 24-h incubation. Insulin secretion, apoptosis, quantitative RT-PCR and western-blotting experiments were then performed. RESULTS: Glucose-stimulated insulin secretion was not affected by C-peptide and, accordingly, mRNA expression of glucose transporter 2 and glucokinase did not differ between islets pre-cultured or not with the hormone. However, apoptosis was significantly lower in islets exposed to C-peptide than in control islets. This was accompanied by a significant increase of mRNA and protein expression of Bcl2, an anti-apoptotic molecule, with no change in the expression of Bax, a pro-apoptotic molecule. CONCLUSION: These results show that in human islets pro-insulin C-peptide has no direct effects on insulin secretion, but it decreases islet cell apoptosis. A direct role of C-peptide on beta-cell mass regulation is therefore suggested.     

Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines

Hyaluronan and hyaluronidases have been proposed to be involved in tumor angiogenesis and invasion. Three hyaluronidases, HYAL1, HYAL2 and HYAL3, are located at the chromosomal region 3p21. In most small cell lung cancer (SCLC) lines the 3p21 region is part of a homozygote or heterozygote deletion. Gliomas are known to exist in a hyaluronan rich environment and express high levels of the hyaluronan receptor CD44. In a panel of SCLC and glioma cell lines the expression of HYAL1, HYAL2 and HYAL3 mRNA was examined. It was observed that the cell lines differed in their ability to splice out a retained intron in the 5' UTR of HYAL1 mRNA. A correlation seems to exist between the ability to splice out the retained 5' end intron of HYAL1 mRNA and the general hyaluronidase activity. In one cell line a substantial part of the hyaluronidase activity was abolished by immunoprecipitation of Hyal1, which strongly indicates that Hyal1 is the principal hyaluornidase in the examined cell lines. During severe hypoxia a significant reduction in both hyaluronidase mRNA and protein activity was found. These results support the theory of involvement of hyaluronidase in the angiogenic and invasive front of tumors.