Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies : evidence from Phase I studies in healthy volunteers

We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs' efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug's pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0-t, and AUC0- 1e). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5-1 hour - a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone

Diagnostic, Therapeutic, Ethic and Legal Issues in caring for dementia: the viewpoint of Medical representative in Modena (Italy)

The clinical outcomes of dementia are characterized by several ethic, diagnostic and therapeutic dilemmas. To evaluate the viewpoint and believes on the diagnostic, therapeutic, ethic and legal issues arising in the management of demented elderly, a 47 item questionnaire was designed and mailed to 898 physicians working in the field of dementia. Our sample consisted of geriatricians, neurologists, psychiatrists and primary care physicians in the Province of Modena. The physicians older than 50 years have a lower average know-ledge about the most recent therapeutic guidelines on dementia. Differences were found in the management of severe dementia according to the setting. There is agreement that the diagnosis should be communicated by family physicians with no differences across speciality. Decision making was the most doubtful field: 15 % of participants considered demented patients capable of informed consent, 46 % questioned it, 27 % was very uncertain and 12 % disagreed. Determining a person's legal status by a proper legal process is an uncommon practice. The majority of the responders agree on giving a support to the carers, but heavy skepticism emerges on its presumed efficacy. There is no homogeneity in physicians' attitude toward demented patients; the clinical setting seems to influence some choices more than the physician's speciality. Ethic issues are often given up or faced with paternalistic attitude. Information and educational processes about diagnostic, ethic and therapeutic options are required to improve the care of demented patients

Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers : a randomized, open-label, 2-period, single-dose, crossover phase 1 study

BACKGROUND: The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interindividual and intraindividual variability. We documented previously that HIV patients taking RAL at 400 mg bid by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability than patients taking the drug by swallowing the tablets. This study extends our previous findings. METHODS: An open-label, 2-period crossover study compared the pharmacokinetics of 2 doses of RAL given at 400 mg every 12 hours (that mimics a bid administration) by swallowing with 1 dose of 800 mg (that mimics a qd administration) by chewing the tablets in 12 healthy volunteers. RAL plasma concentrations were measured by a chromatographic method coupled with mass spectrometry. RESULTS: Subjects taking RAL by chewing had significantly higher drug exposure (RAL area under the curve[AUC](0-24): 40722 \ub1 14843 versus 21753 \ub1 12229 ng \ub7 h/mL, P < 0.0001) and reduced pharmacokinetic variability compared with those taking the drug by swallowing the whole tablet, with no difference in the minimum RAL concentrations (RAL C(min): 36 \ub1 23 versus 43 \ub1 23 ng/mL, P = 0.298). Subjects taking RAL by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability compared with those taking the drug by swallowing. No differences were observed in the minimum RAL concentrations. CONCLUSIONS: RAL at 800 mg once daily by chewing the tablets may represent a novel therapeutic option for the treatment of HIV being associated with higher drug absorption, reduced pharmacokinetic variability, and potentially better compliance compared with patients swallowing the 400-mg bid intact tablets

Assessment of the awareness and management of sleep apnea syndrome in acromegaly. The COM.E.TA (Comorbidities Evaluation and Treatment in Acromegaly) Italian Study Group

In 2007 the Italian COM.E.T.A. (COMorbidities Evaluation and Treatment in Acromegaly) study group started to assess the application in a clinical setting of the Versailles criteria for management of acromegaly complications by a first questionnaire focusing on cardiovascular co-morbidities. A further questionnaire on sleep apnea syndrome (SAS) was delivered by the COM.E.T.A. study group to 107 endocrine centers in Italy. The results of our survey suggest that SAS is a well-known comorbidity even if its estimated prevalence is lower than in the literature. Polysomnography is the preferred tool for diagnosis. Control of SAS is considered relevant both for quality of life and co-morbidities. Continuous positive airway pressure is the cornerstone of therapy, but patients' acceptance may be critical. Control of GH/IGF-I secretion is important to improve SAS. Management of SAS requires cooperation between specialists. \ua92011, Editrice Kurtis