Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Geometrical modified nesbit corporoplasty to correct different types of penile curvature: description of the surgical procedure based on geometrical principles and long-term results.

We present the use of a modified corporoplasty, based on geometrical principles, to determine the exact site for the incision in the tunica or plaque and the exact amount of albuginea for overlaying to correct with extreme precision the different types of congenital or acquired penile curvature due to Peyronie's disease. To describe our experience with a new surgical procedure for the enhancement of penile curvature avoiding any overcorrection or undercorrection. Between March 2004 and April 2013, a total of 74 patients underwent the geometrical modified corporoplasty. All patients had congenital curvature until 90° or acquired stable penile curvature 'less' than 60°, that made sexual intercourse very difficult or impossible, normal erectile function, absence of hourglass or hinge effect. Preoperative testing included a physical examination, 3 photographs (frontal, dorsal and lateral) of penis during erection, a 10 mcg PGE1-induced erection and Doppler ultrasound, administration of the International Index of Erectile Function (IIEF-15) questionnaire. A follow-up with postoperative evaluation at 12 weeks, 12 and 24 months, included the same preoperative testing. Satisfaction rates were better assessed with the use of validated questionnaire such as the International Erectile Dysfunction Inventory of the Treatment Satisfaction (EDITS). Statistical analysis with Student's t-test was performed using commercially available, personal computer software. A total of 25 patients had congenital penile curvature with a mean deviation of 46.8° (range 40-90), another 49 patients had Peyronie's disease with a mean deviation of 58.4 (range 45-60). No major complications were reported. Postoperative correction of the curvature was achieved in all patients (100%). Neither undercorrection nor overcorrection were recorded. No significant relapse (curvature>15°) occurred in our patients. Shortening of the penis was reported by 74% but did not influence the high overall satisfaction of 92% (patients completely satisfied with their sexual life). The erectile function was analyzed in both groups, Student's t-test showed a significant improvement in erectile function, preoperative average IIEF-15 scores were 17.43±4.67, whereas postoperatively it was 22.57±4.83 (P=0.001). This geometrical modified Nesbit corporoplasty is a valid therapy which allows penile straightening. The geometric principles make the technique reproducible in multicentre studies.

Minimally invasive infrapubic inflatable penile prosthesis implant for erectile dysfunction: evaluation of efficacy, satisfaction profile and complications.

Erectile dysfunction (ED), the second most common male sexual disorder, has an important impact on man sexuality and quality of life affecting also female partner's sexual life. ED is usually related to cardiovascular disease or is an iatrogenic cause of pelvic surgery. Many non-surgical treatments have been developed with results that are controversial, while surgical treatment has reached high levels of satisfaction. The aim is to evaluate outcomes and complications related to prosthesis implant in patients suffering from ED not responding to conventional medical therapy or reporting side effects with such a therapy. One hundred eighty Caucasian male suffering from ED were selected. The patient population were divided into two groups: 84 patients with diabetes and metabolic syndrome (group A) and 96 patients with dysfunction following laparoscopic radical prostatectomy for prostate cancer (group B). All subjects underwent primary inflatable penile prosthesis implant with an infrapubic minimally invasive approach. During 12 months of follow-up, we reported 3 (1.67%) explants for infection, 1 (0.56%) urethral erosion, 1 (0.56%) prosthesis extrusion while no intraoperative complications were reported. Mean International Index of Erectile Function-5 (IIEF-5) was 8.2 ± 4.0 and after the surgery (12 months later) was 20.6 ± 2.7. The improvement after the implant is significant in both groups without a statistically significant difference between the two groups (P-value 0.65). Mean Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score 1 year after the implant is 72.2 ± 20.7, and there was no statistically significant difference between groups A and B (P-value 0.55). Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach; and the patient and partner satisfaction is very high. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease after surgery common complications (infection and mechanical failure).

Translation of anticancer efficacy from nonclinical models to the clinic.

Mouse cancer models have provided critical insights into tumor biology; however, clinical translation of these findings has been challenging. This perspective posits that factors impacting on successful translation start with limitations in capturing human cancer pathophysiology and end with challenges in generating robust translatable preclinical end points. A comprehensive approach that considers clinically relevant mouse models with both an integrated biomarker strategy and a complementary modeling and simulation effort will strengthen the current oncology drug development paradigm.

UniPR129 is a competitive small molecule Eph-ephrin antagonist blocking in vitro angiogenesis at low micromolar concentrations.

BACKGROUND AND PURPOSE: The Eph receptor tyrosine kinases and their ephrin ligands are key players in tumorigenesis and many reports have correlated changes in their expression with a poor clinical prognosis in many solid tumours. Agents targeting the Eph-ephrin system might emerge as new tools useful for the inhibition of different components of cancer progression. Even if different classes of small molecules targeting Eph-ephrin interactions have been reported, their use is hampered by poor chemical stability and low potency. Stable and potent ligands are crucial to achieve robust pharmacological performance. EXPERIMENTAL APPROACH: UniPR129 (the L-homo-Trp conjugate of lithocholic acid) was designed by means of computational methods, synthetized and tested for its ability to inhibit the interaction between the EphA2 receptor and the ephrin-A1 ligand in an elisa binding study. The ability of UniPR129 to disrupt EphA2-ephrin-A1 interaction was functionally evaluated in a prostate adenocarcinoma cell line and its anti-angiogenic effect was tested in vitro using cultures of HUVECs. KEY RESULTS: UniPR129 disrupted EphA2-ephrin-A1 interaction with Ki = 370 nM in an elisa binding assay and with low micromolar potency in cellular functional assays, including inhibition of EphA2 activation, inhibition of PC3 cell rounding and disruption of in vitro angiogenesis, without cytotoxic effects. CONCLUSIONS AND IMPLICATIONS: The discovery of UniPR129 represents not only a major advance in potency compared with the existing Eph-ephrin antagonists but also an improvement in terms of cytotoxicity, making this molecule a useful pharmacological tool and a promising lead compound.

Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy.

This study investigates the efficacy and safety of personalized cyclophosphamide (CY) dosing in 50 patients receiving CY along with total body irradiation (TBI). Participants received CY 45 mg/kg with subsequent therapeutic drug monitoring using Bayesian parameter estimation to personalize the second CY dose to a target area under the curve (AUC) for carboxyethylphosphoramide mustard (CEPM) (a reporter molecule for CY-derived toxins) and for hydroxycyclophosphamide (to ensure engraftment). The mean second CY dose was 66 mg/kg; the total dose ranged from 45 to 145 mg/kg. After completion of this phase II study, we compared participants' clinical outcomes with those of concurrent controls (n = 100) who received TBI along with standard CY doses of 120 mg/kg. Patients receiving personalized CY dosing had significantly lower postconditioning peak total serum bilirubin (P = 0.03); a 38% reduction in the hazard of acute kidney injury (AKI) (P = 0.03); and nonrelapse and overall survival rates similar to those in the controls (P = 0.70 and 0.63, respectively) despite the lower doses of CY administered to most of the patients in the personalized dosage group.

2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action.

SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other cancer types. Recently SHP-2 became a new drug target, but till now little has been done in this field. In the present study, 17 2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2 inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation stabilize enzyme-inhibitor complex.

Detection of human papillomavirus DNA, p53 and ki67 expression in penile carcinomas.

Our study is aimed at evaluating the presence of p53 and Ki67 expression by immunohistochemistry in a series of 11 paraffin-embedded penile carcinomas. We also investigated the presence of Human Papillomavirus (HPV) DNA in these tumours and performed an accurate typing by DNA sequencing on positive samples. Immunohistochemistry (IHC) was performed with the anti-p53 and Ki67 mouse monoclonal antibodies. DNA extracted from small sections of each specimen was submitted to amplification with HPV specific general primers; PCR products of the proper length were purified and sequenced. IHC demonstrated nuclear accumulation of mutated p53 and Ki 67 expression in 10/11 tumour samples (90.9%). The prevalence of HPV DNA was 72.7%; the most prevalent type was HPV16. Sequencing analysis revealed the presence of HPV53 (12.5%), HPV18 (25%) and HPV16 (62.5%). Out of the p53 or Ki67 positive carcinomas the percentage of HPV positives was 80% and 70% respectively. Our results indicate that penile carcinoma is frequently associated to high risk HPV and with diffuse p53 and Ki67 expression.

Use of local hyperthermia as prophylaxis of fibrosis and modification in penile length following radical retropubic prostatectomy.

OBJECTIVE: The aim of the study was to evaluate the effectiveness of local hyperthermia in reducing possible penile shortening following radical retropubic prostatectomy. PATIENTS AND METHODS: The study population comprised 40 patients, aged 52-74 years, submitted to radical retropubic prostatectomy. Patients were divided into two groups of 20. In Group A, patients were submitted to local hyperthermia 3 weeks after surgery, three times a week, with treatment lasting 30 min. Patients received a total of 10 applications, which reached a local temperature of 39-40 degrees C. A second cycle was repeated after 1 month. In Group B, patients were submitted only to post-operative follow-up once a month. Penile length was measured in all patients both before and 3 months after surgery in the 'stretching phase' from the pubo-penile junction to the tip of the glans. RESULTS: In Group A patients (hyperthermia treatment), no variation in penile length was observed in 16 cases (80%), while the reduction ranged from 0.5-1.5 cm in four cases (20%). In Group B, 12 patients (60%) showed a reduction in penile length ranging from 0.5-2.5 cm, while penile length remained unchanged in eight patients (40%). CONCLUSIONS: Results of this study demonstrate a mild but statistically relevant reduction in penile shortening following low-grade, externally delivered penile hyperthermia, thus confirming the efficacy of this approach in preventing penile shortening caused by post-ischaemic fibrosis.

Role of hyperthermia in the treatment of Peyronie's disease: a preliminary study.

OBJECTIVE: Previous experience in the treatment of plaque with hyperthermia in orthopaedics led the authors to investigate the effectiveness of this approach in patients with Peyronie's disease. PATIENTS AND METHODS: The study population comprised 60 patients (aged 36-76 years) with advanced Peyronie's disease. Patients were divided into two groups (A and B), with 30 in each. Group A patients underwent local hyperthermia treatment, with 30-min treatment sessions twice a week for 5 weeks. Patients received a total of 10 applications, which reached a local temperature of 39-40 degrees C. A second cycle was repeated after a 1-month interval for a total of 20 treatment sessions. Group B patients were treated with intra-plaque infiltrations using 10 mg verapamil; they received one infiltration once a week for 3 months. Differences between the two groups, as well as between variables (before and after treatment), were analysed using Student t-test and Fisher test. RESULTS: Hyperthermia significantly reduced plaque size and penile curvature and led to an increase in mean scores of erectile function (EF) domain, while verapamil had no such effects. Haemodynamic parameters were not significantly modified in either group. Hyperthermia caused significantly fewer side effects than verapamil infiltrations and was significantly more effective in preventing disease progression. There were no significant differences between the two groups in terms of pain reduction during erection. CONCLUSIONS: Results of this study stress the efficacy of hyperthermia in the treatment of advanced Peyronie's disease.

Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis.

OBJECTIVES: To assess the serum and lower respiratory tract tobramycin concentrations (C(T)) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients with cystic fibrosis (CF) 6 months to 6 years of age. STUDY DESIGN: We performed a dose escalation study of serum C(T) measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) C(T) was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. RESULTS: A 180-mg dose of inhaled tobramycin produced a mean peak serum C(T) of 0.5 microg/mL (SD 0.4; range, <0.2 to 1.4 microg/mL). A 300-mg dose produced a mean peak serum C(T) of 0.6 microg/mL (SD 0.5; range, <0.2 to 1.2 microg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 microg/mL). The target ELF C(T) was 20 microg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 microg/mL). Mean ELF C(T) was 90 microg/mL (SD 54; range, 16 to 204 microg/mL) and exceeded the target concentration in 11 patients. CONCLUSION: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract.

2-Amino-Benzo[d]isothiazol-3-one derivatives: synthesis and assessment of their antiplatelet/spasmolytic effects.

We describe a series of 2-amino-benzo[d]isothiazol-3-one derivatives (2-8), which were synthesized and screened in vitro for inhibition of platelet aggregation and for their spasmolytic activity, with the awareness that the development of antiplatelet agents with additional vasodilation activity could be beneficial in the treatment of various vaso-occlusive disorders. The tested compounds show a powerful antiplatelet activity and various modifications resulted in molecules possessing antiaggregating effects as well as spasmolytic actions.

Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon-alpha.

BACKGROUND: Epidemiological data suggest that chronic hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. Therapy of HCV infection with recombinant interferon-alpha (r-IFN-alpha) can also impair of glucose metabolism. METHODS: To investigate the impact of HCV infection and the therapy with r-IFN-alpha on glucose metabolism we measured insulin sensitivity, glucose effectiveness, and first and second phase insulin secretion, using the minimal modelling analysis of frequently sampled intravenous glucose tolerance tests in 13 nondiabetic patients with HCV-induced liver disease before and after therapy with r-INF-alpha (6 x 106 U, subcutaneously, three times a week over 4 months). Liver biopsy was performed to evaluate and score liver fibrosis as a marker of HCV-induced cell injury. RESULTS: Insulin sensitivity (r = - 0.59, P < 0.05) and first phase insulin secretion (r = - 0.66, P < 0.03) were negatively related to the fibrosis score. Insulin sensitivity rose from 1.96 (SEM 0.37, n = 8) to 5.69 (SEM 0.99, n = 8) 10-4 min-1 per microU mL-1 (P < 0.01) in responders and from 2.51 (SEM 0.61, n = 5) to 6.95 (SEM 1.99, n = 5) in nonresponders after 4 months r-INF-alpha therapy. Fasting free fatty acids decreased significantly to about 50% (P < 0.01) in patients with and without therapy response after 4 months, whereas first phase insulin secretion did not change. CONCLUSIONS: HCV-induced liver injury is related to the deterioration of insulin sensitivity and first phase insulin response, thus impairing glucose homeostasis in these HCV-infected patients. The administration of r-INF-alpha three times a week over 4 months is not associated with an impairment of glucose homeostasis.

Comparison of in vitro and ex vivo antiplatelet effects of 1,2-benzisothiazolin-3-one and its 2-amino derivative.

The in vitro and ex vivo antiplatelet effects of 2-amino-1,2-benzisothiazolin-3-one (1) are compared with those of its parent compound 1,2-benzisothiazolin-3-one (2) and with acetylsalicylic acid (ASA) against different agonists. 2-Amino-1,2-benzisothiazolin-3-one inhibits adenosine diphosphate (ADP)-, arachidonic acid (AA)- and collagen-induced human platelet aggregation in vitro, with IC50 values of 8.90 x 10(-5), 1.50 x 10(-6) and 5.11 x 10(-8) mol/l, respectively. The strong inhibitory activity is significant not only for collagen but also for AA-induced aggregation. The same compound inhibits ex vivo collagen- and particularly AA-induced rabbit platelet aggregation at the tested dose of 10 mg/kg i.m. In view of the potential use of 2-amino-1,2-benzisothiazolin-3-one as antithrombotic agent, the log P values for both 1,2-benzisothiazolin-3-one derivatives 1 and 2 are determined, to gain an understanding of the significance of the 2-amino group in the 1,2-benzisothiazolin-3-one moiety with respect to the biological activity under study.