Targeted delivery of cytotoxic drugs: Challenges, opportunities and new developments

Cytotoxic drugs, which are commonly used for the pharmacotherapy of many forms of cancer, often cause substantial toxicity to the patient without being able to induce long-lasting remissions. Ligands specific to accessible tumor-associated targets, capable of selective localization at the neoplastic site, may facilitate the preferential delivery of anti-cancer drugs, boosting activity and helping spare normal organs. In this article, we present a critical analysis of the limitation of conventional anti-cancer drugs and we contrast monoclonal antibodies and small organic ligands, as vehicles for pharmacodelivery applications

An efficient continuous flow process for the synthesis of a non-conventional mixture of fructooligosaccharides

A sustainable and scalable process for the production of a new mixture of fructooligosaccharides (FOS) was developed using a continuous-flow approach based on an immobilized whole cells-packed bed reactor. The technological transfer from a classical batch system to an innovative flow environment allowed a significant improvement of the productivity. Moreover, the stability of this production system was ascertained by up to 7 days of continuous working. These results suggest the suitability of the proposed method for a large-scale production of the desired FOS mixture, in view of a foreseeable use as a novel prebiotic preparation

Migrant pathways to community mental health centres in Italy.

Background: Many studies indicate that migrants in western countries have limited access to and low utilization of community mental health centres (CMHCs) despite the high prevalence of mental disorders. Aims: We aimed to compare migrant pathways to care across four CMHCs located in different Italian provinces and to identify pathway to care predictors. Methods: Migrants attending the four CMHCs between 1 July 1999 and 31 December 2007 were included in the study. Data were gathered retrospectively from clinical data sets and chart review. Results: Five hundred and eleven (511) migrants attended the four CMHCs, 61% were referred by GPs or other health services and 39% followed non-medical pathways to care (self-referral or through social and voluntary organizations), with important site variations. Younger age and being married were predictors of medical pathways to care; lacking a residence permit and having a diagnosis of substance abuse were related to non-medical pathways. Conclusions: Pathways to CMHCs are complex and influenced by many factors. Non-medical pathways to care seem to be frequent among migrants in Italy. More attention should be paid to developing psychiatric consultation liaison models that also encompass the social services and voluntary organizations

Migrant pathways to community mental health centres in Italy.

Background: Many studies indicate that migrants in western countries have limited access to and low utilization of community mental health centres (CMHCs) despite the high prevalence of mental disorders. Aims: We aimed to compare migrant pathways to care across four CMHCs located in different Italian provinces and to identify pathway to care predictors. Methods: Migrants attending the four CMHCs between 1 July 1999 and 31 December 2007 were included in the study. Data were gathered retrospectively from clinical data sets and chart review. Results: Five hundred and eleven (511) migrants attended the four CMHCs, 61% were referred by GPs or other health services and 39% followed non-medical pathways to care (self-referral or through social and voluntary organizations), with important site variations. Younger age and being married were predictors of medical pathways to care; lacking a residence permit and having a diagnosis of substance abuse were related to non-medical pathways. Conclusions: Pathways to CMHCs are complex and influenced by many factors. Non-medical pathways to care seem to be frequent among migrants in Italy. More attention should be paid to developing psychiatric consultation liaison models that also encompass the social services and voluntary organizations

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation

Acetazolamide serves as selective delivery vehicle for dipeptide-linked drugs to renal cell carcinoma

In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/kg, with a tumor:blood ratio of 80:1 at 6 hours. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, whereas drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamidebased drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX