Where Are the Nanodrugs? An Industry Perspective on Development of Drug Products Containing Nanomaterials

While nanotechnology advancements have been applied to pharmaceutical products, the number of approved nanodrugs by global health authorities has not kept pace with research and development investments in the field. This article reviews the history of nanodrug development and provides an industrial context for realistic expectations in the future.     

Dependence of Dissolution Rate on Surface Area: Is a Simple Linear Relationship Valid for Co-Compressed Drug Mixtures?

A quantitative analysis of the dependence of dissolution rate on the relative surface area occupied by two non-interacting drug mixtures from co-compressed slabs is described. The results from the experimental dissolution rates of each component from naproxen/ phenytoin co-compressed slabs under laminar flow conditions, when corrected for the area occupied by that component in the slab, contradict the stagnant layer model predictions, where dissolution rates are assumed to be directly proportional to the occupied surface area. Simulations from non-mixed co-compressates of naproxen and phenytoin indicated that dissolution rates are proportional to bL^2/3, as reported for pure compounds in the laminar dissolution apparatus by Shah and Nelson. However, for a well mixed co-compressate, which differs with the non-mixed case only in the distribution of particles, this proportionality did not hold. The deviation was explained by carryover of material from one section of the component to the next due to fluid flow, resulting in an increase in apparent effective length of the component in the slab (L_eff).     

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): New Therapy for CKD by a (Pro)Renin-Receptor–Blocking Decoy Peptide

Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II–dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II– independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.     

Information from US FDA——Impact of Severe Weather Conditions on Biological Products & FDA Drug Safety Communication: FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease

The U.S. Food and Drug Administration today approved Imfinzi (durvalumab) for the treatment of patients with stage III non-small cell lung cancer (NSCLC) whose tumors are not able to be surgically removed (unresectable) and whose cancer has not progressed after treatment with chemotherapy and radiation (chemoradiation). “This is the first treatment approved for stage III unresectable non-small cell lung cancer to reduce the risk of the cancer progressing, when the cancer has not worsened after chemoradiation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For patients with stage III lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation.”     

Effect of dihydroergosine (DHESN) on the serotoninergic system and behaviour: Is DHESN a new antidepressive agent?

Acute (50.0 mg/kg) and repeated (0.1–10.0 mg/kg) administration of dihydroergosine (DHESN) to rats over 5 days lowered the concentration of 5-HIAA in the brain. DHESN given acutely increased the brain 5-HT in p-CPA-treated animals and diminished the probenecid-induced increase in brain 5-HIAA. In pargyline-treated rats DHESN enhanced the 5-HT/5-HIAA ratio. DHESN administered to rats repeatedly over 5 days decreased the level of 5-HT in blood platelets, and in vitro at concentrations of 10^-4 M and 10^-3 M inhibited the uptake of [¹⁴C]-5-HT in platelets. DHESN (10.0–100.0 mg/kg) potentiated the 5-HT syndrome produced in rats by pargyline and 5-HTP. This potentiation was blocked with cyproheptadine but not with haloperidol. DHESN (1.0 and 10.0 mg/kg) lowered the locomotor activity of rats and 10.0 mg/kg DHESN also reduced the duration of immobility in rats forced to swim in a restricted space. The results indicate that DHESN, like antidepressants, decreases the turnover of serotonin in the brain and potentiates the 5-HT-mediated behaviour. This might suggest that the drug should be further investigated for its potential antidepressive properties.     

Transport Screening of Drug Cocktails Through an in Vitro Blood-Brain Barrier: Is It a Good Strategy for Increasing the Throughput of the Discovery Pipeline?

PURPOSE: The objective of the current study was to investigate whether blood-brain barrier (BBB) permeability studies in vitro could be accelerated by running several compounds together in the same experiment. METHODS: To address this question, we compared the transport of six compounds run separately with the results of the same compounds run together (cocktails). RESULTS: The study clearly demonstrated that the outcome of the experiments were totally different depending on the strategy used. Furthermore, the study highlights the importance of having the resistance to drug transport offered by filters without cells under control, as the filter membrane itself can be the rate-limiting step for some compounds; in addition, there is always a potential risk of interactions between molecules in cocktails as well as drug-drug interaction at the level of BBB transporters. In this study, the presence of several P-glycoprotein substrates in the drug cocktail was found to cause breakdown of the BBB. CONCLUSIONS: The results demonstrate that unless a strategy that involves running several compounds in the same experiment is properly validated, the results are of little predictive value.     

Guidance values for microcystins in water and cyanobacterial supplement products (blue-green algal supplements): a reasonable or misguided approach?

This article reviews current scientific knowledge on the toxicity and carcinogenicity of microcystins and compares this to the guidance values proposed for microcystins in water by the World Health Organization, and for blue-green algal food supplements by the Oregon State Department of Health. The basis of the risk assessment underlying these guidance values is viewed as being critical due to overt deficiencies in the data used for its generation: (i) use of one microcystin congener only (microcystin-LR), while the other presently known nearly 80 congeners are largely disregarded, (ii) new knowledge regarding potential neuro and renal toxicity of microcystins in humans and (iii) the inadequacies of assessing realistic microcystin exposures in humans and especially in children via blue-green algal food supplements. In reiterating the state-of-the-art toxicology database on microcystins and in the light of new data on the high degree of toxin contamination of algal food supplements, this review clearly demonstrates the need for improved kinetic data of microcystins in humans and for discussion concerning uncertainty factors, which may result in a lowering of the present guidance values and an increased routine control of water bodies and food supplements for toxin contamination. Similar to the approach taken previously by authorities for dioxin or PCB risk assessment, the use of a toxin equivalent approach to the risk assessment of microcystins is proposed.     

Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?

Introduction: There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2).

Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease.

Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.     

UCN-01 (7-hydroxystaurosporine) and other indolocarbazole compounds: a new generation of anti-cancer agents for the new century?

UCN-01 (7-hydroxystaurosporine) is a protein kinase inhibitor which is under development as an anti-cancer agent in the USA and Japan. Although UCN-01 was originally isolated from the culture broth of Streptomyces sp. as a protein kinase C-selective inhibitor, its ultimate target as an anti-cancer agent remains elusive. As a single agent, UCN-01 exhibits two key biochemical effects, namely accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Both these effects may be important for its anti-cancer activity. As a modulator, UCN-01 enhances the cytotoxicity of other anti-cancer drugs such as DNA-damaging agents and anti-metabolite drugs through putative abrogation of G2 and/or S phase accumulation induced by these anti-cancer agents. Currently, in addition to UCN-01, four other indolocarbazole anti-cancer drugs-two protein kinase inhibitors, CGP 41251, CEP-751, and two DNA-damaging agents, NB-506 and a Rebeccamycin analog-are undergoing clinical investigations in the USA, Europe or Japan. In this review, we would like to address the differences and similarities of these indolocarbazole compounds as anti-cancer agents with regard to their mechanism(s) of action, the effects on cell cycle progression, induction of apoptosis and modulation of drug sensitivity.     

Validated LC–MS (ESI) assay for the simultaneous determination of amitriptyline and its metabolite nortriptyline in rat plasma: Application to a pharmacokinetic comparison

A rapid, sensitive and specific method based on high performance liquid chromatography with electrospray ionization mass spectrometry (HPLC–MS/ESI) has been developed for the simultaneous determination of amitriptyline and nortriptyline in rat plasma. Sample preparation involved liquid–liquid extraction with methyl t-butyl ether after alkalified with 0.5 mol/l NaOH. Chromatographic separation was performed on a XB-C4 column (4.6 mm × 250 mm, 5 μm, Welch Materials) with a mobile phase consisting of 10 mM ammonium acetate (0.6‰ formic acid)–acetonitrile (60:40, v/v) at a flow rate of 1.0 ml/min. Calibration curves were linear within the ranges of 10–3200 ng/ml for amitriptyline and 10–1000 ng/ml for nortriptyline. This method was successfully applied to the pharmacokinetic study in rats after intravenous injection of amitriptyline hydrochloride.     

Methodology for a multinational case–population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT)

Purpose

The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case–population study, named SALT (Study of Acute Liver Transplant), is documented here.

Methods

This was a multicentre, multinational retrospective case–population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005–31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals.

Results

The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy.

Conclusion

The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.     

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10‐year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C_min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C_min was set between 2 and 7 mg/L (underexposure, C_min < 2 mg/L; overexposure, C_min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C_min. One thousand and forty‐nine patients had 2484 linezolid C_min assessed during treatment with conventional doses. Median (IQR) linezolid C_min was 5.08 mg/L (2.78–8.52 mg/L). Linezolid C_min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL_C‐G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124–1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL_C‐G estimates >100 mL/min. (OR 3.046; 95% CI 2.234–4.152, p < 0.001). Linezolid C_min was not correlated linearly with CrCL_C‐G (R² = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C_min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.     

Gonadotropin-releasing hormone (GnRH) receptors in tumors: a new rationale for the therapeutical application of GnRH analogs in cancer patients?

Gonadotropin-Releasing Hormone (GnRH) is the hypothalamic decapeptide which plays a key role in the control of reproductive functions. By binding to specific receptors present on the pituitary gonadotropes, GnRH regulates gonadotropin release and, consequently, steroid hormone secretion from the gonads. When given continuously and at high doses, GnRH agonists suppress the pituitary gonadal axis through the down-regulation and desensitization of its own receptors. Based on this rationale, pituitary GnRH receptors represent the target for the successful utilization of GnRH agonists (that are more stable than the native peptide) for the treatment of hormone-dependent tumors (e.g., prostate, breast, endometrial, ovarian cancers). The observation that GnRH receptors are expressed in steroid-dependent tumors, and that their activation reduces cell proliferation and metastatic behavior of cancer cell lines, both in vitro and in vivo (when inoculated into nude mice), indicates a possible additional and more direct antitumor activity for these compounds. Interestingly, GnRH receptors have been shown to be expressed also in androgen-independent prostate carcinoma, as well as in tumors that are not classically considered hormone-related (e.g., melanoma), suggesting a clinical utility of the administration of GnRH analogs also in these tumors. More recently, GnRH agonists have been proposed as useful carriers to target cytotoxic drugs or toxins to cancer cells displaying the specific GnRH receptors. A second form of GnRH (designated GnRH-II) has been discovered in most vertebrates, including humans. GnRH-II has been suggested to act through a 'putative' cognate type II GnRH receptor, which is distributed in different tissues, both normal and tumoral. In humans, a full-length functional type II GnRH receptor has not been found. Therefore, its functions as well as its possible utility as a molecular target for a GnRH-II based therapy in oncology still has to be clarified. This review will focus on the role of GnRH receptors in the control of tumor growth, progression and dissemination. It will also be discussed whether the presence of these receptors might represent an additional rationale for the clinical utility of GnRH analogs as anticancer drugs.