Trends in Translational Medicine and Drug Targeting and Delivery: New Insights on an Old Concept—Targeted Drug Delivery with Antibody–Drug Conjugates for Cancers

According to the JPS Drug Delivery Clinical Trials Database (jpharmscidatabase.org), 37,738, 14,104, and 8060 clinical trials are registered to evaluate (1) drug delivery technology, (2) biomolecule platform, and (3) drug metabolism and pharmacokinetic (PK)–pharmacodynamic (PD) interactions. These numbers represent a 19%–29% increase since 2012. Within biomolecules in clinical testing, antibodies constitute the majority and approximately 6% carry drug conjugates. Paul Ehrlich introduced the antibody–drug conjugate or “magic bullet” concept about a century ago. A monoclonal antibody (mAb)–drug conjugate Mylotarg was licensed for treating cancer in 2000 and exhibits significant liver toxicity and immune hypersensitivity. Plasma drug instability and a bacterial-derived drug may be partly to blame. Progress in antibody–drug conjugation chemistry, understanding how biologic systems respond to antibody–drug conjugates, and unwavering efforts of scientists have enabled successful development of highly potent and effective second-generation antibody–drug conjugates. With the approval of Adcetris for lymphoma in 2011 and Kadcyla in 2013, about a twofold to fourfold gain in cancer response rate is attributed to drug conjugates. With a demonstrated higher safety profile, many more antibody–drug conjugates are in development. The clinical success of Adcetris and Kadcyla has raised hope that antibody-guided “drug bullets” may be truly “magical” in leading to a cure for cancer. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:71–77, 2014     

Site Specific Rectal Drug Administration in Man with an Osmotic System: Influence on “First-Pass” Elimination of Lidocaine

Lidocaine was administered to healthy volunteers at different sites in the rectum. Unchanged drug and monoethylglycinexylidide (MEGX) concentrations were measured in plasma with a newly developed gas chromatographic method. Lidocaine was given rectally by means of an osmotic system (Osmet^®) which delivered 25 mg/h at zero-order rate. In a pilot experiment in two subjects it was shown that lidocaine administration close to the anus for 5 h resulted in higher lidocaine plasma levels as compared to administration at 15 cm from the anus. Six other subjects participated in three separate experiments, in which lidocaine was administered rectally close to the anus and at 7.5 and 15 cm from the anus. A zero-order infusion plasma level profile was found for both the parent compound and its metabolite. The MEGX/lidocaine plasma concentration ratio was calculated for all experiments. After administration most proximal to the anus the mean metabolite/parent drug concentration ratio was significantly less than that obtained after administration at 15 cm from the anus, whereas at approximately 7.5 cm from the anus the values were in-between. Comparison of the AUC lidocaine/AUC MEGX ratios gave similar results; the highest value, 3.2 ± 1.3 (mean ± S. D.), was found after administration close to the anus, while at 15 cm from the anus the ratio was 1.6 ± 0.3 (p < 0.01). The terminal elimination half-lives of lidocaine and MEGX did not differ for the three sites of administration, and the mean values were 110 and 180 min respectively. The results of this study demonstrate that the site of drug administration in the human rectum determines the degree of hepatic first-pass elimination of high-clearance drugs. Maximal avoidance of presystemic elimination is achieved when administration takes place close to the anus.     

New Approaches in Risk Assessment of Drug and Food

W21Safetyassuranceforthedietarysupple mentingredientsofplantorigin HoonjeongKWON(DepartmentofFoodandNutritionandResearchInsti tuteofHumanEcology,SeoulNationalUniversity,Se oul,Korea)Dietarysupplementsneedtoshowstatistically soundevidencefortheclaimedhealtheffect,andthis oftenrequireshighdoseofthematerialwhichinturn raisesthesafetyconcernregardlessofwhetherithas beentraditionallyusedornot,sinceitfrequentlyex ceedsthetraditionaluse.HFFmaterialcanbederived fromthetraditionalfoodsources,me…     

Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?

Even the finest state-of-the art preclinical drug testing, usually in primary hepatocytes, remains an imperfect science. Drugs continue to be withdrawn from the market due to unforeseen toxicity, side effects, and drug interactions. The space program may be able to provide a lifeline. Best known for rockets, space shuttles, astronauts and engineering, the space program has also delivered some serious medical science. Optimized suspension culture in NASA’s specialized suspension culture devices, known as rotating wall vessels, uniquely maintains Phase I and Phase II drug metabolizing pathways in hepatocytes for weeks in cell culture. Previously prohibitively expensive, new materials and 3D printing techniques have the potential to make the NASA rotating wall vessel available inexpensively on an industrial scale. Here we address the tradeoffs inherent in the rotating wall vessel, limitations of alternative approaches for drug metabolism studies, and the market to be addressed. Better pre-clinical drug testing has the potential to significantly reduce the morbidity and mortality of one of the most common problems in modern medicine: adverse events related to pharmaceuticals.     

“Living with the Dirty Secret”: Problems of Disclosure for Methadone Maintenance Clients

Abstract

This article focuses on the management of stigma by methadone maintenance patients. It explores (1) the consequences of this persistent stigma, which necessitates the need for secrecy, (2) the adaptations made in order to successfully “pass as normal,” and (3) the contexts in which methadone-maintained individuals decide to disclose their stigmatized status. The data reported and analyzed were gathered between 1980 and 1989 during a series of studies funded by the National Institute on Drug Abuse. The three studies—“Women on Methadone,” “Getting Off Methadone,” and “Alameda County Methadone Study”—utilized qualitative, in-depth interviews and ethnographic sampling techniques, primarily chain referral sampling. After ten years of interviewing women and men in various stages of their methadone maintenance careers, recurring themes emerged, one of which was that being a methadone patient is a marginal identity; not quite junkie, not quite conventional. Clients' efforts to manage this stigmatized identity were often shrouded in anguish and secrecy. Methadone patients were in a kind of identity limbo; a holding pattern between two extremely different social worlds. They were trying to effect an identity transformation; however, in many circumstances they were still associated with and defined by their “dirty secret.”     

Synthesis and Characterization of Potential Dimers of Gatifloxacin – an Antibacterial Drug

Gatifloxacin is an antibacterial agent belonging to the fourth-generation fluoroquinolone family. Four piperazine-linked fluoroquinolone dimers of Gatifloxacin were observed during the laboratory process for Gatifloxacin and they were identified. The present work describes the origin, synthesis, characterization, and control of these dimers along with the synthesis of Despropylene Gatifloxacin (metabolite).     

Evaluation of Different Mathematical Methods Describing Drug Liberation from New, “Soft-Patch” Type Matrix Systems

The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery–development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery–development process.     

Some Suggestions for “Self-Help” Approaches with Street Drug Abusers

Abstract

Growing evidence supports the hypothesis that cannabis consumption is a risk factor for the development of psychotic symptoms. Nonetheless, controversy remains about the causal nature of the association. This review takes the debate further through a critical appraisal of the evidence. An electronic search was performed, allowing to identify 622 studies published until June 1st 2005. Longitudinal studies and literature reviews were selected if they addressed specifically the issues of the cannabis/psychosis relationship or possible mechanisms involved. Ten epidemiological studies were relevant: three supported a causal relationship between cannabis use and diagnosed psychosis; five suggested that chronic cannabis intake increases the frequency of psychotic symptoms, but not of diagnosed psychosis; and two showed no causal relationship: Potential neurobiological mechanisms were also identified, involving dopamine, endocannabinoids, and brain growth factors. Although there is evidence that cannabis use increases the risk of developing psychotic symptoms, the causal nature of this association remains unclear. Contributing factors include heavy consumption, length and early age of exposure, and psychotic vulnerability. This conclusion should be mitigated by uncertainty arising from cannabis use assessment, psychosis measurement, reverse causality and control of residual confounding.     

The Organization of a Community: Community-Based Prevention of Injecting Drug Use–Related Health Problems

In the 1980s, injection drug users in Australia mobilized and organized as communities to prevent the transmission of HIV/AIDS, hepatitis C, and other injecting-related harms. This article provides a brief history of the development and role of IDU communities in the prevention of drug use–related harms over the past 20 years and introduces the genesis of a new program that aims to improve peer-based, community-organized prevention and harm reduction initiatives. The project's limitations are noted and future needed research is suggested.     

Possible Drug–Metabolism Interactions of Medicinal Herbs with Antiretroviral Agents

Herbal medicines are widely used by HIV patients. Several herbal medicines have been shown to interact with antiretroviral drugs, which might lead to drug failure. We have aimed to provide an overview of the modulating effects of Western and African herbal medicines on antiretroviral drug-metabolizing and transporting enzymes, focusing on potential herb–antiretroviral drug interactions. Echinacea, garlic, ginkgo, milk thistle, and St. John's wort have the potential to cause significant interactions. In vitro and in vivo animal studies also indicated other herbs with a potential for interactions; however, most evidence is based on in vitro studies. Further pharmacokinetic studies to unveil potential Western and especially African herb–antiretroviral drug interactions are urgently required, and the clinical significance of these interactions should be assessed.     

Mortality Associated with Drug Misuse among Blacks in New York City, 1979–1981

A comparison of age-specific death rates from “drug dependence” (ICD 304) among Blacks and Whites in New York City for 1979–1981 found two distinct patterns of mortality. Blacks have higher levels of mortality which extend from the central adult years into middle age while deaths among Whites are confined largely to the younger years (below 35). Among both racial groups, mortality is much higher for males than for females. When male undercount is “corrected,” the ratios between male and female deaths are smaller. The difference in economic opportunities for Whites and Blacks is suggested as a reason why Whites “age out” of the years of highest risk before Blacks.     

Drug–Drug Coamorphous Systems: Characterization and Physicochemical Properties of Coamorphous Atorvastatin with Carvedilol and Glibenclamide

Purpose

In this study, coamorphous form of atorvastatin calcium (ATC) with two drugs, i.e., carvedilol (CVD) and glibenclamide (GLN) in 1:1 stoichiometry, were prepared from solvent evaporation method and they were characterized and their physicochemical properties determined.

Methods

The coamorphous forms were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The kinetic solubility of coamorphous form of ATC with CVD (ATC–CVD) and GLN (ATC–GLN) were determined along with stability of supersaturated state of coamorphous forms using developed accurate and precise UV-net analyte signal standard addition method (chemometrics-based approach) and HPLC.

Results

The results of DSC and analysis of glass transition temperatures (T _g), PXRD, and FT-IR indicated that the crystalline studied drugs were converted to coamorphous forms, with unique thermal behaviors, revealing a molecular interaction between two components. The kinetic solubility data revealed that coamorphous forms have better metastable solubility than those of crystalline state. In addition, these systems showed greater solution stability than those for amorphous form of single components reported in the literature.

Conclusion

Coamorphous ATC–CVD and ATC–GLN were shown to have improved physicochemical and solution stability properties as compared to crystalline components.