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Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.

A drug's physical characteristics, such as colour, could be factors influencing its therapeutic effects. It is not well understood whether people's expectations on drug effects and efficacy are affected by colour, especially among Chinese population. This study was conducted to examine people's expectations on drug effects and efficacy on the basis of drug colour, and to reveal possible gender differences in colour-related drug expectations. Participants (n = 224) were asked to classify seven single-coloured and six two-coloured capsules into one of four categories of drug effects, and to indicate the strength of drug efficacy. It is found that all the coloured capsules yielded non-chance distributions in classifications of drug effects, with six single-coloured and four two-coloured capsules associated with specific drug effects. Colour also conveyed differential strengths of drug efficacy in general and in relation to specific drug effects. There were gender differences in drug expectations for some colours and colour combinations. Practitioner Summary: Drug colour was found to have impacts on perceived drug effects and efficacy. The findings from the present study can be used by ergonomics practitioners to design appropriate drug colours in support of drug differentiation, therapeutic effects and medication adherence.

Introduction: This is the 34th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2016, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 9.50 [7.33, 14.6] (median [25%, 75%]) min, facilitating a near real-time national exposure and information database and surveillance system., Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure., Results: In 2016, 2,710,042 closed encounters were logged by NPDS: 2,159,032 human exposures, 54,019 animal exposures, 490,215 information cases, 6687 human confirmed non-exposures, and 89 animal confirmed non-exposures. US PCs also made 2,718,022 follow-up calls in 2016. Total encounters showed a 2.94% decline from 2015, while health care facility (HCF) human exposure cases increased by 3.63% from 2015. All information calls decreased by 12.5% but HCF information calls increased 0.454%, and while medication identification requests (Drug ID) decreased 29.6%, human exposure cases were essentially flat, decreasing by 0.431%. Human exposures with less serious outcomes have decreased 2.59% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.39% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.54%), cosmetics/personal care products (7.20%), sedatives/hypnotics/antipsychotics (5.84%), and antidepressants (4.74%). As a class, sedative/hypnotics/antipsychotics exposures increased most rapidly, by 10.7% per year (2088 cases/year), over the last 15 years for cases showing more serious outcomes. The top five most common exposures in children age 5 years or less were cosmetics/personal care products (13.3%), household cleaning substances (11.1%), analgesics (9.21%), foreign bodies/toys/miscellaneous (6.48%), and topical preparations (5.07%). Drug identification requests comprised 28.1% of all information calls. NPDS documented 1977 human exposures resulting in death; 1492 (75.5%) of these were judged as related (RCF of 1 - undoubtedly responsible, 2 - probably responsible, or 3 - contributory)., Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in cases involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource for collecting and monitoring US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g. foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the real-time surveillance of national and global public health.

A comparative study of classification models of brain penetration by different approaches was carried out on a training set of 1000 chemicals and drugs, and an external test set of 100 drugs. Ten approaches were applied in this work: seven medicinal chemistry approaches (including "rule of 5" and multiparameter optimization) and also three SAR techniques: logistic regression (LR), random forest (RF) and support vector machine (SVM). Forty-one different medicinal chemistry descriptors representing diverse physicochemical properties were used in this work. Medicinal chemistry approaches based on the intuitive estimation of preference zones of CNS or non-CNS chemicals, with different rules and scoring functions, yield unbalanced models with poor classification accuracy. RF and SVM methods yielded 82% and 84% classification accuracy respectively for the external test set. LR was also successful in CNS/non-CNS (denoted in this study as CNS+/CNS-) classification and yielded an overall accuracy equivalent to that of SVM and RF. At the same time, LR is especially valuable for medicinal chemists because of its simplicity and the possibility of clear mechanistic interpretation.

There is an ever-increasing demand of newer and improved drugs from biological sources to cater to the bio-pharmaceutical sector. Among various other resources, fungal species have an immense contribution owing to their potential to carry out the bio-transformations and drug synthesis in diverse conditions and in an eco-friendly manner. Advancement in the biotechnological processes has accelerated the process. Genome sequence information of various fungal species has opened newer avenues for improved and faster drug targeting and designing. The review highlights the production of pharmaceutical drugs and drug intermediates like antibiotics, anti-cancer, anti-cholesterol, anti-diabetic, immunosuppressant, anti-anxiety, anti-virals and many other drugs from fungus. Many of these have been commercialized and there are many more which are either in research or in clinical trial phase. There is a need to exploit and explore the vast biota of fungi in the hope of discovering untapped therapeutic uses of the earth's countless species of fungus.

Background: This is the 32nd Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2014, 56 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.82 [7.02, 11.17] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system., Methodology: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death., Results: In 2014, 2,890,909 closed encounters were logged by NPDS: 2,165,142 human exposures, 56,265 animal exposures, 663,305 information calls, 6,085 human confirmed nonexposures, and 112 animal confirmed nonexposures. US poison centers (PCs) also made 2,617,346 follow-up calls in 2014. Total encounters showed a 5.5% decline from 2013, while health care facility human exposure cases increased by 3.3% from 2013. All information calls decreased by 17.7% and health care facility (HCF) information calls were essentially flat, decreasing by 0.04%, medication identification requests (Drug ID) decreased 29.8%, and human exposures reported to US PCs decreased 1.1%. Human exposures with less serious outcomes have decreased 3.40% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.29% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.4%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2,368 calls (12.2%)/year) over the last 13 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (14.0%), household cleaning substances (11.0%), analgesics (9.3%), foreign bodies/toys/miscellaneous (6.7%), and topical preparations (5.8%). Drug identification requests comprised 43.3% of all information calls. NPDS documented 1,835 human exposures resulting in death with 1,408 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory)., Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health.[Box: see text].

Solid dispersion has been a topic of interest in recent years for its potential in improving oral bioavailability, especially for poorly water soluble drugs where dissolution could be the rate-limiting step of oral absorption. Understanding the physical state of the drug and polymers in solid dispersions is essential as it influences both the stability and solubility of these systems. This review emphasizes on the classification of solid dispersions based on the physical states of drug and polymer. Based on this classification, stability aspects such as crystallization tendency, glass transition temperature (Tg), drug polymer miscibility, molecular mobility, etc. and solubility aspects have been discussed. In addition, preparation and characterization methods for binary solid dispersions based on the classification have also been discussed.

Objectives: To estimate the proportion of women in early pregnancy prescribed potentially feto-toxic medications at an out-patient clinic in Malawi., Methods: Over six-months the number of women of child-bearing age attending out-patient clinics and prescribed medicines at Mitundu Community Hospital was derived from the hospital's registry and pharmacy records. Women prescribed potentially feto-toxic medicines (using Food and Drug Administration classifications) by medical assessments were subsequently interviewed and pregnancy tested. Exposure to potentially feto-toxic medications was estimated and differences between pregnant and non-pregnant women were described., Results: Of 8970 female outpatients, 1012 (11.3%; 95% CI: 10.6% to 12%) were prescribed potentially feto-toxic medicines. After excluding 740 as unlikely to be pregnant, 209 women had negative pregnancy tests and 63 were confirmed as pregnant, representing one in 16 of women prescribed contraindicated medicines or between 2.8% and 3.5% of all women attending in early pregnancy. Most medicines were FDA rated C or D. Only 152 (55.9%) of these women had been asked about pregnancy and prescribing practices did not discriminate between pregnant and non-pregnant patients., Conclusions: Assessment and prescribing practices for women attending out-patient clinics who might be in early pregnancy were inadequate, increasing the risk of exposure to potentially feto-toxic medicines.

The Biopharmaceutics Classification System (BCS) was developed to facilitate estimation of the in vivo pharmacokinetic performance of drugs from human intestinal permeability and solubility. However, the measurement of human in vivo intestinal permeability, unlike that of solubility, is problematic and inefficient. Thus, rat in vitro intestinal permeability results obtained via the Ussing chamber technique are often used instead. However, these data could be unreliable due to difficulty in maintaining the viability of the dissected intestinal membrane in the Ussing chamber. Therefore, a more efficient method to obtain a reliable in vitro permeability is mandatory. Here, we propose a new approach by introducing a novel factor called the permeability ratio (PR). Basically, PR is a rat in vitro intestinal permeability obtained from the Ussing chamber, which is then corrected by the permeability of lucifer yellow, a paracellular permeability marker. To prove the validity of the method, 12 model drugs representing different BCS classes were tested, and the correlation with human in vivo intestinal permeability was high. More importantly, the new method perfectly classified all 12 model drugs. The results indicate that PR is a reliable factor with high correlation to human in vivo intestinal permeability, which can further be used to accurately predict the BCS classification.

A Right-First-Time approach is described for developing bona fide formulations for First-In-Human (FIH) to Proof-Of-Concept (POC) studies to meet an overarching goal of reduced project cycle time from IND to NDA (as short as four years). Bona fide formulations are tailor-made according to the drug's biopharmaceutical properties including solubility, permeability and stability. Solubilization techniques are used extensively to reduce oral absorption variability for most compounds. Bona fide formulations contain all necessary functional excipients such as diluent, solubilizer, stabilizer, pH adjuster, disintegrant and lubricant so formulation changes are minimized to avoid significant PK bridging studies. Cycle time of FIH formulation development is aligned with IND-enabling toxicology studies, generally 4-6 months. Resources range from 0.5 full time equivalents (FTE) for a BCS-1 compound to 3 FTE for a BCS-4 compound with high drug delivery hurdles. We have achieved our goal by taking the same formulation from FIH to POC 90% of the time and maintaining the same formulation platform from POC to commercial manufacturing 80% of the time in the past eight years. This strategy enables cycle time reduction from 7 to 4 years for IND to NDA by overlapping clinical study phases and eliminating clinical downtime due to PK bridging studies.

The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in development should be evaluated for potential adverse effects on the immune system. Developmental immunotoxicology (DIT) focuses on the concern that early-life (during pre-/post-natal development) exposure to agents which target the immune system may result in enhanced susceptibility to immune-related disease (e.g., infection, autoimmunity, and cancer, particularly leukemia) compared to adults, unique effects not observed in adults, or more persistent effects in comparison to those following adult exposure. This article provides a substantive review of the literature and presents detailed considerations for DIT testing strategies with a specific focus on pharmaceuticals and biopharmaceuticals. In this regard, differences between small molecule and large molecule therapeutics will be considered, along with recommendations for best practices in the assessment of DIT during drug development. In addition, gaps in the DIT knowledge base and current testing strategies are identified. Finally, a summary of an ILSI-HESI-ITC sponsored Workshop conducted in 2010, entitled 'Developmental Immunotoxicity Testing of Pharmaceuticals' will be presented. This Workshop consisted of participants from the pharmaceutical, biotechnology, academic, and regulatory sectors, where many of the issues relating to DIT outlined in this review were discussed, key points of consensus reached, and current gaps in the science identified.

Dermal reactions are the most frequently reported chemical health-related occupational hazard. Identifying dermal sensitizers is important for improving workplace safety. This paper takes a close look at the physico-chemical properties and results from the Local Lymph Node Assay (LLNA) to better understand and predict potent dermal sensitizers. The LLNA was used to identify 28 pharmaceutical agents or chemical intermediates as potent dermal sensitizers, EC3 < 1%. Certain parameters were examined to determine if there was any predictability to identify potent dermal sensitizers. These included a computer structure activity analysis using Derek for Windows, molecular weight (Mw), calculated log P, and the log-linear extrapolation approach for estimating the potency. With Derek for Windows, 13 compounds were identified as negative and 15 as positive for structural alerts, the most common being haloalkanes, and hydrazines. Additional mechanisms of reactivity were postulated for the remaining compounds. The examination of the Mw showed that all molecules had Mw < 550 Da. For 21 compounds, the interpolated vs extrapolated methods for determining the EC3 value were compared. For eight of the 21 compounds, the extrapolated EC3 was in the correct order of magnitude, eight were incorrect (five were too high and three were too low) and five could not be calculated. The use of a tiered approach including examination of the structural and physico-chemical properties and the LLNA to identify potent dermal sensitizers is integral in the selection of effective safe handling guidance to protect from sensitization hazards.

Purpose: The biopharmaceutical classification system has been developed to provide a scientific approach for classifying drug compounds based on their dose/solubility ratio and human intestinal permeability. Therefore in this study a new classification is presented, which is based on a correlation between rat and human intestinal permeability values., Methods: In situ technique in rat jejunum was used to determine the effective intestinal permeability of tested drugs. Then three dimensionless parameters--dose number, absorption number, and dissolution number (D(o), A(n), and D(n))--were calculated for each drug., Results: Four classes of drugs were defined, that is, class I, D(0) < 0.5, P(eff(rat)) > 5.09 x 10(-5) cm/s; class II, D(o) > 1, P(eff(rat)) > 5.09 x 10( -5) cm/s; class III, D(0) < 0.5, P(eff(rat)) < 4.2 x 10(-5) cm/s; and class IV, D(o) > 1, P(eff(rat)) < 4.2 x 10(-5) cm/s. A region of borderline drugs (0.5 < D(o) < 1, 4.2 x 10(-5) < P(eff(rat)) < 5.09 x 10(-5) cm/s) was also defined., Conclusion: According to obtained results and proposed classification for drugs, it is concluded that drugs could be categorized correctly based on dose number and their intestinal permeability values in rat model using single-pass intestinal perfusion technique. This classification enables us to remark defined characteristics for intestinal absorption of all four classes using suitable cutoff points for both dose number and rat effective intestinal permeability values.

The present part II review highlights pharmacokinetic drug-drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug-drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using beta-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., beta-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered.

Idiosyncratic drug reactions (IDRs) of a hepatic origin are a major health concern and a notoriously difficult challenge for the pharmaceutical industry. These types of adverse events are rare, with a typical occurrence of 1 in 100 to 1 in 100,000 patients. Typical adverse outcomes are most likely statistically impossible to predict in traditional preclinical safety studies or clinical trials. Unfortunately, these reactions can pose a significant risk to the public health, resulting in devastating consequences such as irreversible liver injury, liver transplantation and fatality. This review provides many examples of experimental efforts that are underway for a better understanding of molecular events that may be responsible for IDRs. A list of existing hypotheses for IDRs is also provided, each with current literature examples or supporting evidence. The possibilities for developing suitable animal models for the prediction and characterisation of IDRs are elaborated, especially for a drug-inflammation interaction rat model of hepatic IDR. The need for predictive biomarkers of IDR is addressed, with the exploration of some possible candidates. Finally, the use of primary human hepatocyte culture systems is explored as an in vitro system, with application for providing an increased mechanistic knowledge of IDR. Several examples of informative studies on the nature of IDRs that employ toxicogenomic and proteomic technologies are summarised.

One important factor in the abuse potential of an opioid product is the ease with which active drug can be extracted. There are currently no standards for testing or reporting extractability. This article describes the development of an Extractability Rating System for use by the pharmaceutical industry and regulators. Despite several limitations, this effort serves as a call for standardized testing and reporting so that products can be accurately rated, and should help establish goals for drug developers who wish to develop "abuse-resistant" opioid products.

This hierarchical coding system is designed to classify substances into successively subordinate categories on the basis of chemical, physical and biological properties. Although initially developed for occupational cancer epidemiological studies, it is general in nature and can be used for other purposes where a systematic approach is needed to catalogue or analyze large numbers of substances and/or physical properties. The coding system incorporates a multi level approach, where substances can be coded both on the basis of function and composition. On the first level, a three digit code is assigned to each substance to indicate its primary use in the occupational environment (e.g. pesticide, catalyst, adhesive). Substances can then be coded using a ten digit code to indicate structure and composition (e.g. organic molecule, biomolecule, pharmaceutical). Depending on the complexity required, analysis can incorporate the three digit code, ten digit code, or a combination of both. The approach to coding both chemical and biological agents is modeled in part after conventional approaches used by the International Union of Pure and Applied Chemists (IUPAC) and the International Union of Biochemists (IUB). Development of the coding system was initiated in the 1980's in response to a need for a system allowing analysis of individual agents as well classes or groups of substances. The project was undertaken as a collaborative venture between the BC Cancer Agency, Cancer Control Research program (then Division of Epidemiology) and the Department of Chemical and Biological Engineering at the University of British Columbia.

The golden age of drug policy was characterized by the informal regulation of drug use. Formalization of the control over regulation and its increasingly strict, aggressive character led to the emergence of a binary attitude. The main binarisms: pharmaceutical or drug; ban or tolerance; punishment or treatment; psychopathological or pathopsychological approach; subjective or objective knowledge; traditional or alternative. On the basis of Kuhn's paradigm theory, these binarisms can be integrated. Drug policy interventions based on the binary attitude have had regressive effects. Using the work of Sam Sieber, the author distinguishes nine regressive influences: functional imbalance, perverse diagnosis, ricochet, overload, goal displacement, exploitation, provocation, classification, and placation. The regressive influences have caused the escalation of "the drug problem," which in turn has led to further regressive interventions. This vicious circle could be broken by eliminating the four biases--the paternalistic, elitist, rationalist, and activist biases--underlying the regressive interventions.

The behavior of moisture gain and equilibrium moisture content (EMC) was determined for 30 drug substances at relative humidities (RH) ranging from 11% to 93%. Based on the results, the drugs were categorized into different classes, following the classification system proposed by Callahan et al. About 23 fell under Class-I (nonhygroscopic), four under Class-II (slightly hygroscopic), and three under Class-III (moderately hygroscopic). Most of the Class-III drugs converted from solid to liquid state at > 75% RH, and the moisture increase was more than 40% above 90% RH. However, the moisture increase was comparatively much smaller at humidities < 40%-50%. Hence, no drug could be categorized in Class-IV (very hygroscopic), where gain of moisture is generally higher even at lower humidities. The results were correlated to the statements given in the compendia on hygroscopicity, and also the values of loss on drying (LOD). The study suggests that there is a need to rationalize the pharmacopoeial information.

Due to the risk of medications errors from inadvertent interchange of drugs for which names look alike or sound alike, the Joint Commission on Accreditation of Healthcare Organizations now requires that accredited health care organizations develop and maintain programs to minimize these risks. This report lists drug names that can lead to such errors.

Controlled porosity osmotic pumps (CPOPs) are devoid of delivery orifice to release core contents and essentially possess pore-forming agent(s) in coating composition. When the pump comes in contact with aqueous media, pore-forming agent(s) generate pores through which core contents are delivered. Diltiazem hydrochloride (DLTZ) is a freely water-soluble drug and the release rates of DLTZ are higher from oral osmotic pumps including CPOPs, in which the drug release is controlled by concentration of pore-forming agents. The effect of appropriate concentration of hydroxypropyl methyl cellulose and sodium carboxy methyl cellulose mixture on the release of DLTZ from CPOPs was studied. In vitro drug release profiles were compared with that of different marketed controlled release formulations and statistically analysed to examine the suitability of CPOP for twice or once daily administration. Dissolution models were applied to drug release data in order to establish the mechanism of drug release and kinetics. Drug release from the CPOPs was effectively modified with the concentration of pore-forming agent in membrane and concentration of hydrophilic polymers in the core. CPOPs showed minimum 65% of consistent DLTZ release at 16 h. Statistical analysis confirmed that with an increase in the amount of hydrophilic polymers release rate decreased. Drug release from the systems follows Hixson-Crowell cube root model and mechanism of release follow non-Fickian diffusion.

Azoles (imidazoles and triazoles) are used as antifungal agents in agriculture and in medicine, and also for antiestrogen therapy, e.g., for breast cancer treatment. Antifungal activity is based on inhibition of fungal CYP51 (lanosterol 14alpha-demethylase), and estrogen biosynthesis reduction is due to azole inhibition of CYP19 (aromatase). Inhibition of aromatase by antifungal agents is usually an unwanted side effect and may cause endocrine disruption. A fluorimetric assay based on human recombinant CYP19 enzyme with dibenzylfluorescein as a substrate was used to compare the inhibitory potency of 22 azole compounds. Dose responses were established and duplicate datasets were analyzed with a nonlinear mixed-effects model with cumulative normal distribution for the logarithm of concentration. IC50 values (50% inhibitory concentration) of 13 fungicides used in agriculture ranged more than 700-fold, starting from 0.047 microM. The potency of seven human drugs spanned more than 7000-fold, starting from 0.019 microM. Most potent fungicides included prochloraz, flusilazole, and imazalil, and most potent medicinal antifungals were bifonazole, miconazole, and clotrimazole. These in vitro data indicate that the top-ranking azoles used as antifungal agents or drugs are as potent inhibitors of aromatase as are antiestrogen therapeutics used to treat breast cancer. These putative effects of azole agents and drugs on steroid biosynthesis and sex hormone balance should be considered when used in human subjects and also in wildlife exposed to azole fungicides used in agriculture.

A series of studies was performed to address treatment against the former chemical warfare edemagenic gas phosgene. Both in situ and in vivo models were used to assess the efficacy of postexposure treatment of phosgene-induced lung injury using clinically existing drugs. The degree of efficacy was judged by examining treatment effects on pulmonary edema formation (PEF) as measured by wet/dry weight (WW/DW) ratios, real-time (in situ) lung weight gain (LWG), survival rates (SR), odds ratios, and glutathione (GSH) redox states. Drugs included N-acetylcysteine (NAC), ibuprofen (IBU), aminophylline (AMIN), and isoproterenol (ISO). Using the in situ isolated perfused rabbit lung model (IPRLM), intratracheal (IT) NAC (40 mg/kg bolus) delivered 45-60 min after phosgene exposure (650 mg/m(3)) for10 min lowered pulmonary artery pressure, LWG, leukotrienes (LT) C(4)/D(4)/E(4), lipid peroxidation, and oxidized GSH. We concluded that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of GSH, reducing both lipid peroxidation and production of arachidonic acid metabolites. Also in IPRLM, administration of AMIN (30 mg/kg) 80-90 min after phosgene exposure significantly reduced lipid peroxidation and perfusate LTC(4)/D(4)/E(4), reduced LWG, and prevented phosgene-induced decreases in lung tissue cAMP. These data suggest that protective mechanisms observed with AMIN involve decreased LTC(4)/D(4)/E(4) mediated pulmonary capillary permeability and attenuated lipid peroxidation. Direct antipermeability effects of AMIN-induced upregulation of cAMP on cellular contraction may also be important in protection against phosgene-induced lung injury. Posttreatment with ISO in the IPRLM by either combined intravascular (iv; infused into pulmonary artery at 24 microg/min infused) + IT (24 microg bolus) or IT route alone 50-60 min after phosgene exposure significantly lowered pulmonary artery pressure, tracheal pressure, and LWG. ISO treatment significantly enhanced GSH products or maintained protective levels when compared with results from phosgene-exposed only rabbits. These data suggest that protective mechanisms for ISO involve reduction in vascular pressure, decreased LTC(4)/D(4)/E(4)-mediated pulmonary capillary permeability, and favorably maintained lung tissue GSH redox states. For in vivo male mouse (CD-1, 25-30 g) studies IBU was administered ip within 20 min after a lethal dose of phosgene (32 mg/m(3) for 20 min) at 0 (saline), 3, 9, or 15 mg/mouse. Five hours later, a second IBU injection was given but at half the original doses (0, 1.5, 4.5, and 7.5 mg/mouse); therefore, these treatment groups are now referred to as the 0/0, 3/1.5, 9/4.5, and 15/7.5 mg IBU/mouse groups. SRs and odds ratios were calculated for each dose at 12 and 24 h. The 12-h survival was 63% for 9/4.5 mg IBU and 82% for the 15/7.5 mg IBU groups, compared with 25% for saline-treated phosgene-exposed mice. At 24 h, those survival rates were reduced to 19%, 19%, and 6%, respectively. In the 15/7.5 mg IBU group, lung WW/DW ratios were significantly lower than in saline-treated mice at 12 h. Lipid peroxidation was lower only for the 9/4.5 mg IBU dose; however, nonprotein sulfhydryls (a measure of GSH) were greater across all IBU doses. The odds ratio was 5 for the 9/4.5 IBU group at 12 h and 13 for the 15/7.5 mg IBU group, compared with 3.5 for both groups at 24 h. IBU posttreatment increased the survival of mice at 12 h by reducing PEF, lipid peroxidation, and GSH depletion. In conclusion, effective treatment of phosgene-induced lung injury involves early postexposure intervention that could reduce free radical species responsible for lipid peroxidation, correct the imbalance in the GSH redox state, and prevent the release of biological mediators such as leukotrienes, which are accountable for increased permeability.

The purpose of the present study was to examine the relevancy of the high throughput solubility assay and permeability assay to the biopharmaceutics classification system (BCS). Solubility and permeability were measured by high throughput solubility assay (HTSA) and parallel artificial membrane permeation assay (PAMPA), respectively. High throughput solubility assay was performed using simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid without bile acid (SIF, pH 6.8). We categorize 18 drugs based on the BCS using HTSA and PAMPA. Fourteen out of 18 drugs were correctly classified (78% success rate). The result of the present study showed that HTSA could predict BCS class with a high success rate, and PAMPA could also be useful to predict the permeation of drugs.

In an ideal harm reduction model, drugs would be ranked according to their potential to cause harm, with varying implications for control policies and interventions. In such a public health oriented approach, the maximum protection of the public from harm would be balanced with the least possible restriction of freedom. In reality, however, the accuracy and completeness of the necessary information for such a ranking is highly limited. Many other factors not readily incorporated in a rational model, such as values, beliefs, and traditions, also affect drug policy decisions. Thus, rather than relying on acquisition of the necessary knowledge, it may be preferable to focus efforts on developing effective nonlegal measures to reduce drug use and harm. [Translations are provided in the International Abstracts Section of this issue.]