Mode of Action: Reduction of Testosterone Availability—Molinate-Induced Inhibition of Spermatogenesis

Molinate is a preemergent herbicide that has been demonstrated to affect reproduction in the rat via alterations in sperm production. A wealth of standard toxicological studies and targeted research efforts relating to this adverse effect is available, and these were used to evaluate the utility of the Human Relevance Framework (HRF) for noncancer health effects. The hypothesized mode of action involved inhibition of the hydrolysis of cholesterol from high-density lipoprotein in the rat testes, followed by an androgen withdrawal syndrome on spermatogenesis. Some evidence is available that a similar mode of action would not be operable in humans. Despite the wealth of studies conducted in the rat, the weight of evidence is insufficient to define the mode of action for reproductive toxicity in the male rat. A principal deficiency in the database was discordance between the exposure levels observed to cause biochemical disturbances in the testes related to the hypothesized mode of action and the dose levels observed to induce the adverse outcome on spermatogenesis. For this reason, a complete MOA/human relevance analysis is not possible and, based on traditional risk assessment principles, any toxic effects are assumed to be relevant for human risk assessment.     

Pharmacokinetic–Pharmacodynamic Modeling of Doxacurium: Effect of Input Rate

One of the basic assumptions in pharmacokinetic–pharmacodynamic modeling (PK–PD) is that drug equilibration rate constant between plasma concentration and effect (K_e0 ) is not changed by input rate. To test this assumption in a clinical setting, a 25 g/kg iv dose of doxacurium was administered either by bolus injection or 10-min infusion to 15 anesthetized patients. Neuromuscular function was monitored using train-of-four stimulation of the ulnar nerve. For the short infusion dose, arterial concentrations were measured at 1-min intervals during infusion and at frequent intervals thereafter. Following the iv bolus dose, the early PK profile of doxacurium was investigated by measuring doxacurium arterial concentrations every 10 sec during the first 2 min and at frequent intervals thereafter. PK–PD modeling was performed using nonparametric approach with and without including a finite receptor concentration (R_tot ) in the effect compartment. Kinetic parameters were unchanged. For the bolus and the infusion, K_e0 values were 0.053±0.006 and 0.056±0.009 min ^–1 , respectively. Using the R_tot model, corresponding K_e0 values were 0.148±0.016 and 0.150±0.024, respectively. The relatively faster K_e0 obtained with the R_tot model is compatible with the high potency of doxacurium. Our results show that PK–PD parameters derived with either a bolus or an infusion mode of administration are equally reliable.     

Estimation of Intragastric Solubility of Drugs: In What Medium?

Purpose To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. Materials and Methods Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF_SLS, SGF_Triton, FaSSGF, FaSSGF_NaCl, and in various HCl solutions with pH values ranging from 1.2 to 2.9. Results In all cases, FaSSGF performed better than canine aspirates, SGF_SLS, SGF_Triton, or FaSSGF_NaCl in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, −39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. Conclusions Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.     

Subjective symptoms: part of the negative syndrome of schizophrenia?

We present the psychometric and clinical psychopathological properties of the SDSS for the assessment of subjective symptoms as applied to various schizophrenic samples. The subjective deficit syndrome has not been obvious to most investigators, in part because the currently available scales, even those assessing negative symptoms, were not designed to capture it. While the subjective deficit syndrome is not specific to schizophrenia, it may explain what is widely observed as a major public health problem, namely, that officially "remitted" patients continue to fail in social and occupational functioning. The understanding of this syndrome is a prerequisite for better management of these remitted schizophrenic outpatients. Future longitudinal studies including outpatients are needed to address these issues further.     

Tedisamil: master switch of nature?

Decreasing heart rate is potentially useful in ischaemic heart disease. Tedisamil is a bradycardic agent resulting from its ability to inhibit transient outward current (I(to)) in atria. Tedisamil inhibits I(to), potassium current (IK), K(ATP) and the protein kinase A-activated chloride channel in ventricles as well as vascular IK and Ca(2+)-activated IK (IK((Ca))). Tedisamil prolongs cardiac action potentials and the corrected QT (QTc) of the ECG and also increases cardiac refractoriness. Tedisamil is anti-arrhythmic in animal models of ventricular arrhythmias and atrial flutter. The bradycardic effect of tedisamil is associated with a reduction in myocardial oxygen demand. On isolated rat ventricle, tedisamil is a positive inotrope and on isolated rabbit atria, tedisamil reverses the negative inotropic effect of pinacidil. Tedisamil contracts the isolated rat portal vein and aorta, reduces cromakalim-induced relaxations of contracted rat aorta and increases blood pressure in animals and humans. Tedisamil is 96% bound to plasma proteins, has a plasma half-life of about 10 h and is cleared from the kidney unchanged. Clinical trials have shown that the electrophysiology of tedisamil is that of a class III anti-arrhythmic. In coronary artery disease, tedisamil has no effect on inotropism and increases the threshold for angina. Potassium channel blockade with tedisamil may have advantages over calcium channel blockers or K(ATP) channel openers as an anti-ischaemic mechanism in coronary artery disease. In exercise-induced myocardial ischaemia, beta-blockers are probably favourable to tedisamil, as they will limit the increase in heart rate, contractility and blood pressure caused by sympathetic stimulation, whereas tedisamil will not. In heart failure patients, tedisamil reduces heart rate, but increases blood pressure. The usefulness of tedisamil as a bradycardic agent is limited by the increase in blood pressure. A drug that is bradycardic without increasing blood pressure would be an improvement on tedisamil as the master switch of nature for ischaemic heart disease.     

Autism: a target of pharmacotherapies?

Autism is reaching epidemic proportions. The diagnosis can be made as early as 2 years of age, and autistic patients are expected to have a normal life span. Thus, in terms of the number of 'patient years', autism spectrum disorder (ASD) represents a market that is as large as that of the biggest neurological indication, Alzheimer's disease. However, despite the clear unmet medical need no effective treatment is yet available. This could be because the biology of ASD is not clearly understood and thus proper drug treatment has not been possible. However, significant advances are being made toward understanding the mechanisms of the disease. Here, we review the most recent preclinical advances in the hope that they will lead to a breakthrough in the near future.     

Therapeutic failure: importance of genes?

Drug management can be a difficult task in certain situations because of the variable response observed from one patient to another. Genetic factors affecting the pharmacokinetics and pharmacodynamics of drug reactions could explain the interindividual variability in drug response. Pharmacogenetic analysis provides insight into the molecular mechanisms involved in drug response, with the ultimate goal of achieving optimal drug efficacy and safety. Numerous polymorphisms have been described in genes encoding drug-metabolising enzymes, transporters, and receptors. For some drugs, the impact on drug bioavailability and effect has been elucidated. We review here the molecular basis of interindividual variation in drug response and the methods used to identify individual risk of drug failure or toxicity. Clinical applications, concerning enzymes metabolising drugs (cytochrome P4502D6, thiopurine S-methyltransferase and N-acetyltransferase) provide an illustrative demonstration of the usefulness of pharmacogenetic tests in improving patient management. Clinical validation of these tests and new technologies (real-time PCR, DNA chips) should, in the future promote pharmacogenetics in clinical practice and may be lead to more individualized drug therapy.     

Lactones: generic inhibitors of enzymes?

The ability to affect eukaryotic and prokaryotic cellular growth, signaling and differentiation is a continuing focus in the pharmaceutical industry. The fundamental ability to affect these cellular processes is inherent in lactones. Lactones, which are ubiquitous in nature, reflect a broad phylogenetic diversity indicative of their ability to act as simple alkylating compounds, with their in situ activities falling into one of two categories, i.e., protect or conquer. Medically, their utility as pharmaceutical agents range from that of antimicrobial to anti-neoplastic agent depending on the functional groups attached.     

Benzylpiperazine: a drug of abuse?

N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' or 'p.e.p.' pills, which are used to provide a stimulant, euphoric effect akin to that of methylenedioxymethamphetamine (MDMA, 'ecstasy'). BZP predominantly affects dopamine neurotransmission in a similar fashion to known 'drugs of abuse', such as methamphetamine and cocaine, which strongly suggests BZP has abuse liability. BZP is illegal in many countries including the United States of America and Australia, yet it remains legal in the United Kingdom, Canada and New Zealand. There has been little research, to date, on the neurological consequences of high dose or chronic exposure of BZP. Here we provide a comprehensive review of the information currently available on BZP and suggest a need for further research into the mechanisms of action, long-term effects and potentially addictive properties of BZP.     

Transdermal Delivery of Ketoprofen: The Influence of Drug–Dioleylphosphatidylcholine Interactions

Purpose Considering that most inflammatory diseases occur locally and near the body surface, transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) may be an interesting strategy for delivering these drugs directly to the diseased site. To optimize ketoprofen (KP) transdermal delivery we investigated the influence of dioleylphosphatidylcholine (DOPC) on skin permeation.Materials and Methods The formulations studied were: i) a physical mixture of KP and DOPC and ii) DOPC and KP complex, in a molar ratio of 1:3, obtained by dissolution of the components in chloroform followed by drying under a N₂ atmosphere. Both systems were dispersed in mineral oil and the in vitro percutaneous was assayed by absorption using a flow through diffusion cell. Differential Scanning Calorimetry (DSC) and ¹H NMR studies were carried out to characterize KP and DOPC interactions. Geometry optimizations using Density Functional Theory and semiempirical methods, as well as a flexible docking procedure were carried out to obtain a binding model for KP with DOPC. KP solubility and partition studies in the formulations, as well as skin irritation and hypersensitivity assays were also carried out.Results DSC determinations in the complex showed enthalpy and temperature depressions, indicating KP and DOPC interaction. In addition, dipole–dipole interactions between the KP carboxylic acid and OH groups in phospholipids were shown by ¹H NMR studies. Based on the NMR studies, a KP–DOPC binding model is proposed, in which KP is involved by the two long aliphatic chains of the phospholipid. Solubility studies indicated that DOPC improved drug solubility. KP permeation was enhanced by both formulations tested, but the complex also increased its skin uptake. Such behavior could be attributed to the solubilizing, melting and enhancing effects of DOPC. Skin irritation and hypersensitivity were not significantly changed compared to control, suggesting that the formulation may be therapeutically explored for KP transdermal delivery.     

Company Profile: Fujisawa: Analysis of patenting 1992–1996

Fujisawa is the fifth largest pharmaceutical company in Japan. It has an unusually high R&D investment in comparison to overall profitability and remains an almost exclusively Japanese company with a uniquely high proportion of Japanese inventors. The majority of patents filed are anti-infectives, with almost twenty inventions each year. These are dominated by β-lactams and quinolones. Fugisawa's more important inventions are filed first in the UK, leading to families of worldwide patents claiming UK priorities. However, lack of protection in some smaller markets may become a disadvantage for Fujisawa as the company exploits its inventions internationally. The following article profiles the patenting activity of Fujisawa between 1992 and 1996.     

Nebulization of NanoCrystals™: Production of a Respirable Solid-in-Liquid-in-Air Colloidal Dispersion

Pharmaceutical Research -     

Structural Modification Study of Anthracyclinones: Synthesis and Biological Activity of Several Derivatives of η-Pyrromycinone

On the basis of the N–O–O triangular pharmacophore hypothesis postulated earlier in our laboratory, selected side chains with or without the nitrogen atom at the strategic position were incorporated to -pyrromycinone, one of the anthracyclinones derived from the antibiotic cinerubins. Since none of the anthracyclinones (the aglycones of anthracyclines) were reported to have antineoplastic activity, the validity of the proposed hypothesis could be tested. Results indicated that a compound designed in this manner, 1,4-bis[2-(2,2-dimethyloxazolidin-3-yl)ethylamino]-l,4-didehydroxy--pyrromycinone (9c) possessed both in vitro and in vivo antineoplastic activity comparable to that of mitoxantrone. The structure–activity relationship of this class of compounds is discussed.