Gene therapy for renal disorders: what are the benefits for the elderly?

Chronic renal failure is one of the major health problems for the elderly. Currently, about 50% of all patients receiving chronic dialysis for end-stage renal disease (ESRD) are aged 65 years or older. Their first-year mortality rate is as high as 30%. The leading causes of ESRD in the elderly are diabetic nephropathy, hypertension and large vessel diseases, and glomerulonephritis. The elderly are also prone to developing acute renal failure induced by ischaemic injury or nephrotoxic drugs. Gene transfer in experimental animals have been tested in all of these conditions, as well as in animal kidney transplantation models, with various degrees of success. However, there are many obstacles to be overcome before gene therapy can be tested clinically for renal disorders. In particular, the major challenges include determining how to prolong and control transgene expression or antisense inhibition and how to minimise the adverse effects of viral or nonviral vectors. Once these problems are solved, gene therapy will have a role in treating age-related renal impairment.     

Comparative analysis for the institutions of the adulterated 

假劣药品是我国乃至全世界所共同面临的重大社会问题,它严重影响了用药安全,破坏了社会安定和谐。现通过对中美假劣药品现状和监管制度的比较分析,包括假劣药品的界定、规制措施以及受害者的救济制度等方面的比较分析,着重指出了我国假劣药品监管制度的不足,并借鉴美国先进监管经验,就完善我国假劣药品监管制度给出了若干建议,以保障用药安全。     

Improvement for the Synthesis of Centchroman

Ｃｅｎｔｃｈｒｏｍａｎ是一新型非甾体女用口服避孕药，我们对其合成路线进行了改进。其中在ＦｒｉｅｄｅｌＣｒａｆｔｓ烷基化反应中高选择性地获得反式异构体，从而避免了文献报道中的高压氢化和构型转化两个反应单元。共五步反应得到最终产物。收率达４０％。     

Two distinct adrenoceptor-biophases in the vasculature: One for α-and the other for β-agonists

Summary Strips of two canine vessels with different patterns of sympathetic innervation were used: the mesenteric artery which has an adventitio-medial plexus and the saphenous vein in which nerve terminals are distributed throughout the media.The pD₂ of (–)-adrenaline for -and -adrenoceptors was determined for both vessels (in the presence of 0.5 M propranolol and 7 M phentolamine, respectively; in the latter case the strips were contracted by 0.28 M prostaglandin F2) and found to be very similar: 6.96 and 7.01 in the saphenous vein and 6.77 and 6.91 in the mesenteric artery, respectively. The similarity of pD₂ for adrenaline acting on -and -adrenoceptors in both preparations allowed us to compare the effect of inhibition of neuronal uptake by 12 M cocaine with that of inhibition of COMT by 50 M dihydroxy-2-methyl propiophenone (U-0521) on: a) the potency of adrenaline (noradrenaline was used in the saphenous vein only) acting on -and -adrenoceptors and b) the time required by the strips to recover 50% in oil (t ₅₀) after contractions or relaxations caused by 0.23 M adrenaline. In the saphenous vein cocaine increased the potency of both adrenaline and noradrenaline for -effects more than for -effects (2.8 times vs. no increase for adrenaline; 7.1 vs. 1.9 times for noradrenaline) and U-0521 increased the potency of both adrenaline and noradrenaline for -effects more than for -effects (4.1 vs. 2.6 times for adrenaline; 1.8 times vs. no increase for noradrenaline); regarding the termination of action of adrenaline, cocaine prolonged the t ₅₀ 1.6 times after contraction and did not change it after relaxation, whereas U-0521 prolonged the t ₅₀ 6.9 times after relaxation and only 1.8 times after contraction.In the mesenteric artery only sensitivity experiments were done. Cocaine increased the potency of adrenaline by a factor of 2.1 for the -effects while there was no influence on its potency with regard to its -effects, and U-0521 increased the potency of adrenaline for the -effects more than for -effects (3.9 vs. 1.8 times, respectively).These results show that there are two different biophases for sympathomimetic agonists in the vasculature: one for -adrenoceptors which is more under the influence of the neuronal uptake and one for -adrenoceptors which is more under the influence of COMT activity. We conclude that -adrenoceptors are situated close to the nerve endings and -adrenoceptors close to COMT sites. Since these results do not differ qualitatively in two vessels with different patterns of innervation, we conclude that this asymmetry in the distribution of -and -adrenoceptors may be due to either an uneven distribution of cells with only one type of receptors each or due to an uneven distribution of receptors on the same cell.     

Limited-sampling strategy models for estimating the area under the plasma concentration–time curve for amlodipine

Objective: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. Methods: Sixteen healthy volunteers received single 5-mg oral doses of amlodipine, as reference or test formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma concentrations of amlodipine (n = 288), measured by mass spectrometry, were used to develop LSS models. Results: Linear regression analysis of the AUC_0–72 and a “jack-knife” validation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R² = 0.99; bias<0.01%; precision = 0.03%) the AUC_0–72 of amlodipine for each formulation. Validation tests indicate that the 2-point LSS model developed for the reference formulation predicts accurately (R²>0.90): (a) the individual AUC_0–72 for the test formulation in the same group of volunteers; (b) the individual AUC_0–72 for the same reference formulation in another bioequivalence study in Brazilian volunteers; (c) the average AUC_0–72 reported in seven additional international studies performed under protocols similar to the present investigation; (d) the individual AUC_0–72 corresponding to concentration data points provided by a first-order compartmental pharmacokinetic model, when the relative values of either the absorption rate (K _abs) or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original values. Conclusions: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this calcium antagonist, at reduced costs of sample acquisition and analysis, and avoiding sampling at “unsociable” hours. Received: 23 March 1999 / Accepted in revised form: 18 August 1999     

Structure-Transport Relationship for the Intestinal Small-Peptide Carrier: Is the Carbonyl Group of the Peptide Bond Relevant for Transport?

Purpose. The objective of this study was to determine the influence of the peptide bond with emphasis on the carbonyl group on the interaction with and transport by the intestinal small-peptide carrier. Therefore enalapril, a known substrate for the small-peptide carrier, has been modified to an analogue with a reduced peptide bond, enamipril. The transport characteristics of both compounds have been determined. Methods. The in vitro transport studies were performed using rat ileum in Ussing chambers. The transport of enalapril and enamipril were measured in a concentration range from 0.5-8 mM in both directions across the ileum, in the presence and absence of inhibitors. The interaction with the small-peptide carrier was studied by evaluating the ability of enalapril and its analogue enamipril to inhibit the transport rate of amoxycillin. Results. Enalapril shows, besides passive diffusion (P_m 3.06 ± 0.14 · 10^-6 cm/s), saturable transport kinetics (J_max = 16 ± 5 nmol/ h·cm², K_m = 1.86 ± 0.64 mM) which can be inhibited with 10 mM cephalexin. The analogue with a reduced peptide bond does not show saturable transport from the mucosal to the serosal side, and cephalexin does not inhibit the flux of enamipril. However, the transport of enamipril from the serosal to mucosal side of the intestinal membrane is saturable and can be inhibited by 100 M verapamil. Although enamipril is not a substrate for the small-peptide carrier in contrast to enalapril, both enalapril and enamipril are able to inhibit the active transport of amoxycillin with a K_i of 0.41± 0.24 mM and 0.24 ± 0.12 mM respectively. Conclusions. The reduction of the peptide bond of enalapril results in a compound, enamipril, which does not show polarized and saturable transport from the mucosal to the serosal side of the intestinal tissue. Also because the transport of enamipril cannot be inhibited by cephalexin, the analogue with the reduced peptide bond is no longer a substrate for the intestinal small-peptide carrier. Therefore, it can be concluded that the carbonyl group is an essential structural requirement for transport by the small-peptide carrier. In contrast, the interaction with the small-peptide carrier is still present, shown by the inhibition of the fluxes of amoxycillin. Reduction of the peptide bond of enalapril resulted in a new substrate for the P-glycoprotein efflux pump.     

Two for the price of one?

Pulmonary vascular medial hypertrophy due to enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and/or decreased PASMC apoptosis is a primary cause of increased pulmonary vascular resistance and arterial pressure in patients with pulmonary arterial hypertension. While many factors can contribute to this form of vascular remodeling, it is generally agreed upon that altered transmembrane ion flux via ion channels is involved. While much focus has centered on the role of cations and cation channels in controlling PASMC contraction and proliferation, anion efflux via Cl- channels has recently gained interest for its role in SMC proliferation, differentiation, migration, contraction, and angiogenesis. In this issue, Dai et al. report that the putative volume-sensitive ClC-3 channel is upregulated in PASMC from monocrotaline-induced pulmonary hypertensive rats and in inflammatory cytokine-treated canine PASMC. They also provide evidence that ClC-3 upregulation may protect against oxidative stress-induced PASMC necrosis, thereby improving PASMC survival and promoting medial hypertrophy.     

GABA pharmacology--what prospects for the future?

Following the recognition of GABA as an inhibitory neurotransmitter, the discovery of high affinity GABA uptake, and the characterisation of GABA receptors great progress has been made in developing GABA pharmacology. Tiagabide, the first marketed GABA uptake inhibitor may be followed by new and more selective uptake inhibitors. Knowledge of the molecular pharmacology of GABA-A receptors, both synaptic and non-synaptic, may lead to improved anti-anxiety/anticonvulsant agents devoid of the sedative and dependence liabilities of earlier compounds and new hypnotics. Gaboxadol (THIP) is an example of a novel hypnotic that acts on GABA-A receptors by a non-benzodiazepine mechanism. Exploiting neurosteroid interactions with GABAergic mechanisms also holds much future promise.     

Secondary patents in the pharmaceutical industry: missing the wood for the trees?

Introduction: The critics of the Innovator pharmaceutical industry allege that secondary patents are trivial modifications over the primary patent, which extend its term and delay the entry of the generics in the market place. The protagonists regard secondary patents a result of continuous research and development (R&D), which help them introduce and protect new, differentiated products.

Areas covered: The areas covered are Product life cycle management (PLCM), Drug approval process, Orange book (OB) listed patents, US patent data.

Expert opinion: Our analysis of the patents and products of four innovators viz., AstraZeneca, Takeda, Eisai and Wyeth in the field of proton pump inhibitors (PPI’s) and Merck and Pfizer in the field of Statins shows that secondary patents help innovators sustain competition against other innovators in the specific product segment. The number of secondary patents listed in OB per NCE depends on the innovators interest in exploiting the NCE, the success of R & D effort and product lifecycle management strategy in the wake of market competition. Market entry decisions of innovators are strategic rather than a mere fallout of the secondary patents granted. Entry of another innovator is more unpredictable and hurts the first entrant more vis a vis the entry of generics who can enter the market when the patents protecting a product are no more enforceable, and hence more predictable. Generic entry in the field of PPI’s shows that the term of the primary patent is not extended by the secondary patents.     

Azithromycin: indications for the future?

The global challenge of optimally treating bacterial infections is continuously evolving. Azithromycin, the first azalide antibiotic, presents pharmacokinetics and pharmacodynamics that allow for a simple dosing regimen with minimal side effects. Current azithromycin uses include a variety of community-acquired respiratory tract, skin and soft tissue, and sexually transmitted disease infections. Azithromycin has also demonstrated substantial activity against atypical organisms such as Mycobacterium avium complex (MAC) and Chlamydia trachomatis. Due to a never-ending need for new antibiotic therapies, several other potential indications for azithromycin are being researched. This article will present various current research associated with azithromycin's potential use for malaria, trachoma, coronary artery disease (CAD), Pseudomonas aeruginosa infections, erythema migrans, short-term therapy for respiratory infections, typhoid, cryptosporidiosis, pelvic inflammatory disease, acne, Mediterranean spotted fever and MAC. As bacterial and parasite resistance patterns fluctuate globally, azithromycin may be an alternative therapy for the previously mentioned indications, which will also enhance patient compliance and therefore effectively eradicate infection worldwide.     

A Valid Equation for the Well-Stirred Perfusion Limited Physiologically Based Pharmacokinetic Model that Consistently Accounts for the Blood–Tissue Drug Distribution in the Organ and the Corresponding Valid Equation for the Steady State Volume of Distribution

A consistent account of the assumptions of the well-stirred perfusion limited model leads to the equation for the organ tissue that does not coincide with that often presented in books and papers. The difference in pharmacokinetic profiles calculated by the valid and the commonly used equations could be quite significant, particularly due to contribution of the organs with relatively large perfusion volume, and especially for drugs with small tissue–plasma partition coefficient and high blood–plasma concentration ratio. Application of the valid equation may result in much faster initial drop of drug plasma concentration time curve and significantly longer terminal half-life, especially for low extraction ratio drugs. An equation for the steady state volume of distribution consistent with the well-stirred model described by the valid equation is provided. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:475–485, 2010     

Mycophenolate mofetil for solid organ transplantation: does the evidence support the need for clinical pharmacokinetic monitoring?

The need for clinical pharmacokinetic monitoring (CPM) of the immunosuppressant mycophenolate mofetil (MMF) has been debated. Using a previously developed algorithm, the authors reviewed the evidence to support or refute the utility of CPM of MMF. First, MMF has proven efficacy for prevention of organ rejection in renal and cardiac transplant populations. In addition, the pharmacologically active form of MMF, mycophenolic acid (MPA), can be measured readily in plasma, and relationships between the incidence of rejection and MPA predose concentrations and MPA area under the curve (AUC) have been reported. A lower limit of the therapeutic range (MPA predose concentrations >1.55 microg/mL, as measured by enzyme multiplied immunoassay technique [EMIT], or MPA AUC >30 or 40 microg. h/mL, as measured by high-performance liquid chromatography [HPLC]) has been suggested to prevent rejection in renal allograft patients. Similarly, in cardiac transplant patients, decreased incidences of organ rejection have been reported in patients with MPA concentrations >2 or 3 microg/mL (using EMIT) and total AUC values >42.8 microg. h/mL (using HPLC). However, the relationship between pharmacokinetic parameters and adverse events in renal and cardiac transplant patients remains unclear. Due to the nature of antirejection therapy, the pharmacologic response of MMF is not readily assessable, and therapy is life-long. MPA pharmacokinetics exhibit large inter- and intrapatient variability and may be altered in specific patient populations due to changes in protein binding, concomitant disease states, or interactions with concurrent immunosuppressants. Therefore, on the basis of current evidence, CPM can provide more information regarding efficacy of MMF than clinical judgment alone in select patient populations. However, further randomized, prospective trials are required to clarify unresolved issues. Specifically, an upper limit of the therapeutic range, above which the risk of side effects is increased, needs to be elucidated for MMF therapy. Other future directions for research include determining a practical limited sampling strategy for MPA AUC; clarifying the relationship between free MPA concentrations, efficacy, and toxicity; and defining the pharmacodynamic relationship between activity of inosine monophosphate dehydrogenase (the enzyme inhibited by MPA) and risk of rejection or adverse effects.