Synthese neuer potentiell analgetisch bzw. antibiotisch wirksamer Pyridazino[4,3-e][1,3]oxazinone und Pyrimido[4,5-c]pyridazinone

Synthesis of New Potentially Analgesically and Antibiotically Active Pyridazino[4,3-e][1,3]oxazinones and Pyrimido[4,5-c]pyridazinones The carboximidoylchlorides 1a–d react with water and N-nucleophiles to the ureas 6a–d and 7a–c resp., to the guanidines 9a–d – 15a–d , and to the 1,2,4-oxadiazoles 18a–d . 14a–d and 15a–d were converted into the 1,2,4-triazoles 16a–d and 17a–d . 6a–c as well as 10a–d and 11a–d can be cyclized to the title pyridazino[4,3-e][1,3]oxazin-5-ones 8a–c and to the pyrimido[4,5-c]pyridazin-5(8H)-ones 19a–d and 20a–d .     

Novel insights into Lp(a) physiology and pathogenicity: more questions than answers?

Lipoprotein(a) (Lp(a)) is of interest to both basic researchers who endeavour to understand the mechanism of action of this unique lipoprotein, as well as to clinicians who are interested in the contribution of Lp(a) to cardiovascular risk profiles. The Lp(a) particle contains a moiety that is indistinguishable from circulating LDL, covalently linked to the unique glycoprotein component apolipoprotein(a) (apo(a)). Since the 1970s, epidemiological data have been accumulated that, on balance, indicate that elevated plasma Lp(a) concentrations are an independent risk factor for vascular diseases. Apo(a) is highly homologous to the fibrinolytic proenzyme plasminogen, containing many tandemly-repeated kringle motifs similar to several of those found in the plasminogen molecule; the size of the kringle domain in apo(a) gives rise to Lp(a) isoform size heterogeneity which is a hallmark of this lipoprotein. The similarity between Lp(a) and plasminogen led to speculation of a bridging role for Lp(a) in atherothrombotic disease based on the duality of the structure of this lipoprotein. In this scenario, LDL would contribute to the proatherosclerotic properties of the particle, while apo(a) would interfere with the normal fibrinolytic functions of plasminogen, thereby inhibiting the breakdown of thrombi formed in the vasculature. Many in vitro and in vivo studies have suggested a prothrombotic role for Lp(a) which is attributable to the apo(a) component of the particle. However, there are a number of unique properties that apo(a) confers to Lp(a) which are independent of its similarity to plasminogen. These include the ability of apo(a)/Lp(a) to affect platelet function, to contribute to endothelial dysfunction, and to inhibit the clearance of chylomicron remnant particles in a transgenic mouse model. Very recent data have revealed a potential role for Lp(a) in the preferential binding of oxidized phospholipid adducts through one of the kringle motifs in apo(a). Many questions remain to be answered regarding the role of Lp(a) in atherothrombotic disease. This article will review the relevant literature concerning the contribution of Lp(a) to risk for both atherosclerotic and purely thrombotic disorders, as well as the proposed mechanisms of Lp(a) pathogenicity related to the structure of this lipoprotein. Emerging areas of interest in the field including the role of apo(a) isoform size as a risk factor for CHD - independent of Lp(a) levels - will also be discussed, as will speculation as to the possible physiological role of Lp(a). Future directions in the field as well as recommendations for the use of Lp(a) in clinical contexts will also be addressed.     

Contraction of guinea pig lung by synthetic oligopeptides related to human C3a

Complement-derived human C3a is a 77 residue protein whose biological activities include the contraction of guinea pig ileum and parenchymal lung strips. The C3a molecule is active at submicromolar concentrations and the spasmogenic activities are absolutely dependent on a carboxy-terminal arginyl residue. Studies with synthetic peptide analogues of C3a have localized the active site for all spasmogenic functions at the carboxy-terminal portion of the native molecule. Studies reported here demonstrate that the spasmogenic action of C3a on guinea pig parenchymal lung tissue is mimicked by synthetic peptides based on the carboxy-terminal sequence of C3a. Synthetic peptides with sequences corresponding to the 5, 8, 13 and 21 carboxy-terminal residues of C3a all possess spasmogenic activity on lung tissue. Molar activities of the synthetic peptides relative to that of C3a increase as the length of the peptide increases. The activity of the pentapeptide C3a 73-77 is only 0.5% that of C3a, while those of C3a 70-77 and C3a 65-77 are 3.8 and 7.8%, respectively. A 21 residue peptide, C3a 57-77, exhibits activity equivalent to native C3a. The synthetic peptides, unlike C3a, fail to produce tachyphylaxis. We compared C3a reactivity of guinea pig parenchymal lung strips with those of the synthetic C3a peptides in the presence of various inhibitor combinations. Responses of lung strips to C3a or the C3a peptides were not significantly inhibited by the antihistamine pyrilamine. However, lung responses to synthetic C3a peptides, like those to C3a, were inhibited by indomethacin. Complete inhibition of responses to C3a or the synthetic C3a peptides was produced in the presence of indomethacin, FPL55712 and pyrilamine.     

Palisaded encapsulated neuroma--a classic presentation of a commonly misdiagnosed neural tumor

We present a case report of a classical presentation of palisaded encapsulated neuroma (PEN) of the skin occurring on the nasolabial crease and a review of the literature. A young woman presented with a smooth lobulated papule on the cheek enlarging over 2 years. Histologic examination revealed a well-circumscribed dermal nodule of small spindle cells with wavy nuclei arranged in fascicles, consistent with the diagnosis of PEN. PEN is a previously described, benign cutaneous neural tumour, with a histological appearance between that of a neurofibroma and a schwannoma. Though not uncommon, PEN remains under-diagnosed by many pathologists. Clinically, PEN is most commonly misdiagnosed as a basal cell carcinoma, a nevus, or as a neurofibroma.     

Complement factors C3a and C5a have distinct hemodynamic effects in the rat

In the rat, C5a infusion mediates well-defined effects including hypotension and neutropenia. Conversely, the comparative effect of C3a in the rat is not yet defined. In the current study, we have investigated C3a receptor (C3aR) activation in the rat, using recombinant human C3a, the C3aR agonist WWGKKYRASKLGLAR, which is a C-terminal analogue of C3a, and a nonpeptide C3aR antagonist SB-290157, as pharmacological tools. In vitro, C3a and WWGKKYRASKLGLAR selectively bound to C3aRs and induced degranulation of C3aR-transfected RBL-2H3 cells. C3a or WWGKKYRASKLGLAR-induced degranulation was dose-dependently antagonized in a surmountable fashion by the nonpeptide C3aR antagonist. Intravenous infusion of C3a and WWGKKYRASKLGLAR to rats induced a rapid, transient and concentration-dependent hypertensive response, which was mediated by C3aR-induced prostanoid release. C3a and WWGKKYRASKLGLAR caused a small drop in circulating neutrophils, but a rise in circulating neutrophils was evident after 90–120 min. In contrast to C3a, C5a infusion resulted in hypotension, and rapid and transient neutropenia. These results demonstrate that C3a and C5a mediate distinct effects on blood pressure and circulating polymorphonuclear leukocytes in the rat.     

Synthesis and HIV-1 inhibitory properties of new tetrahydrobenzoquinazolinedione and tetrahydrobenzocycloheptenuracil derivatives and of their thioxo analogues.

Some new tetrahydrobenzoquinazolinediones 2a-4a, tetrahydrobenzocycloheptenuracils 5a, 6a and their thioxo analogues 2b-6b were synthesized within a project aimed at obtaining new HIV-1 tricyclic inhibitors whose scaffold includes a pyrimidine and a phenyl ring, which are present in various HIV-1 non-nucleoside inhibitors. Among the tetrahydrobenzoquinazolinediones 2a-4a, compounds 3a and 4a, in which the tricyclic system is respectively in an angular or linear arrangement, proved to possess a HIV-1 inhibitory activity which was in the micromolar range, while compound 2a, in which the tricyclic system is in the angular arrangement opposite to that of 3a, was found to be completely inactive. As regards the tetrahydrobenzocycloheptenuracil derivatives (5a and 6a), only 5a showed an inhibitory activity similar to that of 3a and 4a. Furthermore, all thioxo analogues 2b-6b were found to be devoid of any activity.     

C5a/C5ades-Arg-induced increase in blood pressure in the guinea pig: role of thromboxane

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment C5a. Knowledge of the alterations in blood pressure induced by C5a as well as the mediators responsible for the blood pressure changes may provide information concerning the potential role of C5a in the adverse hemodynamic responses associated with complement activation. The purpose of this study was to characterize changes in mean arterial pressure in the guinea pig after intravenous challenge with a combination of guinea pig C5a plus C5a(des-Arg) (C5a/C5a(des-Arg)) and determine the mediators responsible for the transient increase in blood pressure which was observed. Mean arterial pressure was monitored in mechanically ventilated pentobarbital-anesthetized guinea pigs. Intravenous injection of C5a/C5a(des-Arg) consistently caused a marked but transient rise in blood pressure. A transient hypotensive response was also seen with injection of markedly higher doses of guinea pig C5a/C5a(des-Arg). Various pharmacological antagonists were used to determine the mediators responsible for the increase in blood pressure induced by guinea pig C5a/C5a(des-Arg). We found that the LTD4 antagonist L-649,923 did not inhibit the transient rise in blood pressure. However, the cyclooxygenase inhibitor indomethacin inhibited the C5a/C5a(des-Arg)-induced pressor response as did the thromboxane synthetase inhibitor U-63557A and the thromboxane receptor antagonist SQ 29,548. In addition, the C5a/C5a(des-Arg)-induced pressor response was not inhibited by the H1 antagonist pyrilamine, but was inhibited in part by the alpha-adrenergic antagonist phentolamine. Also, the response was reduced in animals depleted of circulating platelets or white blood cells. Thus, the results of our studies suggest that intravenously injected guinea pig C5a/C5a(des-Arg) causes release of the vasoconstrictor thromboxane, most likely from circulating white blood cells or platelets, resulting in a transient rise in blood pressure in the guinea pig. In addition, release of catecholamines may contribute to the pressor response observed.     

Preparation and stereochemical integrity of certain thioesters of 2-arylpropionic acids and related compounds

2-Arylpropionate thioesters 5, 6a/6b and 7a/7b, 2-aryloxypropionate thioesters 8a/8b and 2-alkoxy-2-arylacetate thioesters 9a/9b were prepared from thiol 4 and the corresponding carboxylic acids. Thioesters 6a/6b, 7a/7b, 8a/8b and 9a/9b were monitored for evidence of inter-conversion between epimers in acetonitrile solvent at 40 degrees C, by optical activity in the cases of 6a/6b and 7a/7b, and by 1H NMR spectroscopy in the cases of 8a/8b and 9a/9b. Only in the case of thioesters 9a/9b was significant inter-conversion between epimers observed.     

Synthesis, antimicrobial and anti-cancer activities of some new N-ethyl, N-benzyl and N-benzoyl-3-indolyl heterocycles

A series of 1-(N-substituted-1H-indol-3-yl)-3-arylprop-2-ene-1-ones (2a, b-4a, b) were prepared and allowed to react with urea, thiourea or guanidine to give pyrimidine derivatives 5a, b-13a, b. Reaction of 2a, b-4a, b with ethyl acetoacetate in the presence of a base gave cyclohexanone derivatives 14a, b-16a, b. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 17a, b-19a, b. On the other hand, reaction of 2a, b-4a, b with some hydrazine derivatives, namely hydrazine hydrate, acetyl hydrazine, phenylhydrazine and benzylhydrazine hydrochloride, led to the formation of pyrazole derivatives 20a, b-31a, b. Moreover, reaction of 2a, b-4a, b with hydroxylamine hydrochloride gave isoxazole derivatives 32a, b-34a, b. The newly synthesized compounds were tested for their antimicrobial activity and showed that 4-(N-ethyl-1H-indol-3-yl)-6-(p-chlorophenyl)-pyrimidine-2-amine (11b) was the most active of all the test compounds towards Candida albicans compared to the reference drug cycloheximide. Eighteen new compounds, namely pyrimidin-2(1H)-ones 5a, b-7a, b, pyrimidin-2(1H)-thiones 8a, b-10a, b and pyrimidin-2-amines 11a, b-13a, b derivatives, were tested for their in vitro antiproliferative activity against HEPG2, MCF7 and HCT-116 cancer cell lines. 4-(N-ethyl-1H-indol-3-yl)-6-(p-methoxyphenyl)-pyrimidin-2-amine (11a) was found to be highly active with IC(50) of 0.7 μmol L(-1).     

Effects of plasticizers and surfactants on the film forming properties of hydroxypropyl methylcellulose for the coating of diclofenac sodium tablets

Hydroxy propyl methyl cellulose (HPMC) 5cPs, an aqueous soluble polymer was employed for coating diclofenac sodium (DFS) tablets 25 mg for protecting the integrity of the drug yet rendering the drug to release at a faster rate on contact with the gastric environment. Proper optimization for the aqueous based film coating formulation was undertaken primarily employing plasticizers like polyethylene glycol (PEG) 400 and propylene glycol (PG). The defect free selected formulations were further subjected for studying the effects of surfactants like sodium lauryl sulphate (SLS) and Tween-80 along with the plasticizers. The quality of the aqueous film coats or the plasticizer efficiency in case of PEG-400 is in the order 1.5 > 0.5 > 1.0% and for PG 1 > 4 > 3% which can be stated on the basis of less incidence of major coat defects like chipping, cracking, orange peel, roughness, blistering, blooming, picking. The quality of aqueous film coat or the surfactant efficiency in case of SLS + PEG-400 is in the order 0.3 < 0.5 < 0.1% and SLS + PG is in the order 0.5 < 0.1 < 0.3%. In case of Tween-80 + PEG-400 the order is 0.3 < 0.5 < 0.1% and Tween-80 + PG is in the order 0.3 < 0.1 < 0.5%. Elegant film formation can be stated from fewer incidences of coat defects. The obtained coated tablets eventually satisfied all the normal physical parameters like thickness, weights, and weight gain, drug content, crushing strength, percent friability, disintegration time, dissolution profile and possible drug–polymer interactions. ANOVA was undertaken followed by Dunnet multiple comparison for the dissolution profile considering uncoated as the standard. The difference was considered significant at p ⩽ 0.01.     

A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a

Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is π-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. π-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the π-TRTX-Pc1a-ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of π-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a β-hairpin loop that was revealed to be mobile over a wide range of time scales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin-receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side-chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of π-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful π-TRTX-Pc1a mimetics.     

Recent developments in C5/C5a inhibitors

Complement factor 5a (C5a) is formed upon complement system activation in response to infection, injury or disease. Whilst C5a is a potent mediator of immune and inflammatory processes, excessive production or inadequate regulation of C5a has been implicated in the pathogenesis of numerous immuno-inflammatory diseases, predominantly through experimental studies utilising animal models of disease. Both acute and chronic conditions may benefit from C5a inhibition, including rheumatoid arthritis, inflammatory bowel disease, asthma, psoriasis, haemorrhagic shock and neurodegenerative conditions. The potentially broad clinical application for treatments that inhibit the activity of C5a at C5a receptors and the large global market for anti-inflammatory therapeutics have made C5a and the C5a receptor attractive targets for academic and commercial drug development programmes. In the past 5 years, interest in C5a as a drug target has grown substantially, and this activity has resulted in a collection of patents and scientific papers reporting novel C5a and C5a receptor inhibitors and antagonists, and generated a secondary stream of patent applications broadly claiming the use of C5/C5a inhibitors as a method of treating various immune and inflammatory conditions. This paper will review the physiology and pathophysiology of C5a and discuss the development of C5a and C5a receptor inhibitors in light of the recent scientific and patent literature.     

Average bioequivalence evaluation: general methods for pilot trials

In clinical development of a bioequivalent (BE) drug product, a two-step strategy is commonly adopted. In the first step, a pilot BE trial is conducted to evaluate the acceptability of the test drug product as a candidate for further evaluation in a subsequent pivotal BE trial. In the second step, a full-scale pivotal BE trial is conducted to formally establish bioequivalence. The objective and criterion of a pilot BE trial are different from those of a pivotal BE trial. In practice, however, a pilot BE trial is often inappropriately designed and analyzed based on the criterion for a pivotal BE trial. One main reason is the lack of well-established design and analysis methods for a pilot BE trial. To close this gap in practice, this study proposes a Pilot Acceptance Range method specfically constructed for analyzing a pilot BE trial within the framework of a two-step strategy. For designing a crossover pilot BE trial, this paper derives the power function and provides an easy-to-use method for determining the sample size.     

Symmetrical analysis of risk-benefit

To quantify the value of a medical therapy the benefits are weighed against the risks. Effectiveness is defined by objective evidence from predefined endpoints. This benefit is offset against the disadvantage of adverse events. The safety assessment is usually a subjective summary of concerns that can often be neither confirmed nor dismissed. But sometimes a clinical database is so large that a parameter common to both efficacy and safety can be quantified with reasonable certainty: myocardial infarction (MI) is used here as an example. Recently the Food and Drug Administration (FDA) proposed set limits for the incidence of MI as a safety threshold for diabetes treatment. Setting a threshold before something is considered as a safety concern opens the possibility of setting a threshold for clinically important efficacy. When a parameter is common to both safety and efficacy, then logically a unit change in either direction should be of equal weight in the risk and benefit analysis. For example, a doubling in the incidence of myocardial infarction as a safety signal should be given equal weight to the halving of the incidence of myocardial infarction as an efficacy signal. Similarly, if FDA guidance suggests that a less than a 30% increase in the incidence of MI as a safety parameter is considered acceptable, for example for diabetes treatment, when there is no other major toxicity, this opens a debate about a possible inverse threshold for clinical benefit for drugs that reduce a risk factor, such as antihypertensives.     

Effects of human anaphylatoxins on guinea pig atria

Purified human C3a and C5a produce positive inotropic effects on spontaneously contracting atria isolated from guinea pigs. The increased amplitude of contraction induced by C5a has a threshold at 1 X 10(-9)M. This effect is concentration dependent, increasing by 180% at 1.7 X 10(-7)M C5a. The threshold concentration for a C3a-induced effect is four times greater than that for C5a. The C3a-induced effect is also concentration dependent, maximizing at 1 X 10(-7)M. Above that concentration, the increased response to C3a reaches a plateau value at approximately a 70% greater amplitude than that of untreated tissue. Unlike effects induced by anaphylatoxins in other tissues, these positive inotropic responses are not tachyphylactic. The same atrium will respond repeatedly to either C3a or C5a for a period of up to 4 h. Studies with histamine, leukotriene and prostaglandin inhibitors revealed that the anaphylatoxin-induced responses are not solely histamine mediated. Cimetidine partially inhibited the response of isolated guinea pig atria to C5a (e.g. 25%) and failed to affect the response of this tissue preparation induced by C3a. FPL 55712 inhibited the response to both anaphylatoxins by approximately 40%. The atrial response to C3a was inhibited by more than 70% by indomethacin, whereas the response to C5a was unaffected. This is the first report characterizing the specific action of purified C3a and C5a on isolated cardiac tissue. It was concluded that C3a acts primarily via prostaglandins and leukotrienes while C5a affects contractile intensity via vasoamines and leukotrienes.     

Glycosylation of fluoroquinolones through direct and oxygenated polymethylene linkages as a sugar-mediated active transport system for antimicrobials.

We report herein the synthesis and biological testing of several glycosylated derivatives of some fluoroquinolone antibiotics. In particular, we have prepared several glycosylated derivatives of ciprofloxacin (2) in which the carbohydrate units are linked to the free secondary amine of the piperazine unit by: (a) no linker (e.g., a glycosylamine), (b) a beta-oxyethyl linker, and (c) a gamma-oxypropyl linker. Both glucose and galactose were used as carbohydrates so that six compounds of this type were prepared, e.g., no linker 4a,b, oxyethyl linker 5a,b, and oxypropyl linker 6a,b. In addition the aryl glycosides of glucose and galactose (7a,b) were prepared from the active 1-(4-hydroxyphenyl)fluoroquinolone (3.) The syntheses of the glycosylamines 4a,b involved the direct condensation of glucose and galactose with the hydrochloride salt of ciprofloxacin (2). For the oxyalkyl-linked compounds, we first prepared the peracetylated omega-bromoalkyl glycopyranosides 14a,b and 15a,b and then coupled them to the allyl ester of ciprofloxacin (11) to give, after saponification to remove all of the esters, the desired fluoroquinolone carbohydrates 5a,b and 6a,b. The final series was prepared from 2,4,5-trifluorobenzoyl chloride (22) which gave 3 in four precedented steps. Coupling of 3 with the peracetylated glucosyl and galactosyl halides 12a,b and 26 afforded, after saponification, the desired aryl glycosides 7a,b. Six of these derivatives of ciprofloxacin-4a,b, 5a,b, and 6a,b-were subjected to microbiological screening. Of the six, compound 6a showed the highest activity. Since 6a would give the hydroxypropyl-substituted ciprofloxacin on hydrolysis and its activity is approximately 4-8 times less than that of ciprofloxacin (2), this implies that compound 6a is probably being actively transported. Thus preliminary results suggest that some of the compounds are stable in culture conditions and may be differentially transported by multiple resistant organisms. In some cases, the addition of a linker and a carbohydrate to ciprofloxacin lessens, but does not eliminate, antimicrobial activity.     

Reaktionen von 1-Amino-thioxanthon-6,6-dioxiden mit Formamid

Reactions of 1-Amino-thioxanthone-6,6-dioxides with Formamide 1-Amino-4-methyl-thioxanthone-6,6-dioxide (5a) reacts with formamide to the benzothiopyrano-quinazolines 4a and 7a , the benzothiopyrano-indole 6a , the thioxanthene 3a and the quinazolines 1 and 8. 1, 7a and 8 were obtained also from 4a and formamide.     

Average Bioequivalence Evaluation: General Methods for Pilot Trials

In clinical development of a bioequivalent (BE) drug product, a two-step strategy is commonly adopted. In the first step, a pilot BE trial is conducted to evaluate the acceptability of the test drug product as a candidate for further evaluation in a subsequent pivotal BE trial. In the second step, a full-scale pivotal BE trial is conducted to formally establish bioequivalence. The objective and criterion of a pilot BE trial are different from those of a pivotal BE trial. In practice, however, a pilot BE trial is often inappropriately designed and analyzed based on the criterion for a pivotal BE trial. One main reason is the lack of well-established design and analysis methods for a pilot BE trial. To close this gap in practice, this study proposes a Pilot Acceptance Range method specifically constructed for analyzing a pilot BE trial within the framework of a two-step strategy. For designing a crossover pilot BE trial, this paper derives the power function and provides an easy-to-use method for determining the sample size.     

Interactions between the dopamine agonist, bromocriptine and the efflux protein, P-glycoprotein at the blood-brain barrier in the mouse.

Bromocriptin (BCT) is a dopaminergic receptor agonist, poorly transported through the blood-brain barrier (BBB) and responsible for central side effects. Interactions between BCT and the efflux protein, P-glycoprotein (Pgp), have been described in vitro but nothing is known in vivo nor at the BBB level. At the BBB, in vivo, we investigated BCT as (i) a Pgp substrate by comparing the brain uptake in CF1 mdr1a(-/-) and mdr1a(+/+) mice with or without inhibitors of Pgp (valspodar, elacridar); (ii) a Pgp inducer by looking at the effect of repeated doses of BCT on cerebral uptake of digoxin and comparing it to the effect of dexamethasone and rifampicin; (iii) a Pgp inhibitor by determining the effect of a single dose of BCT on cerebral uptake of digoxin and comparing it to the effect of valspodar. CF1 mdr1a(-/-) mice showed much higher brain uptake of BCT than CF1 mdr1a(+/+) mice and brain uptake of BCT was higher in CF1 mdr1a(+/+) mice pre-treated with valspodar or elacridar indicating that BCT is a Pgp substrate at the BBB level. Brain uptake of digoxin was not modified in CF1 mdr1a(+/+) mice pre-treated with a single dose or repeated doses of BCT, indicating that BCT is neither a Pgp inductor nor a Pgp inhibitor at the BBB in the chosen experimental setting. In vivo, at the mouse BBB level and in our experimental conditions, bromocriptin is a Pgp substrate but is not a Pgp modulator.     

An estimation method of the clearance for a one-compartment model of a single bolus intravenous injection by a single sampling

In clinical trials, sometimes only a single drug concentration can be measured from a patient, because of the burden on the patient. From a single concentration, we cannot generally obtain point estimates of each pharmacokinetic parameter in a patient. In this article, we propose a method to estimate the clearance using a one-compartment model of a single-bolus intravenous injection from a single concentration at a sampling point between 1.5 and 2.5 half-lives. This method requires an assumed value for the volume of distribution but is robust to misspecification. This approach is illustrated by simulated concentration data and cadralazine concentration data.