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AAPS PharmSciTech Mar 2013This study evaluated the effect of counterions on the physicochemical properties of prazosin salts. Salt forms of prazosin, namely, mesylate, besylate, tosylate,...
This study evaluated the effect of counterions on the physicochemical properties of prazosin salts. Salt forms of prazosin, namely, mesylate, besylate, tosylate, camsylate, oxalate, and maleate, were prepared and compared with the marketed anhydrous and polyhydrate forms of prazosin hydrochloride. Physicochemical characterization was performed in the order of crystallinity, hygroscopicity, solubility, and stability to select the optimal salt(s). Permeability study in Caco-2 cell lines and in vivo bioavailability study in rat model were investigated to ascertain their biopharmaceutical advantage. All salt forms were crystalline, nonhygroscopic (except the anhydrous hydrochloride salt), and had solubility in the range of 0.2 to 1.6 mg/ml. All salts were physically and chemically stable at 40°C/75% relative humidity, but degraded in UV-visible light, except the anhydrous hydrochloride salt. Prazosin mesylate was selected as the optimal salt, as it possessed higher solubility, permeability, and bioavailability, compared to the commercial hydrochloride salts. Hydrochloride salt is reported to have poor bioavailability that is partially attributed to its low solubility and extensive common-ion effect in the gastric region. Factors like hydrophilicity of the counterion, hydration state of the salt, and melting point of the salt contribute to the physicochemical properties of the salts. This study has implications in the selection of an optimal salt form for prazosin, which is suitable for further development.
Topics: Adrenergic alpha-Antagonists; Caco-2 Cells; Calorimetry, Differential Scanning; Chromatography, Gas; Humans; Mass Spectrometry; Prazosin; Salts; Solubility; Thermogravimetry
PubMed: 23250707
DOI: 10.1208/s12249-012-9889-x -
Anesthesiology Aug 2005The authors tested the hypothesis that the intravenous anesthetic fentanyl would attenuate the pulmonary vasoconstrictor response to alpha1-adrenoceptor activation. They...
BACKGROUND
The authors tested the hypothesis that the intravenous anesthetic fentanyl would attenuate the pulmonary vasoconstrictor response to alpha1-adrenoceptor activation. They also investigated the alpha1-adrenoceptor subtypes that could potentially mediate this effect of fentanyl.
METHODS
Endothelium-denuded canine pulmonary arterial rings were suspended for isometric tension recording. Dose-response curves for the alpha1-adrenoceptor agonist phenylephrine were generated in the absence and presence of fentanyl. The effects of inhibiting alpha2 (rauwolscine), alpha1 (prazosin), alpha1A (5-methylurapidil), alpha1B (chloroethylclonidine), and alpha1D (BMY 7378) adrenoceptors on phenylephrine contraction were also investigated. Receptor "protection" studies were performed to investigate the specific role of alpha1B adrenoceptors in mediating fentanyl-induced changes in phenylephrine contraction. Finally, competition binding studies were performed in rat-1 fibroblasts stably transfected with human alpha1-adrenoceptor complementary DNAs corresponding to the alpha1A-, alpha1B-, or alpha1D-adrenoceptor subtypes to directly assess whether fentanyl can compete for the alpha1-adrenoceptor activation pocket.
RESULTS
Fentanyl attenuated phenylephrine contraction in a dose-dependent fashion. Rauwolscine had no effect on phenylephrine contraction. Phenylephrine contraction was inhibited by prazosin and abolished by chloroethylclonidine but was relatively resistant to inhibition by 5-methylurapidil and BMY 7378. Pretreatment with fentanyl before exposure to chloroethylclonidine increased the maximal contractile response to phenylephrine compared to chloroethylclonidine pretreatment alone. Competition binding studies revealed that fentanyl binds to all three alpha1-adrenoceptor subtypes, with a fivefold greater affinity for the alpha1B-adrenoceptor compared with the alpha1D-adrenoceptor subtype.
CONCLUSION
Phenylephrine-induced contraction is primarily mediated by alpha1B-adrenoceptor activation in canine pulmonary artery. Fentanyl attenuates phenylephrine contraction by binding to alpha1B adrenoceptors.
Topics: Anesthetics, Intravenous; Animals; Clonidine; Dogs; Dose-Response Relationship, Drug; Fentanyl; Hydrogen-Ion Concentration; In Vitro Techniques; Phenylephrine; Piperazines; Prazosin; Pulmonary Artery; Receptors, Adrenergic, alpha-1; Vasoconstriction
PubMed: 16052115
DOI: 10.1097/00000542-200508000-00016 -
British Journal of Pharmacology May 2013α1 -adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the α1 A -AR selective antagonist silodosin (compared to... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
α1 -adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the α1 A -AR selective antagonist silodosin (compared to tamsulosin and prazosin) on ureter pressures in a rat model of ureter obstruction, and on contractions of human and rat isolated ureters.
EXPERIMENTAL APPROACH
After ethical approval, ureters of male rats were cannulated beneath the kidney pelvis for in vivo ureteral intraluminal recording of autonomous peristaltic pressure waves. A partial ureter obstruction was applied to the distal ureter. Mean arterial blood pressure (MAP) was recorded. Approximate clinical and triple clinical doses of the α1 -AR antagonists were given intravenously. Effects by the α1 -AR antagonists on isolated human and rat ureters were studied in organ baths.
KEY RESULTS
Intravenous silodosin (0.1-0.3 mg kg(-1) ) or prazosin (0.03-0.1 mg kg(-1) ) reduced obstruction-induced increases in intraluminal ureter pressures by 21-37% or 18-40% respectively. Corresponding effects by tamsulosin (0.01 or 0.03 mg kg(-1) ) were 9-20%. Silodosin, prazosin and tamsulosin reduced MAP by 10-12%, 25-26% (P < 0.05), or 18-25% (P < 0.05) respectively. When effects by the α1 A -AR antagonists on obstruction-induced ureter pressures were expressed as a function of MAP, silodosin had six- to eightfold and 2.5- to eightfold better efficacy than tamsulosin or prazosin respectively. Silodosin effectively reduced contractions of both human and rat isolated ureters.
CONCLUSIONS AND IMPLICATIONS
Silodosin inhibits contractions of the rat and human isolated ureters and has excellent functional selectivity in vivo to relieve pressure-load of the rat obstructed ureter. Silodosin as pharmacological ureter stone expulsive therapy should be clinically further explored.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Arterial Pressure; Dose-Response Relationship, Drug; Humans; Indoles; Male; Muscle Contraction; Prazosin; Rats; Rats, Sprague-Dawley; Species Specificity; Sulfonamides; Tamsulosin; Ureter; Ureteral Obstruction
PubMed: 23373675
DOI: 10.1111/bph.12123 -
Canadian Medical Association Journal Nov 1977
Topics: Drug Evaluation; Humans; Hypertension; Prazosin; Quinazolines
PubMed: 912636
DOI: No ID Found -
British Journal of Pharmacology Nov 1977
Comparative Study
Topics: Animals; Clonidine; Dogs; Prazosin; Quinazolines; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Species Specificity
PubMed: 201328
DOI: No ID Found -
Molecular Metabolism Oct 2017Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in...
OBJECTIVE
Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in the offspring. Pharmacological interventions required as a consequence of gestational problems, e.g. hypertension, can potentially interfere with correct fetal programming. As epigenetic alterations are usually only revealed later in life and not detected in studies focusing on early perinatal outcomes, little is known about the long-term epigenetic effects of gestational drug treatments. We sought to test the consequences of maternal α1-adrenergic antagonism during pregnancy, which can occur e.g. during hypertension treatment, for the endocrine and metabolic phenotype of the offspring.
METHODS
We treated C57BL/6NCrl female mice with the α1-adrenergic antagonist prazosin during pregnancy and analyzed the male and female offspring for endocrine and metabolic abnormalities.
RESULTS
Our data revealed that maternal α1-adrenergic blockade caused dwarfism, elevated body temperature, and insulin resistance in male offspring, accompanied by reduced IGF-1 serum concentrations as the result of reduced hepatic growth hormone receptor (Ghr) expression. We subsequently identified increased CpG DNA methylation at the transcriptional start site of the alternative Ghr promotor caused by the maternal treatment, which showed a strong inverse correlation to hepatic Ghr expression.
CONCLUSIONS
Our results demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance. The findings are of immediate clinical relevance as combined α/β-adrenergic blockers are first-line treatment of maternal hypertension.
Topics: Adipose Tissue, Brown; Adrenergic alpha-1 Receptor Antagonists; Animals; Animals, Newborn; Dwarfism; Epigenesis, Genetic; Female; Fetal Development; Hypertension; Insulin Resistance; Insulin-Like Growth Factor I; Liver; Male; Mice; Mice, Inbred C57BL; Prazosin; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, Somatotropin; Thermogenesis
PubMed: 29031714
DOI: 10.1016/j.molmet.2017.06.016 -
The Journal of General and Applied... Apr 2020Prazosin (PRZ), a drug used to treat hypertensive patients, is an emergent contaminant in water systems. PRZ is an alpha-adrenergic receptor blocker used to treat...
Prazosin (PRZ), a drug used to treat hypertensive patients, is an emergent contaminant in water systems. PRZ is an alpha-adrenergic receptor blocker used to treat anxiety, and is believed to reach the environment through human excretion, irresponsible disposal of unused medicine, and waste products from manufacturing plants. The purpose of this research was to isolate and characterize potential microbes for PRZ biodegradation and to identify the degradation pathway. After screening, isolated strain STP3 showed a capability for PRZ degradation and was chosen for further analysis. Resting cell assays with PRZ were conducted to identify the intermediate metabolites formed from biodegradation by Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) analysis. Two metabolites degraded from PRZ by STP3 were successfully found, and as these metabolites are derived from the main structure of PRZ, their presence proved PRZ degradation. Draft genome sequencing analysis of STP3 was performed to identify potential enzymes for PRZ biodegradation based on the metabolites found.
Topics: Bacillus; Biodegradation, Environmental; Metabolic Networks and Pathways; Prazosin; Soil Microbiology; Soil Pollutants; Tropical Climate
PubMed: 31281138
DOI: 10.2323/jgam.2019.04.001 -
Anticancer Research Jan 2015Medullary thyroid carcinoma (MTC) is a tumor associated with poor prognosis since it exhibits high resistance against conventional cancer therapy. Recent studies have...
BACKGROUND/AIM
Medullary thyroid carcinoma (MTC) is a tumor associated with poor prognosis since it exhibits high resistance against conventional cancer therapy. Recent studies have shown that quinazolines exhibit a pro-apoptotic effect on malignant cells. The aim of the present study was to elucidate whether MTC cells are affected by quinazolines, in particular prazosin.
MATERIALS AND METHODS
Proliferation, apoptosis and cell morphology of the MTC cell line TT were analyzed by WST-1 assay, caspase 3/7 activation tests and microscopy. Fibroblasts were used as control for non-malignant cells.
RESULTS
Prazosin potently inhibited the growth of TT cells, induced apoptosis and caused vacuolization, as well as needle-like filopodia. Fibroblasts were affected by prazosin in the same way as MTC cells.
CONCLUSION
MTC cells are responsive to prazosin treatment similar to other malignancies. The fact that fibroblasts also respond to prazosin further highlights the importance to identify the unknown pro-apoptotic target of quinazolines.
Topics: Antihypertensive Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Medullary; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Prazosin; Receptors, Adrenergic, alpha-1; Thyroid Neoplasms
PubMed: 25550532
DOI: No ID Found -
British Journal of Pharmacology Jul 20041 Alpha1-adrenoceptors (ARs) play an important functional role in the liver; yet little is known about their cellular location. We identified the subtypes present in... (Comparative Study)
Comparative Study
1 Alpha1-adrenoceptors (ARs) play an important functional role in the liver; yet little is known about their cellular location. We identified the subtypes present in wild-type (WT) and alpha1B-AR knockout (KO) mice livers at 3 and 4 months of age, and investigated their distribution in hepatocytes. 2 The fluorescent alpha1-AR antagonist quinazolinyl piperazine borate-dipyrromethene (QAPB) was used to visualise hepatic alpha1-ARs and radioligand binding with [3H]-prazosin was used to quantify the alpha1-AR population. 3 QAPB and [3H]-prazosin bound specifically to hepatic alpha1-ARs with nanomolar affinity. The cellular distribution of alpha1-ARs was similar in WT and alpha1B-AR KO hepatocytes; QAPB binding was distributed diffusely throughout the cell with no binding evident on the plasma membrane. Radioligand binding produced Bmax values as follows: 3-month WT - 76+/-3.3 fmol mg(-1); 4-month WT - 50+/-3.1 fmol mg(-1); 3-month alpha1B-AR KO - 7.4+/-0.73 fmol mg(-1); 4-month alpha1B-AR KO - 30+/-2.0 fmol mg(-1). 4 In 3- and 4-month WT liver, all antagonists acted competitively. RS100329 (alpha1A-selective) and BMY7378 (alpha1D-selective) bound with low affinities, indicating the presence of alpha1B-ARs. In 4-month alpha1B-AR KO liver prazosin produced a biphasic curve, whereas RS100329 and BMY7378 produced monophasic curves of high and low affinity, respectively, indicating the presence of alpha1A-ARs. 5 In conclusion, we have made the novel observation that alpha1-ARs can compensate for one another in the absence of the endogenously expressed receptor; yet there appears to be no subtype-specific subcellular location of alpha1-ARs; the WT livers express alpha1B-ARs, while alpha1B-AR KO livers express alpha1A-ARs. This study provides new insights into both hepatocyte and alpha1-AR biology.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Binding, Competitive; Boron Compounds; Cell Membrane; Genotype; Hepatocytes; Kinetics; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Microscopy, Confocal; Piperazines; Prazosin; Radioligand Assay; Receptors, Adrenergic, alpha-1; Thymine; Tritium
PubMed: 15210583
DOI: 10.1038/sj.bjp.0705872 -
British Journal of Pharmacology Oct 19791 The effects of the highly selective alpha(1)-adrenoceptor antagonist, prazosin, and the relatively selective alpha(2)-adrenoceptor antagonist, yohimbine, on the...
1 The effects of the highly selective alpha(1)-adrenoceptor antagonist, prazosin, and the relatively selective alpha(2)-adrenoceptor antagonist, yohimbine, on the pressor responses to intravenous injections of phenylephrine and noradrenaline have been examined in anaesthetized cats and pithed rats in an attempt to determine whether alpha(1)- and alpha(2)-adrenoceptors are located postsynaptically on vascular smooth muscle.2 In anaesthetized cats prazosin caused a much greater reduction in the pressor responses to phenylephrine than to noradrenaline or splanchnic nerve stimulation (after adrenalectomy). Yohimbine was of similar potency in reducing the pressor responses to each stimulus.3 A differential blocking activity of prazosin against intra-arterial injections of phenylephrine and noradrenaline was also demonstrated in the blood-perfused cat hind limb. As in the whole animal, prazosin was more potent against phenylephrine than noradrenaline. A similar, though less marked, effect was seen in the mesenteric circulation, but not in the renal circulation, where prazosin was almost equipotent in reducing responses to phenylephrine and noradrenaline.4 In pithed rats prazosin was a potent, competitive antagonist of phenylephrine, but had little effect against noradrenaline; only the responses to high doses of noradrenaline were reduced by prazosin. Yohimbine was approximately equipotent as an antagonist of phenylephrine and noradrenaline. In the anococcygeus muscle, prazosin was as potent an antagonist of noradrenaline as it was of phenylephrine on vascular smooth muscle.5 The results suggest that there are two types of alpha-adrenoceptor in the vasculature of cats and rats. Phenylephrine produces pressor responses by stimulating one type of postsynaptic alpha-adrenoceptor that is blocked by prazosin and yohimbine; these are alpha(1)-adrenoceptors. Noradrenaline exerts some of its effect via these receptors but most of its effect appears to be exerted through prazosin-insensitive receptors. The latter receptors appear to differ from alpha(2)-adrenoceptors.
Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Cats; Female; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Prazosin; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Regional Blood Flow; Spinal Cord; Yohimbine
PubMed: 40647
DOI: 10.1111/j.1476-5381.1979.tb08668.x