Ocular Distribution of Papaverine Using Non-aqueous Vehicles.

Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber's hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 µg/g of tissue), followed by the conjunctiva (0.74 ± 0.18 µg/g) and sclera (0.25 ± 0.06 µg/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues. Graphical abstract.

Postmortem tissue distribution of morphine and its metabolites in a series of heroin-related deaths.

The abuse of heroin (diamorphine) and heroin-related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin-related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin-related deaths. The presence of 6-monoacetylmorphine (6-MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with solid-phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6-MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.

PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS.

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-µm column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose.

Preparation and clinical evaluation of nano-transferosomes for treatment of erectile dysfunction.

OBJECTIVE: The goal of the present study was to formulate topical nanocarriers of the low-cost vasodilator, papaverine hydrochloride (PH), as an alternative to the painful penile injections. The injections are used for both diagnosis and treatment of erectile dysfunction. Transdermal nano-transferosome (T), the ultraflexible nanoliposome, was used as a nanocarrier to enhance the penetration of the papaverine to the penis. METHODS: Different nano formulas were prepared and characterized for their encapsulation efficiency, particle size, zeta potential, and cumulative drug release. The formula acquired the best characteristics was incorporated into 2% (w/v) hydroxypropyl methylcellulose hydrogel base. The gel containing transferosomal papaverine hydrochloride (PH) and that containing free PH were clinically compared using color flow Doppler measurements. RESULTS: The results revealed that transferosome 3 (T3) had the highest entrapment efficiency approaching 72%, low particle size of 220 nm, and zeta potential of -33.4 mV. The formula released 73% of its initial drug content within 2 hours. The clinical evaluation showed the increase in the cavernous artery diameter from 0.53 mm to 0.78 mm and the increase in the peak systolic flow velocity from 5.95 cm/second to 12.2 cm/second, both of which were found to be significant at P<0.05. CONCLUSION: It is evident from the study that the transferosomes can be used as a carrier of papaverine hydrochloride for both diagnosis and treatment of the erectile dysfunction. This new strategy could be used successfully in the treatment of erectile dysfunction and in male impotency.

Pharmacokinetics of intraluminally administered serum papaverine for spasm prophylaxis of the internal mammary artery.

BACKGROUND: Papaverine (Paveron N™ Linden Arzneimittel Vertrieb GmbH, Germany) is a widely used agent for preventing spasm in mammary artery preparations. The question addressed in this study is whether the intraluminal administration of papaverine can result in detectable absorption of the drug into the systemic arterial circulation. METHODS: In 15 patients (age 65 ± 6 years; body mass index 28.9 ± 3.7), an internal mammary artery (IMA) was prepared during coronary artery bypass grafting (CABG). A maximum of 3 mL of a 1 mg/1 mL diluted papaverine solution was injected intravascularly (intraluminally) for spasm prophylaxis. The IMA was closed proximally and distally with bulldog clamps. Blood samples were taken immediately after administration (T1), after 20 minutes (T2), and at the end of the operation (T3). Samples were measured in a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system consisting of a binary pump from Agilent (Waldbronn, Germany) coupled to a high-throughput screening (HTS) PAL injection system (CTC, Zwingen, Switzerland) and a tandem mass spectrometer (API 4000, AB Sciex, Darmstadt, Germany). Papaverine was analyzed in positive mode using an electrospray ion source. Quantitation was performed using Analyst 1.5 software (AB Sciex, Darmstadt, Germany). RESULTS: The newly developed LC-MS/MS method was successfully established for the detection of papaverine in plasma samples. The highest plasma papaverine levels were determined at time point T1 (mean 54.7 ± 39 ng/mL, range 16.6-179 ng/mL). The concentration was already halved 20 minutes after administration (T2) (mean 23.3 ± 2 ng/mL, range 4.6-118 ng/mL). Because of the short half-life and the hemodilution in the extracorporeal circulation, at the end of the operation papaverine (T3) had already fallen to just above the limit of detection (mean 4.1 ± 3.9 ng/mL, range 1.3-16.9 ng/mL). At time point T1, a significant negative correlation was determined between plasma levels and systemic diastolic, but not systolic, blood pressure. CONCLUSION: Papaverine was successfully determined systemically in plasma by LC-MS/MS after intraluminal administration in the IMA. Systemic circulatory effects are dependent on the detected quantity. Group size and the absence of a control group are considerable limitations.

[Influence of Perftoran nanoemulsion on blood plasma concentrations of lipophilic drugs].

The influence of perfluorocarbon blood substitute Perfloran on the plasma concentrations of bendazole, drotaverine, ketorolac and verapamil upon intravenous introduction after Perfloran infusion (5 ml/kg) has been investigated on rabbits. It has been found that the plasma concentrations of verapamil, drotaverine and bendazole (highly lipophilic drugs with log(P) = 4.5, 4.9 and 3.5, respectively) increased in the presence of Perfloran. The influence of Perfloran on the concentration of weakly lipophilic ketorolac was less significant. Perfloran effectively bound drotaverine, ketorolac and verapamil in vitro, whereas the binding of ketorolac by the emulsion particles was weak. Evidently, the infusion of hydrophobic nanoemulsion Perftoran elevates the sorption capacity of plasma and creates prerequisites for the redistribution drugs and favors increase in their concentrations.

Biopharmaceutical characterization of some new papaverine decomposition products.

2,3,9,10-Tetramethoxy-12-oxo-12-H-indolo[2,1-a]isoquinolinium chloride 1 (compound X) and 13-(3,4-dimethoxyphenyl)-2,3,8,9-tetramethoxy-6a, 12a-diazadibenzo[a,g] fluorenylium chloride 2 (compound NF) are new papaverine oxidation products. A solution of compound 1 bleaches on addition of sodium hydroxide solution. A new entity, 2-(2-carboxy-4,5-dimethoxyphenyl)-6,7-dimethoxyisoquinolinium inner salt 3 (compound WP), is formed. The physico-chemical properties of compounds 1-3, such as solubility in water and lipophilicity, have been measured. The IC50 for compounds 1 and 3 was also assessed.

Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation.

Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC(50) values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [(11)C]papaverine and the in vitro and in vivo evaluation of [(11)C]papaverine as a potential positron emission tomography (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with (11)C was achieved by O-methylation of the corresponding des-methyl precursor with [(11)C]methyl iodide. [(11)C]papaverine was obtained with approximately 70% radiochemical yield and a specific activity >10 Ci/mumol. In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [(11)C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [(11)C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [(11)C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [(11)C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.

Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine.

RATIONALE: Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. In rats, PPI deficits induced by dopamine (DA) agonists are reversed by antipsychotics. Inhibition of the striatum-rich phosphodiesterase (PDE)10A may represent a novel antipsychotic mechanism. Previous studies were controversial, showing antipsychotic-like profiles in measures of PPI for the preferential PDE10A inhibitor papaverine (PAP) but not the novel PDE10A inhibitor TP-10. OBJECTIVE: The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI. MATERIALS AND METHODS: PPI deficits were induced in rats by apomorphine (APO; 0.1, 0.5 mg/kg) or D: -amphetamine (AMPH; 4 mg/kg). PAP (3, 10, 30 mg/kg) or haloperidol (HAL; 0.1 mg/kg) was tested against these agonists in Sprague-Dawley (SD) or Wistar (WI) rats. Prepulse intervals ranged from 10 to 120 ms. Further tests evaluated the effects of PAP on spontaneous locomotion, AMPH (1 mg/kg)-induced hyperlocomotion, and core body temperature (T degrees ). RESULTS: HAL reversed APO-induced PPI deficits but PAP failed to reverse APO- and AMPH-induced PPI deficits at all doses, strains, pretreatment times, and prepulse intervals. PAP (30 mg/kg) significantly reduced AMPH hyperlocomotion in SD rats, and a similar pattern was detected in WI rats. This PAP dose also strongly reduced spontaneous locomotion and T degrees in SD rats. CONCLUSION: Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.

Disruption of the blood-brain barrier by intra-arterial administration of papaverine: a technical note.

INTRODUCTION: Various endovascular techniques can be used to treat cerebral vasospasm after aneurysmal subarachnoid haemorrhage (SAH) including intra-arterial administration of vasodilator drugs such as papaverine or nicardipine and balloon dilatation of the affected vessel segment. Papaverine is known to have side effects, and we report a possible new one. MATERIALS AND METHODS: After the treatment of cerebral vasospasm in a SAH patient by intra-arterial administration of papaverine into the left posterior cerebral artery, severe mesencephalic extravasation of blood and contrast media was detected. RESULTS: After reviewing the literature, the authors conclude that interruption of the blood-brain barrier by papaverine most likely combined with a secondary hyperperfusion phenomena, and perhaps a direct toxic effect on brain tissue was the mechanism of this major complication. CONCLUSION: In treating vasospasm in areas with a high density of perforating arteries, especially in the posterior circulation, papaverine should be used cautiously because a safe regimen has yet to be established. In this situation, alternative agents such as calcium channel blockers could be considered, but evidence-based data are still missing.

[Absorption of papaverine, laudanosine and cepharanthine across human intestine by using human Caco-2 cells monolayers model].

Absorption of papaverine (PAP), laudanosine (LAU) and cepharanthine (CEP) as some chemical constituents of traditional Chinese medicines in human intestine were studied. By using Caco-2 (the human colonic adenocarcinoma cell lines) cell monolayers as an intestinal epithelial cell model, the permeability of PAP, LAU and CEP were studied from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. The three alkaloids were measured by reversed-phase high-performance liquid chromatography coupled with UV detector. Transport parameters and apparent permeability coefficients (Papp) were then calculated and compared with those of propranolol as a control substance of high permeability and atenolol as a control substance of poor permeability. The Papp values of PAP, LAU and CEP were (3.524+/-0.223) x 10(-5), (2.821+/-0.050) x 10(-5) and (6.524+/-0.052) x 10(-5) cm s(-1) from AP side to BL side, and (5.095+/-0.508) x 10(-5), (2.646+/-0.146) x 10(-5) and (5.495+/-0.036) x 10(-5) cm s(-1) from BL side to AP side, respectively. Their Papp values were identical with those of propranolol, which is a transcellular transport marker. On the other hand, the efflux transport of PAP was 1.45 times higher than its influx transport with 0.69 rate of P(app A-->B)/P(app B-->A). But P(app A-->B)/P(app B-->A) values of LAU and CEP were 1.07 and 1.19, respectively, which suggested that the efflux transport have not been involved in their absorbed mechanism in Caco-2 cells monolayers. There is a good correlation between the Papp value and apparent distribution coefficient (Log D) at pH 7.35 for the three alkaloids. PAP, LAU and CEP can be absorbed across intestinal epithelial cells, and they are completely absorbed compounds. PAP may have been involved in efflux mechanism in Caco-2 cells monolayers model from the basolateral-to-apical direction. The O/W (oil/water) partition coefficient plays key role in their transmembrane permeation.

Dopamine D1 receptor imaging in the rodent and primate brain using the isoquinoline +-[11C]A-69024 and positron emission tomography.

In vivo pharmacokinetic and brain binding characteristics of (+)-[(11)C]A-69024, a high-affinity-D1-selective dopamine receptor antagonist, were assessed with micro-PET and beta-microprobes in the rat and PET in the baboon. The biodistribution of (+)-[(11)C]A-69024 in rats and baboons showed a rapid brain uptake (reaching a maximal value at 5 and 15 min postinjection in rats and baboons, respectively), followed by a slow wash out. The region/cerebellum concentration ratio was characterized by a fourfold higher uptake in striatum and a twofold higher uptake in cortical regions, consistent with in vivo specific binding of the radiotracer in these cerebral regions. Furthermore, this specific (+)-[(11)C]A-69024 binding significantly correlated with the reported in vitro distribution of dopamine D1-receptors. Finally, the specific uptake of the tracer in the striatum and cortical regions was completely prevented by either a pretreatment with large doses of nonradioactive (+/-)A-69024 or of the D1-selective antagonist SCH23390, resulting in a similar uptake in the reference region (cerebellum) and in other brain regions. Thus, (+)-[(11)C]A-69024 appears to be a specific and enantioselective radioligand to visualize and quantify brain dopamine D1 receptors in vivo using positron emission tomography.

Tissue distribution of moxaverine-hydrochloride in the rabbit eye and plasma.

OBJECTIVE: The aim of this study was to determine the tissue distribution and epithelial penetration of moxaverine-hydrochloride (MOX) in the rabbit eye. METHODS: For systemic application, a radioactively labeled MOX solution was injected into the ear vein of Dutch-belted pigmented male rabbits. For topical dosing, an identical solution was administered. At predetermined time points, rabbits were sacrificed, the eyes dissected, and the amount of MOX in the ocular tissues measured. To examine the MOX permeability across the corneal epithelium, transport studies using rabbit corneal epithelial cell culture were conducted and the respective apparent permeability coefficient in absorptive (a to b) or secretive (b to a) direction was calculated. RESULTS: Topical delivery resulted in high concentrations of MOX in the cornea and conjunctiva, although other tissues of the anterior part yielded lower MOX concentrations. In the tissues of the posterior part, high amounts were detected in the retina. Plasma levels were low. The apparent permeability coefficient across corneal epithelial cell layers was in the range of 10(5) cm/s, exhibiting no apparent directionality. CONCLUSION: A topical dosing of MOX to posterior regions of the eye seems feasible. MOX levels in the posterior part of the eye were remarkably high, without causing stringent plasma levels. The high apparent permeability coefficient of MOX across the corneal epithelial cell layers might be caused by the lipophilic nature of the drug and was in the range of other compounds with comparable physicochemical properties.

Bioavailability study of drotaverine from capsule and tablet preparations in healthy volunteers.

The bioavailability of drotaverine (CAS 14009-24-6) was investigated after oral administration of a drotaverine capsule preparation (20 mg Droxa mite) and compared to that of a reference tablet preparation. The preparations were investigated in 23 healthy volunteers, aged between 20 and 27 years, according to a randomised two-way, cross-over design in the fasted state. Blood samples for determination of drotaverine plasma concentrations were collected at pre-defined time points up to 30 h following drug administration. A washout period of two weeks separated both treatment periods. Drotaverine plasma concentrations were determined by means of a validated HPLC method (UV detector, imipramine HCl salt as an internal standard). The limit of detection was 6 ng/ml. Values of 1593.92 +/- 949.70 ng x h/l (95% confidence interval (CI): 1183.20-2004.60) for the test and 1705.48 +/- 737.78 ng x h/l (95% CI: 1386.40-2024.50) for the reference preparation AUC(0-infinity) demonstrate a nearly identical extent of drug absorption. Maximum concentrations--Cmax of 121.89 +/- 37.03 ng/ml (95% CI: 104.05-139.80) and 121.85 +/- 37.97 ng/ml (95% CI: 107.09-135.74) and time to reach maximum plasma concentration--Tmax of 1.29 +/- 0.42 h (95% CI: 1.11-1.48) and 1.14 +/- 0.34 h (95% CI: 0.99-1.29) achieved for the test and reference preparations did not differ significantly. The relative bioavailability (AUC(0-infinity) ratio test/reference) and Cmax ratio test/reference were 103.15% (90% CI: 81.68-124.60) and 103.74% (90% CI: 94.10-113.38), respectively. AUC was calculated using two different methods. There were no significant differences between the obtained values. Since the 90% CI for both, AUC and Cmax ratios were within the 80-125% interval proposed by the European Agency for the Evalution of Medicinal Products (CPMP) and the Food and Drug Administration, it is concluded that the new drotaverine capsule formulation is therapeutically equivalent to the conventional formulation for both, the extent and the rate of absorption after single dose administration in healthy volunteers.

Effects of crystalline microstructure on drug release behavior of poly(epsilon-caprolactone) microspheres.

This study investigates the release behavior of papaverine from poly(epsilon-caprolactone) (PCL) microparticles prepared by the oil/water solvent evaporation method. Microparticles were characterized in terms of crystalline morphology, size, drug loading, and encapsulation efficiency by using differential scanning calorimetry (DSC), small angle X-ray scattering (SAXS), scanning electron microscopy (SEM), and UV spectrometry. The release behavior of papaverine was governed by the microstructure of PCL microparticles, suggesting that the environment for diffusion changes according to processing conditions such as polymer solution concentration, thermal history, and polymer molecular weight. As the PCL solution concentration increased, the drug release behavior showed a more sustained pattern. This result indicates that the size of the PCL microparticles is a determining factor for drug release. And when higher PCL molecular weight is used for preparation of microparticles, it led to a rapid release. Furthermore, a more delayed pattern of drug release profile was obtained in the sample prepared with higher thermal treatment. These results suggest that the crystalline microstructure of PCL microparticles plays an important role in its drug release behavior.

[Experimental study on enhancement of tissue expansion with papaverine cream].

OBJECTIVE: To evaluate the effect of external use of papaverine cream on enhancement of tissue expansion. METHODS: 8 mini pigs were randomly divided into 4 groups. During inflation, papaverine was given externally in group A, through a delivery system in group B, though intramuscular injection in group C. Papaverine was not given in group D. The time of inflation, the expansion rate, the surviving length of expanded flaps and the papaverine concentration in the fibrous capsule in each group were examined. Histologic and electroscope examinations of the expanded tissue were made. RESULTS: The average inflation time was 28.9 +/- 4.5 days in group A, 34.0 +/- 2.6 days in group B, 37.6 +/- 4.8 days in group C and 38.5 +/- 3.5 days in group D. There was significant difference between each group(P < 0.05). The average surviving length of expanded flaps in group A was 13.67 +/- 1.28 cm, 11.07 +/- 0.88 cm in group B, 10.79 +/- 0.49 cm in group C, and 9.49 +/- 0.77 cm in group D. There was significant difference between each group (P < 0.01). Histologic examinations of the expanded tissue suggested that there were no significant differences in thickness of epidermis, derma and fibrous capsule among the four groups. Electroscope examinations of the myofibroblast in fibrous capsule showed that there were smaller nuclei, fewer microfilaments and fewer mitochondrias and rougher endoplastic reticulume in group A than those in other groups. The concentration of papaverine in fibrous capsule of group A was 3.5 +/- 1.2 micrograms/g. Papaverine was detected neither in the skin of other groups nor in the blood of all groups. CONCLUSIONS: 1. Papaverine cream can permeate through skin and maintain high concentration and continuous effect in local tissue. 2. External use of papaverine cream can inhabit the function of myofibroblast in fibrous capsule, increase inflation rate, accelerate expansion process, and improve microcirculation of the expanded skin with a result of prolongation of surviving length of expanded flaps. 3. The technique of enhancing tissue expansion with external use of papaverine has the advantages of convenient delivery, cheapness, no more injury and infection, and no side effects etc. It is a safe, effective, simple, and reliable method for accelerating tissue expansion.

(+)-[76Br]A-69024: a non-benzazepine radioligand for studies of dopamine D1 receptors using PET.

(+)-[76Br]A-69024 is a specific and enantioselective dopamine D1 receptor radioligand. The Bmax of (+)-[76Br]A-69024 measured in vitro on rat striatum membranes was 320 +/- 25 fmoles/mg protein with an apparent dissociation constant of Kd = 0.6 +/- 0.1 nM. The inactive enantiomer, (-)-[76Br]A-69024, displayed no affinity in the same assay. In vivo, the biodistribution (+)-[76Br]A-69024 in rats showed a rapid and high uptake in the striatum (1% ID/g), followed by a slow wash out. The striatum/cerebellum concentration ratio (index of specific binding) reached a maximum value of 10 at 60 minutes post injection. A tissue to cerebellum ratio of 2.8 and 1.5 was also observed for frontal and posterior cortex respectively. With the pharmacologically inactive enantiomer, (-)-[76Br]A-69024, the brain uptake was determined to be non specific since a striatum/cerebellum ratio of approximately 1 was observed throughout the time course of the experiment. The selectivity of (+)-[76Br]A-69024 uptake was demonstrated in competition experiments. The specific uptake in the striatum and cortical regions was completely prevented after administration of the D1 antagonist SCH 23390. Pre-treatment of rats with unlabelled (+)A-69024 also displayed the same regional inhibition of (+)-[76Br]A-69024 uptake. Pre-administration of rats with spiperone (D2) and ketanserin (5-HT2/5-HT2C) showed no inhibitory effect on (+)-[76Br]A-69024 uptake in any brain region. Using (+)-[76Br]A-69024, PET study in baboon demonstrated a preferential accumulation of the radioactivity in the striatum, frontal and posterior cortex which was displaced to the level of the cerebellum by SCH 23390. These results suggest that (+)-[76Br]A-69024 may deserve further investigation as a potential radioligand for studying striatal and cortical dopamine D1 receptors using PET.

[Determination of papaverine hydrochloride in skin and blood and the drug contents in pig skin].

OBJECTIVE: To explore the application of ultraviolet spectrophotometer in determining papaverine hydrochloride content in blood and skin and to determine the intradermal content after local external application of papaverine hydrochloride. METHODS: Phosphate buffer solution (pH = 10, ionic strength = 0.4) was added into the blood or ground skin tissue containing papaverine hydrochloride, and papaverine hydrochloride was extracted with chloroform-hexane mixture (ratio:2:3). After oscillation and centrifugation, partial organic phase was retrieved and dried in 60 degrees C water bath. The dried product was dissolved in 1 mol/L HCl and then underwent filtration through 0.2 micron membrane. The ultraviolet apectrophotometry was applied to determine the content of papaverine hydrochloride in the filtrate. 2% papaverine hydrochloride cream was applied on pig's skin and skin specimen was retrieved at given time to determine the papaverine hydrochloride content in skin tissue with ultraviolet spectrophotometry. RESULTS: The absorbance spectrum of the extract was typical of that of papaverine hydrochloride, with no miscellaneous peak. The extractive rate of papaverine hydrochloride in blood of was more than 92% and that in skin tissue more than 87%. Eight hours after external application of 2% papaverine hydrochloride cream on pig skin, the content of papaverine hydrochloride in skin tissue was more than 90 micrograms/g, significantly higher than the effective concentration of papaverine hydrochloride. CONCLUSIONS: Ultraviolet spectrophotometry is a simple, economical and reliable method for the determination of papaverine hydrochloride content in blood and skin tissue, with good reproducibility and sensibility. External application of papaverine hydrocholine cream can provide efficient permeation and drug concentration in the skin.