Effect of clonidine to prevent agitation in children after sevoflurane anaesthesia: a randomised placebo controlled multicentre trial.

INTRODUCTION: Post-operative agitation (PA) is a common problem (20-70%) in children anaesthetised with sevoflur-ane. Clonidine is widely used off-label in children for several indications, including PA, but the current level of evidence is limited. Our aim is to investigate the impact of prophylactic intravenous (IV) clonidine administered at the end of surgery on the incidence and degree of PA. Furthermore, the pharmacokinetic profile of IV clonidine in children is not well established and our aim is to obtain pharmacokinetic data relating hereto. METHODS: This is a multicentre, randomised and blinded clinical trial in which we will be enrolling 380 children aged 1-5 years who are planned for anaesthesia with sevoflurane and fentanyl. Inclusion is based on computer-generated randomisation (1:1) and stratified by age and site. The study drug is administered IV approximately 20 min. before the expected completion of surgery (intervention: clonidine 3 µg per kg; placebo: equal quantity of saline). CONCLUSION: The primary outcome is PA measured on the Watcha scale. The secondary outcomes include post-operative pain relief and adverse effects, including a 30-day follow-up. In total, 40 children will be allocated to drug assay sampling, enabling a compartmental pharmacokinetic analysis. FUNDING: Funded by the participating departments and by two unrestricted scientific grants from the Danish Society of Anaesthesia and Intensive. TRIAL REGISTRATION: This study was approved by the Danish Health and Medicines Authority (EudraCT number 2014-001466-10), the Ethics Committee of the Capital Region of Denmark (H-2-2014-072) and registered with Clinicaltrials.gov (NCT02361476).

Effects of sympatholytic therapy on postmenopausal symptoms in hypertensive postmenopausal women.

OBJECTIVE: The short-term effects of two sympatholytic antihypertensive drug treatments, ß-blocking agent atenolol and imidazoline receptor-1 agonist moxonidine, on postmenopausal symptoms and their relationship to antihypertensive and insulin sensitivity effect were studied. DESIGN: This was a double-blind, prospectively randomized study in a multicenter, multinational setting in 112 hypertensive, overweight, postmenopausal women without hormone therapy. METHODS: Treatment was either with moxonidine, 0.6 mg/day, or with atenolol, 50 mg/day, for 8 weeks. The main outcome measures were blood pressure, insulin sensitivity by Matsuda sensitivity index and postmenopausal symptoms (hot flushes, palpitations, insomnia, irritability, depression and general impression of the symptoms (GIS) through a questionnaire. RESULTS: Both atenolol and moxonidine caused a significant reduction in diastolic blood pressure of 9.5 mmHg and 6.2 mmHg, respectively. The severity of hot flushes and palpitations were reduced significantly in both treatment groups. Relief from hot flushes was recorded in 43% of women taking atenolol and in 27% (not significant between the groups) of moxonidine-treated patients. Palpitations were relieved in 41% and 25% (not significant between the groups) of the women in the atenolol- and moxonidine-treated groups, respectively. In the atenolol group, insomnia and GIS were reduced significantly, with relief of symptoms occurring in 33% and 27% of the patients. A change in irritability was seen in blood pressure responders during the treatment in the atenolol group. There was no correlation between improvement of insulin sensitivity and relief of postmenopausal symptoms. CONCLUSIONS: In this study, two sympatholytic antihypertensives, atenolol and moxonidine, provided relief from hot flushes and palpitations, and atenolol additionally helped with insomnia and improved GIS.

Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach.

BACKGROUND/AIMS: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. METHODS: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. RESULTS: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. CONCLUSION: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.

Comparative pharmacokinetics and pharmacodynamics of tablet, suspension and paste formulations of atenolol in cats.

This study compared the pharmacokinetic and pharmacodynamic profiles of an extemporaneously prepared (compounded) atenolol paste and suspension for oral administration, against the commercially available divided tablet in healthy cats. Eleven healthy cats (mean: age 4 ± 0.4 year, weight 5.0 ± 0.7 kg) were dosed twice-daily with 12.5 mg atenolol (tablet, paste or suspension) for 7 days in a randomized cross-over design with a 7-day wash-out period. On day 7, an electrocardiogram was performed before and immediately after stress provocation (jugular venipuncture) at prestudy screening, and at 2, 6 and 12 h after morning dosing. Systolic arterial blood pressure (BP) was assessed following the second electrocardiogram. Plasma was collected at prestudy screening, and at 1, 2, 6 and 12 h to measure atenolol plasma concentrations. Mean atenolol dose was 2.5 mg/kg (range: 2.1-3.3 mg/kg). Stress-induced rise in heart rate was attenuated (P < 0.05) at every time point compared to baseline for all formulations. Although the paste significantly attenuated stress-induced elevation in heart rate at all time points, the effect was not consistently equivalent to the tablet. The BP was not altered (P > 0.05) at any time point by any formulation. In conclusion, there were no significant differences (P > 0.05) in any of the pharmacokinetic parameters or pharmacodynamic profiles of the paste and suspension compared to the commercially available tablet.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects neurons and repairs the Parkinson disease-like symptoms in a rat 6-hydroxydopamine model. We show a three-dimensional solution structure of human MANF that differs drastically from other neurotrophic factors. Remarkably, the C-terminal domain of MANF (C-MANF) is homologous to the SAP domain of Ku70, a well known inhibitor of proapoptotic Bax (Bcl-2-associated X protein). Cellular studies confirm that MANF and C-MANF protect neurons intracellularly as efficiently as Ku70.

Enantioselective pharmacokinetic-pharmacodynamic modelling of carvedilol in a N-nitro-l-arginine methyl ester rat model of secondary hypertension.

OBJECTIVES: The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic-pharmacodynamic (PK-PD) modelling. METHODS: Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L-NAME rats received L-NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK-PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. KEY FINDINGS: A dose-dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S-carvedilol as compared with the R-enantiomer was found in both experimental groups. Although the PK-PD properties of the S-carvedilol chronotropic effect were not altered in L-NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L-NAME rats. CONCLUSIONS: Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L-NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.

N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a "chemical knock-out equivalent" to assess the impact of efflux transporters on oral drug absorption in the rat.

The utility of the diaminoquinazoline derivative CP-100,356 as an in vivo probe to selectively assess MDR1/BCRP-mediated drug efflux was examined in the rat. CP-100,356 was devoid of inhibition (IC(50) >50 microM) against major human P450 enzymes including P4503A4. In human MDR1-transfected MDCKII cells, CP-100,356 inhibited acetoxymethyl calcein (calcein-AM) uptake (IC(50) approximately 0.5 +/- 0.07 microM) and digoxin transport (IC(50) approximately 1.2 +/- 0.1 microM). Inhibition of prazosin transport (IC(50) approximately 1.5 +/- 0.3 microM) in human BCRP-transfected MDCKII cells by CP-100,356 confirmed the dual MDR1/BCRP inhibitory properties. CP-100,356 was a weak inhibitor of OATP1B1 (IC(50) approximately 66 +/- 1.1 microM) and was devoid of MRP2 inhibition (IC(50) >15 microM). In vivo inhibitory effects of CP-100,356 in rats were examined after coadministration with MDR1 substrate fexofenadine and dual MDR1/BCRP substrate prazosin. Coadministration with increasing doses of CP-100,356 resulted in dramatic increases in systemic exposure of fexofenadine (36- and 80-fold increase in C(max) and AUC at a CP-100,356 dose of 24 mg/kg). Significant differences in prazosin pharmacokinetics were also discernible in CP-100,356-pretreated rats as reflected from a 2.6-fold increase in AUC. Coadministration of CP-100,356 and P4503A substrate midazolam did not result in elevations in systemic exposure of midazolam in the rat. The in vivo methodology should have utility in drug discovery in selective and facile assessment of the role of MDR1 and BCRP efflux transporters in oral absorption of new drug candidates.

Use of oral clonidine for sedation in ventilated paediatric intensive care patients.

OBJECTIVES: We aimed to document our experience with oral clonidine when used as a sedative in combination with intravenous morphine and lorazepam in a group of mechanically ventilated children with single-organ, respiratory failure. In particular, our objectives were to establish the relationship between oral dose, plasma concentration, and sedative effect, and second, to document the side-effect profile. DESIGN: Prospective, cohort study over a 72-h period. SETTING: Regional paediatric intensive care unit. PATIENTS AND PARTICIPANTS: Twenty-four children were enrolled (median age 3 months) of whom ten were excluded (six due to extubation before 72 h, three sedation failures, one protocol violation). MEASUREMENTS AND RESULTS: Plasma clonidine was measured using gas chromatography mass spectrometry, and sedation assessed using the COMFORT score. Using a dose of 3-5 microg/kg every 8 h, plasma concentrations appeared to plateau at approximately 41 h giving a mean value of 1.38 ng/ml (95% confidence interval 1.0-1.8). Adequate sedation was achieved during 82% (837/1022 h) of the study period; however, this decreased to 70.3% when analysed on an intention-to-treat basis. There was a concomitant overall decrease in the average hourly requirements for both morphine ( P = 0.02) and lorazepam ( P = 0.003). There were no documented episodes of bradycardia, hypotension or hyperglycaemia. CONCLUSIONS: Oral clonidine may be a safe and effective sedative in combination with morphine and lorazepam for young children with single-organ, respiratory failure. This agent may also exhibit opioid and benzodiazepine sparing effects in this patient group. A full pharmacokinetic study is warranted.

The role of thoracic epidural analgesia in cardiac surgery

It is suggested that TEA improves the myocardial metabolic supply and demand relationship and thereby affords myocardial protection. This is supported by a reduction in myocardial stunning and infarct size in animal models and by improved perioperative hemodynamic stability and reduced markers of ischemic injury in clinical studies. Other beneficial effects include reliable stress response attenuation with a reduction in postoperative analgesia resulting in improved pulmonary function following cardiac surgery. It is furthermore clear that to achieve improved outcome, it is essential that the use of TEA be extended well into the postoperative period as an analgesic component of a multimodal postoperative approach, which should also include such things as early enteral feeding and mobilization. However, because of the potential risk of epidural hematoma, with possible permanent neurological injury, it is essential that the use of TEA be justified through studies showing improved outcomes (e.g., reduced major myocardial events and improved graft patency). This will require large, well-designed multicenter clinical trials and an international registry for complications. Until then, it is essential that epidural anesthesia during cardiac surgery be used cautiously, following recommended guidelines

Evaluation of USP apparatus 3 for dissolution testing of immediate-release products.

We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f(2) similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.

Astroglial and microglial reaction after a partial nigrostriatal degeneration induced by the striatal injection of different doses of 6-hydroxydopamine.

Astroglial and microglial activation was analyzed in adult male Wistar rats after a unilateral striatal injection of different doses (8, 4 and 1 micrograms) of 6-hydroxydopamine (6-OHDA). Control animals received the injection of the same volume of the solvent. The rotational behavior was registered by a rotometer 24 and 72 hours, 7, 10, 14 and 22 days after lesion. Following, animals were sacrificed and the tyrosine hydroxylase (TH) positive dopamine cells, the glial fibrillary acidic protein (GFAP) immunolabeled astrocytes and the OX42 immunoreactive microglia were visualized by mean of immunohistochemistry and quantified by stereologic method employing the optical disector and the point intercepts. The apomorphine (0.5 mg/kg)-induced circling behavior was seen only after 8 micrograms of 6-OHDA from 72 hours postlesion until sacrifice. Decreases of the TH immunoreactive terminals and cell bodies were found in the sampled fields of the striatum and pars compacta of the substantia nigra (SNc), respectively, after 8 and 4 micrograms of 6-OHDA. The GFAP immunohistochemistry revealed increases in the number/density of astroglial cells in the ipsilateral neostriatum (137% of control) and ipsilateral SNc (83% of control) and also in the volumeal fraction of the astroglial processes in the ipsilateral neostriatum (30% of control) and ipsilateral SNc (38% of control) in the rats with higher dose of the neurotoxin. Increases in the number of OX42 microglial labeled profiles and in the volumeal fraction of microglial processes were found in the ipsilateral neostriatum (67% and 27%, respectively, of control) and ipsilateral SNc (100% and 50%, respectively, of control) in the 8 micrograms 6-OHDA injected rats. These results suggest that the retrograde degeneration induced by a intrastriatal injection of a small dose of the 6-OHDA leads to an astroglial and microglial reaction in the nigrostriatal dopamine pathway. The interaction between activated glial cells may be involved in the wounding and repair events in the partial lesioned nigrostriatal system as well as in the paracrine responses to surviving dopamine neurons.

Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects.

OBJECTIVE: To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects. METHODS: A single 40-mg dose of paroxetine was administered orally to one poor metabolizer and 15 healthy subjects recruited from 223 Korean extensive metabolizers whose phenotypes were predetermined by use of the metoprolol MR. Genotypes were determined by allele-specific polymerase chain reaction and the GeneChip microarray technique. Pharmacokinetic parameters were estimated from plasma concentrations of paroxetine for more than 240 hours after the oral dose. RESULTS: The oral clearance and area under the plasma concentration versus time curve (AUC) of paroxetine were best described by a nonlinear relationship with metoprolol MR at correlation coefficients of 0.82 and 0.91, respectively (P < .05). Nine extensive metabolizer who were either homozygous or heterozygous for CYP2D6*10B had significantly lower oral clearance values of paroxetine than six extensive metabolizers with CYP2D6*1/*1. The AUC of paroxetine in subjects who were homozygous for CYP2D6*10B (666.4 +/- 169.4 ng/mL x h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 +/- 55.9 ng/mL x h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 +/- 816.9 ng/mL x h) than that of subjects who were homozygous CYP2D6*10B/*10B mainly because of two atypical subjects whose metoprolol MR was not associated with the CYP2D6*10B genotype and who showed greater AUC and lower oral clearance than subjects with homozygous CYP2D6*10B. CONCLUSIONS: The CYP2D6 activity measured by metoprolol MR was a strong predictor of paroxetine disposition in Korean extensive metabolizers. In general, the extensive metabolizers with the CYP2D6*10B allele seemed to have higher plasma concentrations of paroxetine than extensive metabolizers with the wild-type CYP2D6 genotype. However, quantitative prediction of paroxetine disposition from the CYP2D6*10B genotype alone was not perfect because several Korean extensive metabolizers had metoprolol MRs that were not associated with the genotype.

Transport and metabolic characterization of Caco-2 cells expressing CYP3A4 and CYP3A4 plus oxidoreductase.

PURPOSE: To further characterize CYP3A4-transfected Caco-2 cells with regard to morphological, transport, and metabolic properties, and to evaluate a different Caco-2 cell strain transfected with both CYP3A4 and oxidoreductase (OR). METHODS: Transfected Caco-2 cells, Caco-2 TC7 cells, and wild-type Caco-2 cells grown onto Millicell were used. We determined the morphological characteristics of transfected cell monolayers using light and transmission electron microscope. We determined the transport and metabolic capabilities of the transfected cells, TC7 cells, and wild-type cells with a variety of drugs, nutrients, and marker compounds. RESULTS: The transfected Caco-2 cells formed a tight monolayer with TEER values and mannitol transport similar to the untransfected parent cell strain (wild type). However, the transfected cells (grown onto Millicell) reached maturity approximately 33% faster than the wild-type cells. Permeabilities of propranolol, nifedipine, testosterone, linopirdine, mannitol, and cephalexin were similar in transfected and wild-type Caco-2 cells. On the other hand, the transfected cells of early passages were much more metabolically active, and metabolized standard CYP3A4 substrates (e.g., testosterone and nifedipine) as much as 100 times faster than untransfected cells. In addition, metabolism of standard substrates was inhibitable by ketoconazole and TAO. Using comparable data, the transfected cells metabolized testosterone the fastest, followed by linopirdine and nifedipine (approximate ratio: 10:6:2). The metabolites of standard substrates were generally preferably excreted to the apical membrane. CONCLUSION: The monolayers of newly transfected cells (CYP3A4 + OR) have a significantly increased level of CYP3A4 activities compared to untransfected cells. These cell monolayers also have desirable morphological and transport characteristics that are similar to untransfected cells.

Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6.

BACKGROUND AND OBJECTIVES: Drug metabolism is influenced by liver disease because of the central role that the liver plays in metabolic activities in the body. However, it is still unclear how activities of specific drug-metabolizing enzymes are influenced by the presence and severity of liver disease. As a consequence, alteration in metabolism of specific drugs cannot be easily predicted or appropriate dosage adjustment recommendations made. METHODS: The activities of cytochromes P450 (CYP) 2C19 and 2D6 were investigated in a group of patients with mild or moderate liver disease (n = 18) and a group of healthy control subjects (n = 10). The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours. RESULTS: The elimination of S-mephenytoin was severely reduced among patients with liver disease, resulting in a 79% decrease in plasma clearance for all patients combined. This reduction was related to the severity of disease, patients with moderate disease being affected more severely than patients with mild disease. Similar differences were observed in the urinary excretion of 4'-hydroxymephenytoin metabolite. By contrast, there was no effect on the disposition of R-mephenytoin or debrisoquin. CONCLUSION: These results show selectivity in the effect of liver disease on activities of specific metabolizing enzymes, CYP2C19 being more sensitive than CYP2D6. They suggest that recommendations for modification in drug dosage in the presence of liver disease should be based on knowledge of the particular enzyme involved in metabolism of the drug. The results emphasize the need for further studies of each specific drug-metabolizing enzyme in the presence of liver disease.

The effects of aging on anesthetic pharmacology.

Aging alters both the pharmacokinetic and the pharmacodynamic aspects of anesthetic requirement. Studies of the relationship between drug concentration and effect in older adults clearly demonstrate a decline in median effective dose requirement for agents that act within the central nervous system, but there appears to be little change in the dose required for peripheral effects such as neuromuscular blockade. Most drugs also undergo somewhat slower biotransformation and demonstrate prolonged clinical effects if they require hepatic or renal degradation, although many newer agents such as remifentanil and cisatracurium have organ-independent pathways that are not affected by age. In some cases, however, the appearance of increased sensitivity to a given dose of anesthetic or opiate may actually reflect higher-than expected plasma concentrations of drug following a rapid intravenous injection. Therefore, it is impossible to completely separate the interactions between pharmacodynamic and pharmacokinetic factors associated with aging. The use of pharmacological sympathectomy with intrathecal agents and with sympatholytic adrenergic agonists may further improve outcome in a patient population at high risk because of reduced functional reserve, increased incidence of polypharmacy, and the consequences of age-related disease.

Decreased myocardial 123I-MIBG uptake in Parkinson's disease.

We studied myocardial 123I-metaiodobenzylguanidine (MIBG) accumulation in 12 patients with Parkinson's disease (PD). MIBG is an analog of norepinephrine (NE) and a tracer for sympathetic neuron integrity and function. MIBG uptake of the myocardium was significantly lower in PD than in controls. The heart to mediastinum ratio (H/M) was calculated by using the average count per pixel for the heart and mediastinum. In PD, H/M was lower than in controls (P<0.0001), while the washout ratio of the heart was higher (P<0.001). A decrease in myocardial accumulation of MIBG was observed in the early stage of PD. This suggests that the measurement of MIBG may help the diagnosis of early PD, and the causative factor underlying in PD may be operating the NE neuron as well as dopamine neuron.

Impaired cardiac uptake of meta-[123I]iodobenzylguanidine in Parkinson's disease with autonomic failure.

OBJECTIVE: To selectively investigate postganglionic sympathetic cardiac neurons in patients with Parkinson's disease and autonomic failure. MATERIAL AND METHODS: Metaiodobenzylguanidine (MIBG) is a pharmacologically inactive analogue of noradrenaline, which is similarly metabolized in noradrenergic neurons. Therefore the uptake of radiolabelled MIBG represents not only the localization of postganglionic sympathetic neurons but also their functional integrity. Ten patients with Parkinson's disease and autonomic failure underwent standardized autonomic testing, assessment of catecholamine plasma levels and scintigraphy with [123I]MIBG. RESULTS: The cardiac uptake of MIBG, as demonstrated by the heart/mediastinum ratio, was significantly lower in patients in comparison with controls. Scintigraphy with MIBG allowed the selective in-vivo investigation of postganglionic sympathetic cardiac efferents in patients with autonomic failure, a procedure which was previously confined to post-mortem examination. CONCLUSION: These findings point to a relevant postganglionic pattern of involvement of the autonomic nervous system (ANS) in Parkinson's disease and autonomic failure.

Ocular absorption of Pz-peptide and its effect on the ocular and systemic pharmacokinetics of topically applied drugs in the rabbit.

PURPOSE: To determine the corneal and conjunctival penetration of 4-phenylazobenzyloxycarbonyl-L-Pro-L-Leu-Gly-L-Pro-D-Arg (Pz-peptide) and to evaluate its effect on the corneal and conjunctival penetration of hydrophilic solutes as well as on the ocular and systemic absorption of topically applied atenolol and propranolol in the rabbit. The hydrophilic solutes were mannitol, fluorescein, FITC-dextran 4,000, and FITC-dextran 10,000. METHODS: Drug penetration across the rabbit cornea and conjunctiva was evaluated using the modified Ussing chamber. Ocular and systemic absorption of topically applied atenolol and propranolol was evaluated by analyzing the drug concentration in various anterior segment tissues at 45 min and in the blood over 240 min, respectively, following topical instillation of 25 microl of 20 mM atenolol or propranolol solution to the rabbit eye. RESULTS: The conjunctiva was 29 times more permeable than the cornea to 3 mM Pz-peptide. Conjunctival Pz-peptide transport was 1.7 times more extensive in the mucosal-to-serosal than in the opposite direction, whereas corneal Pz-peptide transport showed no directionality. The apparent permeability coefficient of Pz-peptide across the cornea and the conjunctiva increased over the 1-5 mM range, suggesting that Pz-peptide enhanced its own transport across both epithelial tissues. The cornea appeared to be more sensitive than the conjunctiva to the penetration enhancement effect of Pz-peptide. Thus, whereas Pz-peptide elevated the corneal transport of mannitol, fluorescein, and FD4 by 50%, 57%, and 106%, respectively, it did not affect the conjunctival transport of mannitol and fluorescein, while enhancing FD4 transport by only 46%. Moreover, while Pz-peptide enhanced the ocular absorption of topically applied hydrophilic atenolol, it did not affect the ocular absorption of lipophilic propranolol. Interestingly, Pz-peptide did not affect the systemic absorption of either beta adrenergic antagonist. CONCLUSIONS: Pz-peptide appears to facilitate its own penetration across the cornea and the conjunctiva. Pz-peptide appears to increase the ocular absorption of topically applied hydrophilic but not lipophilic drugs, while not affecting the systemic absorption of either type of drugs.

Cardiac sympathetic nerve function assessed by [131I]metaiodobenzylguanidine after ischemia and reperfusion in anesthetized dogs.

BACKGROUND: Accumulation of 131I-labeled metaiodobenzylguanidine ([131I]MIBG), a radiolabeled norepinephrine analog, is reduced in infarcted myocardium, suggesting loss of cardiac sympathetic nerve viability. Histopathologic studies, however, indicate that the nerve endings ae morphologically intact. Experiments were therefore designed to determine the mechanism of reduced MIBG accumulation. METHODS AND RESULTS: Desipramine, a specific blocker or neuronal norepinephrine reuptake, was used to separate the portions of total myocardial [131I]MIBG accumulation attributable to neuronal and nonneuronal uptake mechanisms. Sixteen dogs underwent circumflex coronary artery occlusion for 60 minutes followed by a 5-hour reperfusion. [131I]MIBG was injected intravenously 1 hour after reperfusion. The left ventricle was removed and incubated in triphenyltetrazolium chloride to identify infarcted and viable myocardium within the zone at risk. Preliminary studies in sham-operated dogs showed that pretreatment with desipramine (5 mg/kg) reduced [131I]MIBG accumulation 4 hours after injection to 38.9% of untreated controls. Chemical sympathectomy by topical phenol resulted in a similar decrease in [131I]MIBG accumulation (to 45.7% of normal), and desipramine did not produce further inhibition of [131I]MIBG accumulation over that produced by phenol alone, indicating that the inhibitory effect of desipramine on neuronal accumulation of [131I]MIBG was essentially complete. In dogs undergoing ischemia-reperfusion, myocardial samples from infarcted and viable postischemic areas showed 64.5% +/- 11.85 and 84.7% +/- 9.1% of normal [131I]MIBG activity, respectively (both, p < 0.01 vs normal area, n = 9). With desipramine pretreatment (n = 7), accumulation of [131I]MIBG decreased in all areas. Neuronal accumulation was reduced uniformly in infarcted, viable postischemic, and normal areas by 30% to 35% compared with sham-operated controls. In contrast, nonneuronal accumulation was only 39.3% in infarcted areas and 84.6% in viable postischemic areas compared with normal areas, and these decreases accounted entirely for the reduced total [131I]MIBG accumulation. CONCLUSIONS: Reduced [131I]MIBG accumulation in infarcted myocardium after 60 minutes of ischemia and 5 hours of reperfusion is attributable to a deficit in nonneuronal accumulation and not to decreased accumulation by sympathetic nerves.