The present study examines the possibility that lesions induced by intrastriatal injections of endothelin-1 (ET-1, 0.43 nmol/0.5 microliter) are ischemic in nature due to a vasoconstriction of the cerebral microvessels. In time course and dose-response experiments with ET-1 and in comparisons with ET-3, the volume of the lesions has been determined based mainly on the disappearance of striatal nerve cells, using a computer assisted morphometrical analysis. The blood flow in the neostriatum close to the site of injection of ET-1 was determined acutely by Laser-Doppler flowmetry. The acute metabolic effects of ET-1 were also studied on striatal superfusate levels of lactate, pyruvate, dopamine and its metabolites DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) using an intrastriatal microdialysis probe. Dose related striatal lesions were observed with ET-1 (0.043-0.43 nmol) with a peak lesion volume after 24-48 h and the possible existence of a penumbra area. ET-3 showed a reduced potency to produce striatal lesions compared to ET-1. The lesions induced by ET-1 were prevented by coinjection with dihydralazine, a vasodilator drug. Acutely ET-1 (0.43 nmol/0.5 microliter) produced a prolonged reduction of the cerebral blood flow down to 40% of control values and temporary increases of striatal lactate and DA efflux, the latter change being very marked. Also a significant reduction of DOPAC and HVA was observed. These neurochemical changes were all prevented by treatment with dihydralazine.(ABSTRACT TRUNCATED AT 250 WORDS)

Different factors limit or enable reclassification, affecting consumer access to medicines in different countries. For countries attempting to reduce barriers to reclassification, solutions may include garnering government support for reclassification, support and flexibility from the medicines regulator, having a pharmacy-only and/or pharmacist-only category, providing market exclusivity, ensuring best practice in pharmacy, and minimizing the cost and delays of reclassification.

BackgroundSwitching or reclassifying medicines with established safety profiles from prescription to non-prescription aims to increase timely consumer access to medicines, reduce under-treatment and enhance self-management. However, risks include suboptimal therapy and adverse effects. With a long-standing government policy supporting switching or reclassifying medicines from prescription to non-prescription, the United Kingdom is believed to lead the world in switch, but evidence for this is inconclusive. Interest in switching medicines for certain long-term conditions has arisen in the United Kingdom, United States, and Europe, but such switches have been contentious. The objective of this study was then to provide a comprehensive comparison of progress in switch for medicines across six developed countries: the United States; the United Kingdom; Australia; Japan; the Netherlands; and New Zealand.MethodsA list of prescription-to-non-prescription medicine switches was systematically compiled. Three measures were used to compare switch activity across the countries: “progressive” switches from 2003 to 2013 (indicating incremental consumer benefit over current non-prescription medicines); “first-in-world” switches from 2003 to 2013; and switch date comparisons for selected medicines.ResultsNew Zealand was the most active in progressive switches from 2003 to 2013, with the United Kingdom and Japan not far behind. The United States, Australia and the Netherlands showed the least activity in this period. Few medicines for long-term conditions were switched, even in the United Kingdom and New Zealand where first-in-world switches were most likely. Switch of certain medicines took considerably longer in some countries than others. For example, a consumer in the United Kingdom could self-medicate with a non-sedating antihistamine 19 years earlier than a consumer in the United States.ConclusionProactivity in medicines switching, most notably in New Zealand and the United Kingdom, questions missed opportunities to enhance consumers' self-management in countries such as the United States.

No abstract

No abstract

No abstract

In order to evaluate rectal administration of salbutamol (SB), five healthy volunteers were dosed orally and rectally with racemic SB (0.1 mg/kg) solution. Compared with the oral SB, the rectal SB gave significantly higher serum SB concentration immediately after dosing but slightly lower levels in the elimination phase. The Cmax following rectal administration was 17.9 ng/ml (17.0 ng/ml for oral administration), the tmax 0.67 h (1.5 h for oral administration) and the AUC 98.2 ng/ml/h (100 ng/ml/h for oral administration). Heart rate also rose more rapidly to a maximum of 70% above baseline values after rectal dosing. The rate continued to be twice larger than after oral dosing for up to 5 h. The concentration versus response curves indicated that rectal SB was more effective than oral SB at increasing heart rate at the same SB concentration in serum. A plausible explanation for this phenomenon might be a difference in the stereo-selective first-pass metabolism of the two enantiomers. Therefore, the rectal dose of SB administered as a suppository for prophylactic treatment of asthma should be lower than that used orally.

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22–38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.