In vitro/in vivo functionality of Catapres-TTS

The in vitro and in vivo functionality of Catapres-TTS, a transdermal therapeutic system that delivers the alpha adrenergic receptor agonist clonidine, is discussed in terms of the drug transport kinetics and resultant plasma drug concentration profiles. The design of Catapres-TTS is presented as an optimization by which the best combination of system performance characteristics is obtained within the inherent limitations of the transdermal drug transport properties and the known pharmacokinetic and pharmacodynamic properties of the drug. Clonidine is a potent antihypertensive agent with a relatively low therapeutic index. For Catapres-TTS, the majority of control over the drug input rate resides within the system, rather than within the skin, which significantly reduces the variability in drug input rate and resulting plasma drug concentration both within and between patients. Moreover, the presence of a rate-control element in the system allows for patterning of the drug release rate. An initial bolus of drug is placed in the contact adhesive layer, where its transport into the skin is not inhibited by the rate control element in the system, for reduction in the time needed to achieve steady state drug input. The selection of the loading dose of drug is described as an optimization between the minimization of the lag time and the maintenance of constant plasma drug concentrations during the crossover period between system applications in chronic therapy.     

Evaluation of the legal risk of a ‘missed’ cancer in two breastscreen services

Variation in opinions of medical experts is a problem for both the legal and medical profession. This is particularly relevant in breast imaging. BreastScreen Queensland and New South Wales have developed a review protocol to assess ‘reasonableness’ of radiological opinions. It is hoped that the protocol will be acceptable to the courts and will result in a fair outcome for all parties involved in a medico-legal dispute.     

The effect of substance P and other tachykinins on inositol phospholipid hydrolysis in rabbit retina, superior colliculus and retinal cultures

Substance P and eledoisin stimulate the accumulation of inositol phosphates in a dose-dependent manner in retinal and superior colliculus slices of the rabbit. The EC50 values for substance P and eledoisin in both tissues were of the same order (1.5-4.9 microM), suggesting that the receptors in the two tissues were alike with characteristics of the SP-P subtype rather than the SP-E subtype. These data suggest that the SP-immunoreactive material in the retinal ganglion and amacrine cells is identical. The effectiveness for a number of tachykinin substances at 10(-5) M for stimulating inositol phosphates accumulation was as follows: Substance P greater than eledoisin greater than neurokinin A greater than neurokinin B greater than substance P (octapeptide) greater than substance P (pentapeptide). Spantide [(D-Arg1, D-Try7.9, Leu11) substance P] and (D-Pro2, D-Try7.9) substance P did not stimulate inositol phospholipid hydrolysis. However, spantide, at a concentration of 10(-6) M, was an antagonist of the effect produced by substance P, but had no action on the effect produced by neurokinin A or neurokinin B. Substance P and other tachykinins were also effective in stimulating inositol phosphates accumulation in 3-5-day-old rabbit retinal cultures but did not elicit a response in the older (25-30-day-old) cultures which lacked neurones but contained Müller cells. Furthermore, substance P was only active in the younger cultures in stimulating an increase in internal calcium levels. It is therefore concluded that retinal tachykinin receptors linked to phosphoinositide turnover and calcium mobilisation are associated exclusively with neurones and not with Müller cells.     

Simple non-radioactive detection of the CFTR mutation N1303K by artificial creation of a restriction site.

N1303K is one of the most frequent non-delta F508 mutations causing cystic fibrosis in Central Europe. Since no restriction site is altered by this mutation and no other frequent mutations are known so far in exon 21, the detection requires a separate and laborious test. A mismatched primer was used to create an artificial Hin dIII site in amplified wildtype DNA, which is destroyed by the mutation. This allows for rapid and convenient detection by restriction enzyme digestion.     

TGFβ-1 regulation of VEGF production by breast cancer cells

Background: Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor identified to date. TGFβ-1 acts as an indirect angiogenic agent. Methods: VEGF and TGFβ-1 were measured in the serum of breast cancer patients and agematched controls and in tumor tissue of cancer patients by ELISA. VEGF protein and mRNA expression by breast tumor cell lines were examined, and the effect of TGFβ-1 on VEGF production in these cells was assessed. Results: VEGF levels were significantly higher (P=.03) in the serum of patients with breast cancer compared to age-matched controls. A positive correlation was found between serum (r=0.539) and tumor tissue (r=0.688) levels of VEGF and TGFβ-1. Metastatic MDA-MB-231 breast cancer cells produce more VEGF than do the primary BT474 cells. TGFβ-1 significantly (P<.05) increased production of VEGF. Conclusions: Breast cancer cells constitutively produce VEGF protein and mRNA. There is a relationship between VEGF and TGFβ-1 levels in breast cancer patients, and TGFβ-1 regulates VEGF expression by breast cancer cells. Presented at the 50th Annual Cancer Symposium of the Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

In Vivo Proton Spectroscopy of Intracranial Infections and Neoplasms

The chemical characteristics of 10 neoplastic and 11 infectious brain masses were studied by in vivo ¹H magnetic resonance spectroscopy. In tumors, peak height ratios of n-acetyl-L-aspartate to choline were decreased compared to those in normal brain tissue and infectious masses (p < 0.02), but the ratios in normal brains and those with infections did not differ. N-acetyl-L-aspartate—to-creatine/phosphocreatine ratios were significantly lower in infectious masses and tumors compared to normal brain tissue (p = 0.003). However, in progressive multifocal leukoencephalopathy, N-acetyl-L-aspartate appeared relatively unchanged. Lactate was greater than choline in 9 of 11 brains with infection, 0 of 14 control brains, and 1 of 10 tumors. Lactate-to-choline ratios were significantly elevated in infectious masses compared with tumors (p < 0.01). ¹H magnetic resonance spectroscopy is promising for the noninvasive diagnosis of focal brain masses.     

The bright pituitary gland--a normal MR appearance in infancy

Signal intensities of the pituitary gland were measured on T1-weighted sagittal MR images of 25 patients younger than 20 years old. We found that the signal intensities in the eight patients who were 8 weeks old or younger were higher (shorter T1) than those in the 17 older patients. We also noted a difference in the signal intensities across the pituitary gland, the signal being higher in the posterior part of the gland than in the anterior part. We attribute the high signal intensities to the rapid intrauterine pituitary growth, so that at term pituitary protein synthetic activity is at a maximum. Possibly, an increase in the bound fraction of the water molecules of the gland may also be present in the neonatal pituitary as compared with the older gland, but this remains to be proved. The higher signal in the posterior pituitary gland may be due to lipid in the pituicyte cells of the posterior pituitary gland.     

Invited review: Neuroprotective properties of certain beta-adrenoceptor antagonists used for the treatment of glaucoma.

Although it is known that ganglion cell death causes loss of vision in glaucoma, the pathogenesis of the disease is complex, probably involving an initial ischemic insult to the ganglion cell axons and glial cells with the ganglion cell bodies eventually being affected. It may therefore be necessary to blunt many stages in the pathogenesis of the disease to obtain a clinically effective neuroprotective strategy. In animal experiments, one cause of ganglion cell death in ischemia is an overactivation of glutamate receptors and a subsequent rise in intracellular levels of sodium and calcium ions as well as a generation of reactive oxygen species. In contrast, optic nerve death in ischemia is mainly caused by an influx of sodium and reversal of the sodium/calcium exchanger, which leads to a rise in intracellular calcium. Thus, a substance that reduces the influx of sodium will protect the ganglion cell axon, and if it also reduces calcium influx and/or acts as an antioxidant it will protect the ganglion cell body in addition. Of all antiglaucoma drugs, only beta-blockers have both calcium and sodium channel blocking activity, with betaxolol being the most efficacious of those analyzed. In addition, of the tested ophthalmic beta-blockers only metipranolol has powerful antioxidant properties. Moreover, laboratory studies on rats have shown that topically applied beta-blockers attenuate ischemic injury to ganglion cells by mechanisms that do not appear to involve an action on beta-receptors. Thus, of the substances used to lower intraocular pressure in glaucoma, beta-blockers have unique additional characteristics that also give them the capacity to act as neuroprotectants.