Ultrastructural features of NPY-containing neurons in the rat striatum

In the present study, we examined the ultrastructure of striatal neurons containing neuropeptide Y (NPY) which were labeled by an immunohistochemical method using peroxidase-conjugated F(ab) fragments in the rat. Each of the 26 neurons identified had a deeply indented oval nucleus. The cytoplasm, which was mainly concentrated at the emergence of the dendrites, contained an abundant Golgi apparatus and a well-developed granular endoplasmic reticulum. Dendrites were poorly branched and rarely exhibited varicosities or dendritic spines. NPY-immunoreactive (Ir) axons were small in diameter and unmyelinated. These features corresponded to a subpopulation of striatal neurons classified as aspiny type IV in previous Golgi studies. Axon terminals forming symmetrical synapses were numerous on the NPY-Ir perikarya and proximal dendrites. On distal NPY-Ir dendrites, synaptic contacts were mainly of the asymmetrical type, suggesting that NPY neurons are contacted by at least 2 categories of afferent fibers. Several NPY-Ir axonal processes and boutons were found to form symmetrical synapses with dendrites, dendritic spines and perikarya belonging to spiny type neurons. These data were consistent with the view that NPY may act as a neurotransmitter of striatal interneurons. Moreover, the frequent observation of NPY axonal processes in the close vicinity of striatal vessels suggested that NPY might also play a role in the control of cerebral vasomotricity. Thirty hours after intranigral injection of 6-hydroxydopamine to induce a degeneration of nigrostriatal dopamine terminals, some characteristic degenerative boutons were observed in close apposition to NPY-Ir cell bodies, suggesting that NPY neurons are under a direct nigrostriatal dopaminergic influence.     

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 rat tail model for estimating dermal absorption of lindane

Dermal absorption of the insecticide lindane was determined following topical application of ring 14C-labeled lindane to the tail of Sprague-Dawley rats. The tail was tested as a practical alternative to the rat mid-dorsal (back) region, and the data obtained were compared to those with rat back and with those of rhesus monkeys in our previous reports. There was no significant difference between total percentage urinary 14C recovery for rats dosed on the tail with occlusive tail covers (52 +/- 6.2%; t1/2 = 2.7 d) compared to those with nonocclusive covers (55 +/- 4.4%; t1/2 = 2.9 d). Neither the total percentage urinary recovery nor the t1/2 values obtained for the rat tail and rat back models differed significantly. Carbon-14 activity was still detectable in urine samples taken after 72 d post-treatment. However, an extensive tissue analysis failed to demonstrate 14C activity persisting at 72 d, with the exception of trace levels detected in blood serum and tail tissue. Advantages of the rat tail model are highlighted.     

Flecainide versus quinidine in the prevention of paroxysms of atrial fibrillation

We compared the efficacy of flecainide versus quinidine in preventing paroxysms of atrial fibrillation in a randomized open crossover study. Twenty-six patients with weekly attacks of atrial fibrillation during the last 3 months, objectified by 24-h holter monitoring or 12-lead electrocardiogram (ECG) were treated for a period of 3 months with flecainide 100 mg b.i.d. or quinidine 500 mg b.i.d. Efficacy was assessed by 24-h holter monitoring and a questionnaire at the end of each month. Dosage was adjusted to flecainide 100 mg t.i.d. or quinidine 500 mg t.i.d. if patients still had symptomatic paroxysms of atrial fibrillation according to a questionnaire or on holter monitoring. In 46% of the patients, flecainide 100 mg b.i.d. caused total abolition of supraventricular tachycardia; after dose adjustment it caused 50% total abolition. For quinidine, the figures are 16% (p less than 0.05) and 32% (NS), respectively. Side effects occurred with flecainide only after dose adjustment (23%), but on quinidine they occurred before (8%) and after dose adjustment (20%). We conclude that flecainide suppresses paroxysms of atrial fibrillation significantly more often as compared with quinidine in the lower dosage regimen. Optimal treatment dosage of flecainide is 100 mg b.i.d. After quinidine dose adjustment, the difference in efficacy is no longer significant. However, side effects necessitating discontinuation of quinidine developed in 20% of the patients as compared to none in patients treated with flecainide 100 mg b.i.d.     

Risk factors for abruptio placentae

In a prospective study 90 patients who had confirmed abruption of the placenta were compared with a control group. Significantly more patients who had abruptio placentae were unmarried, smoked cigarettes, received no antenatal care, had coitus within the 48 hours preceding delivery, developed intrapartum hypertension and had a lower ponderal index than the controls. More patients with abruptio placentae had proteinuria and antepartum hypertension but statistical significance was not reached. In addition, the incidence of intra-uterine growth retardation was higher in these patients.     

Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Validation of a Flow-Through Diffusion Cell for Use in Transdermal Research

A flow-through finite-dose diffusion cell has been designed for use in transdermal drug delivery research. The diffusion cell consists of an upper donor chamber and a lower receiver compartment through which a continuous supply of fresh solvent flows. The flow is directed to an automatic fraction collector. To validate the flow-through cell, its performance was compared directly against that of a conventional single-reservoir Franz cell. Homologous alkyl p-aminobenzoates were diffused through dimethylpolysiloxane membranes, and permeability coefficients increased with increasing chain length, reaching a plateau at the butyrate ester for both types of cells. This behavior suggests a shift from membrane-controlled diffusion to boundary layer control. Permeation of the butyrate and valerate compounds was significantly faster when the flow-through cell was used, suggesting that better mixing is obtained through the flow-through cell design. Considering the advantages offered in terms of time and labor saved through its use, the flow-through cell with automatic fraction collector appears to be a viable alternative to the conventional Franz cell.     

4-Aminopyridine affects synaptosomal protein phosphorylation in rat hippocampal slices

Rat brain hippocampal slices were incubated with or without the convulsant 4-aminopyridine (4-AP). From these slices a crude mitochondrial/synaptosomal membrane fraction was prepared and analyzed for endogenous protein phosphorylation. 4-AP (10(-5) M) stimulated the phosphorylation of a 50 kDa protein by 86%. The phosphorylation of this 50 kDa protein is Ca2+/calmodulin-dependent and we suggest that this protein is the lower molecular weight subunit of Ca2+/calmodulin-dependent protein kinase II (CaMK II).