Clonidine Use and Abuse Among Methadone Program Applicants and Patients

Forty-eight consecutive applicants and 30 known clonidine-abusing methadone patients at three methadone treatment programs were surveyed regarding their use of clonidine. Two distinct patterns of clonidine use emerged. Of 22 applicants who took clonidine illicitly, 15 used it primarily to decrease opioid withdrawal, as well as for its sedating effect. Applicants mostly obtained it from physicians, used an average dose of 0.37 mg at a time, and about one third believed clonidine to be addictive. In contrast, clonidine-using patients took clonidine primarily for its psychoactive effects, including the interaction with methadone, in addition to decreasing opioid withdrawal. Patients obtained clonidine frequently on the street and from family or friends, but less from physicians. The average reported dose for patients was 0.6 mg. The vast majority of these patients felt clonidine was addictive. Our findings, when coupled with the risk inherent in clonidine overdose, suggest that further research into the identification and treatment of clonidine abuse among methadone patients is warranted.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Inhibition of GABA-gated chloride channel function by arachidonic acid

The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.     

Does the end-to-end venous anastomosis offer a functional advantage over the end-to-side venous anastomosis in high-output arteriovenous grafts?

This study explores the hemodynamics, mechanics, and biologic response of end-to-end versus end-to-side venous anastomoses in a canine arteriovenous graft model. Femoral polytetrafluoroethylene grafts were implanted bilaterally in a paired fashion (n = 22). Detailed local hemodynamic measurements were made by use of color Doppler ultrasound imaging at 1, 4, 8, and 12 weeks after implant. Measurements included volumetric flow rate and Doppler-derived spectral window (percent window) as a measure of turbulence. Amplitude and velocity of vessel wall movement were also measured. Volume of perivascular tissue vibration quantitated kinetic energy transfer through the vessel wall. Volumetric flow rate (end to end, 1013 +/- 70 ml/min; end to side, 1015 +/- 72 ml/min), percent window (end to end, 6.6% +/- 0.6%, end to side, 5.6% +/- 0.4%) and volume of perivascular tissue vibration (end to end, 19.6 +/- 1.2 ml, end to side, 16.3 +/- 1.8 ml) were statistically equivalent in the two graft types (end to end vs end to side p greater than 0.05). Both graft types developed venous intimal-medial thickening of a similar magnitude: end to end, 0.35 +/- 0.05 mm, end to side, 0.43 +/- 0.09 mm, normal vein 0.070 +/- 0.004 mm (analysis of variance [ANOVA] p less than 0.001, p less than 0.01 for end to end or end to side vs control, end to end vs end to side p greater than 0.05 by Student-Newman-Keuls test). The best correlations with venous intimal-medial thickening were obtained from inverse percent window (r = 0.84, p less than 0.001) and volume of perivascular tissue vibration (r = 0.68, p less than 0.001). In the end to end configuration the relative amplitude of venous wall movement decreased, and the relative velocity of wall motion increased over time. We conclude that in the circumstances of this high flow arteriovenous graft model the end-to-end venous anastomosis does not significantly differ from the end-to-side venous anastomosis in terms of flow stability, turbulence, or kinetic energy transfer. The magnitude of the hyperplastic response is statistically equivalent for the two anastomotic types, but the pattern is somewhat different, possibly providing evidence for differences in stress distribution. Differences in the relative amplitude and velocity of vessel wall movement suggest that anastomotic geometry may affect the way in which kinetic energy is dissipated at the graft/vessel interface.     

Antipsychotics with inverse agonist activity at the dopamine D3 receptor

Summary In NG 108-15 cells expressing the recombinant human D₃ receptor, dopamine agonists enhance [³H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [³H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D₃-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D₃ receptor on [³H]thymidine incorporation pathway, but not on the cAMP pathway.     

Lyme disease: ocular manifestations

We present three cases of Lyme disease, complicated by ocular manifestations. These included optic nerve abnormalities and corneal opacities.     

Keratoacanthoma-Like Squamous Cell Carcinoma Within the Fibroepithelial Polyp

Acrochordons (skin tags) are often considered clinically insignificant cutaneous redundancies that should be removed and destroyed with no histopathologic analysis performed. One rarely finds another neoplasm within an acrochordon. We describe a patient with an acrochordon that contained a squamous cell carcinoma that had features resembling a keratoacanthoma. This is the first time to our knowledge that an invasive squamous cell carcinoma has been described within an acrochordon.     

Documentation of students' clinical reasoning using a computer simulation

Computer simulations can provide both a clinical experience for teaching problem solving and a method of documenting a student's clinical reasoning style. The CAMPS simulation consists of approximately 500 items describing a patient's history, physical examination and laboratory results, and treatments. The student has full option to select any item in any order, producing a wide variation of performances. Since all of the students interact with the same clinical problems, the faculty member can make comparisons of that individual student with the class. From the record of the simulation encounter, the person responsible for student evaluations can prepare a narrative that lists the overall performance, the specific omissions and commissions, and comparisons with the class. Experience with a group of 111 students in a basic pediatric course showed that this method of documenting clinical inquiry detected a variety of levels of performances. Comparisons of the results of these tests with the faculty observations showed that 16% of these students who were judged to be very good or excellent in problem solving by the faculty performed at least 1 SD below the class average on the simulations. This project highlights the power of computer simulations to provide documentation of student performance with the additional benefit of a cost of less than $1 per student.     

Steady state verapamil tissue distribution in the dog: differing tissue accumulation

Plasma, heart, and extracardiac tissue verapamil concentrations were measured after sustained intravenous infusions in 11 dogs to determine the differential tissue accumulation of verapamil. A steady state verapamil concentration of 327 +/- 50 ng/ml decreased the mean arterial blood pressure from 104 +/- 9 to 90 +/- 6 mm Hg (p = 0.08) and the P-R interval increased from 118 +/- 4 to 176 +/- 13 ms (p less than 0.001) with second-degree atrioventricular block developing in 6 animals. Verapamil accumulated in organs in the following order: Lung much greater than kidney greater than spleen greater than ventricular myocardium = liver greater than atrial myocardium greater than cerebral cortex greater than fat = skeletal muscle. Levels in the ventricular free wall were consistently greater than atrial levels, but no difference was observed between left versus right-sided cardiac chambers. In summary, affinity of different organs for verapamil is highly variable and organ-specific; furthermore, differential intracardiac chamber accumulation occurs.     

Dynamic pituitary and ovarian changes occurring during the anestrus to estrus transition in the golden hamster

Anestrous hamsters exhibit daily afternoon gonadotropin and progesterone surges, but little estrogen secretion. In the first experiment, short day anestrous females were transferred to long days to detect hormonal changes associated with recovery of cyclicity. Morning and afternoon blood samples were taken at increasing durations in long days. Females autopsied at their first vaginal estrus after transfer to long days differed from long day estrous controls only in their lower uterine weights. Some females at all durations exhibited signs of recovery, though they had not yet shown estrus. They did not display afternoon gonadotropin surges and had low circulating progesterone but high estradiol levels, stimulated uteri, and enhanced follicular development. Results of the second and third experiments provided evidence that the daily gonadotropin surges are not the cause per se of anestrus, and that changes in estrogen secretion are essential for the transition to and from anestrus. Phenobarbital blockade of the daily surges in anestrous females did not result in increased follicular growth and estrogen secretion. Furthermore, daily afternoon injections of gonadotropins it appears that the daily surges in anestrous hamsters simply reflect low estradiol levels. It is still not known what signal promotes rapid follicular maturation during the recovery from anestrus. Once initiated, however, this recovery appears to occur within a few days, with a rapid cascade of events. First, follicular development and estrogen secretion resume, and the daily LH surges cease. Then, progesterone levels decline, and an ovulatory surge of gonadotropins is triggered.