Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography

In previous in vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.     

MR-guided intravascular catheter manipulation: feasibility of both active and passive tracking in experimental study and initial clinical applications

PURPOSE: To evaluate clinically the feasibility and usefulness of MR-guided intravascular procedures with either active or passive tracking. METHODS: With an active MR tacking system and a 0.2 Tesla open MR imager, real-time and biplane displays of positions of a receive-only coil at the tip of catheters were obtained. For passive tracking, 4 Fr catheters with suitable susceptibility for passive tracking were used. Passive tracking with a 1.5 Tesla MR imager could be performed with parameters of TR 15-50 msec, TE 2.2-2.7 msec, and FA 30 degrees. The temperature of each tracking catheter was monitored in vitro. Clinical trials were performed on six patients (three each). The catheter was introduced to the superior mesenteric artery (SMA) under MR guidance by active or passive tracking to perform MR imaging during arterial portography. RESULTS: The temperature increased minimally. In humans, the SMA and celiac artery could be easily introduced on active tracking. MR-guided manipulation of catheters by active or passive tracking in the model and in dogs' vessels was very successful. Introduction of the catheter into the SMA was successful in two cases of active tracking and in all cases of passive tracking. CONCLUSION: The MR-guided intravascular manipulation of catheters by active or passive tracking may be a clinically feasible method.     

Transdermal contraceptive patches

Many contraceptive methods have been developed for fertility regulation, either reversible or irreversible, in males and females. Oral contraceptives have been considered the most popular form of reversible contraception. However, they must be taken consistently, on a daily basis for 21 or 28 days of each menstrual cycle, in order to achieve the maximal outcomes of contraception. Moreover, their contraceptive efficacy has been reportedly affected by their interactions with many drug products taken concurrently for other conditions. To resolve the dilemma of daily compliance and the risk of potential interactions with drugs taken orally, several non-traditional delivery systems have been developed to permit contraceptive agents and their combinations to be administered via a non-oral route, and also at a lesser frequency of administration, so as to enhance treatment compliance, maximize therapeutic outcomes, and minimize adverse effects. One typical example is the successful development of the ethinylestradiol/norelgestromin patch for achieving contraception in females via transdermal delivery. With topical application on intact skin, each patch delivers a combination of norelgestromin and ethinylestradiol for a week. With a treatment schedule of 3 weeks with a patch on and 1 week without a patch for each menstrual cycle, the ethinylestradiol/norelgestromin patch has achieved a clinical efficacy that is considered bioequivalent to oral contraceptives (with an unintended pregnancy rate of 0.8% per woman-year for the patch versus 0.1% per woman-year for the combined oral contraceptive). Stimulated by the marketing success of the ethinylestradiol/norelgestromin transdermal contraceptive patch, and a growing recognition of the therapeutic benefits realized by delivering an orally inactive progestin via a transdermal route, other transdermal drug delivery systems (DDS), such as transdermal gels and a metered-dose transdermal spray system, have also been developed. Further transdermal contraceptive patches have also been developed. One of these is similar to the ethinylestradiol/norelgestromin patch, in that it is fabricated from an adhesive polymer matrix diffusion-controlled DDS; however, it has a two times smaller patch size (to minimize localized reactions at the application site). This was made possible by substituting norelgestromin with a more potent progestin called gestodene, that has a higher skin permeation rate. The other transdermal patch that has been developed employs a microreservoir partition-controlled delivery system, to provide dual-controlled delivery of estradiol (a natural estrogen) and levonorgestrel (another potent synthetic progestin) at constant rates (zero-order kinetics). Clinical studies have demonstrated that these two new patch systems may be attractive alternative forms of contraception, since ovulation inhibition has been achieved in all subjects who wear the transdermal patch for 3 weeks, replacing it on a weekly basis. A transdermal gel has been formulated to contain elcometrine, which has a progestational potency that is 100 times that of progesterone but is orally inactive, in an alcoholic solution. Preliminary clinical studies have indicated that suppression of ovulation was achieved in the majority of subjects receiving daily application of the transdermal gel. To address the problems associated with the dosing accuracy of the transdermal gel, due to difficulty controlling the area and size of the application site, the feasibility of delivering the transdermal gel from a metered-dose transdermal spray system is currently under evaluation by the Population Council.     

Longitudinal Observation of a Patient with Leri-Weill Dyschondrosteosis and SHOX Haploinsufficiency

Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features, a certain proportion of idiopathic short stature and Leri-Weill dyschondrosteosis (LWD). Here we report a Japanese female with LWD. Her physical growth, skeletal deformity, and endocrine status were recorded longitudinally. She exhibited a constant growth rate (average + 6.2 cm/yr) from 6 to 9 yr old, followed by a downward shift at 10 yr old. Her final height was 135 cm (–4.4 SD for an adult female) and weight was 50.5 kg (–0.3 SD) at 12 yr and 10 mo old. Mesomelia and cubitus valgus were noticed from 2 yr old, and metaphyseal lucency and epiphyseal hypoplasia of the medial side of the distal radius were detected at 6 yr old. Madelung deformity was obvious at 10 yr old, when menarche occurred. Fluorescence in situ hybridization (FISH) analysis demonstrated a single copy of the SHOX gene. The short stature of the patient was thought to be exaggerated by the combination of SHOX haploinsufficiency and relatively early puberty.     

Differential distribution of ionic channels and muscarinic receptors at the cat tracheal neuromuscular junction

The ionic and pharmacological properties of atropine-sensitive excitatory junction potentials (EJPs) were investigated by the double sucrose gap and microelectrode membrane potential recording methods, and compared with those of inward currents evoked by carbachol (I(CCh)), in cat tracheal smooth muscle. A single and repetitive field stimulation (10-30 V, 50 micros, 20 Hz) evoked atropine-inhibitable EJPs and associated twitch-like contractions. Reduction in external Na+ concentration strongly, but in the external Cl- concentration, decreased the EJP amplitude after 5 min superfusion, although prolonged exposure to low Cl- solutions attenuated the EJPs modestly. Chloride channel blockers such as 9-AC and niflumic acid (each 100 microM), at concentrations high enough to inhibit I(CCh) almost completely, failed to abolish the EJPs. Pirenzepine, AF-DX116 and 4-DAMP all effectively inhibited the EJPs at their concentrations to block respective muscarinic receptor subtypes relatively specifically, while depletion of internal stores by 10 mM caffeine and/or 3 microM ryanodine caused only a partial decrease in the EJP amplitude. These properties are considerably different from those of I(CCh) which is activated exclusively through activation of the M3 receptor/IP3-mediated Ca2+ release pathway and reflects mostly a Ca2+-dependent Cl- current, and suggests the differential distribution of muscarinic receptors and ionic channels inside and outside of the cholinergic neuromuscular junction of this muscle.     

Unique maternal deletion of 15q in a patient with some symptoms of Prader-Willi syndrome

BACKGROUND: Human chromosome 15q11-q13 is a critical region for Prader-Willi syndrome (PWS) and Angelman syndrome (AS) and most of the genes are under the condition of imprinting mechanism. PWS results from the loss of expression of paternally expressed genes and AS of maternally expressed genes. In this study molecular studies about a patient with congenital anomalies and mental retardation are analyzed. METHODS: Highly polymorphic microsatellite markers were analyzed by PCR. These markers exist within 15q11-q13 and distal to 15q13. RESULTS: Only the maternal D15S986 locus within 15q11-q13 was deleted and other markers were biallelic. CONCLUSIONS: The result of maternal small region deletion in this patient is different from the typical PWS with paternal chromosome deletion and it suggests that nearby the deleted region there exists a gene (genes) which is not imprinted but needs biallelic expression.     

Performance of degree of accumulation with 201Tl-SPECT in 13 cases of lung cancer smaller than 2 cm

The aim of this study was to determine the sensitivity of 201Tl-chloride for small lung cancers. The study subjects consisted of 13 cases of surgically verified lung cancer smaller than 2 cm who had undergone 201Tl-SPECT prior to surgery, owing to the difficulty of establishing a diagnosis of lung cancer based on diagnostic CT. Among 13 cases, four showed positive accumulation in early and delayed SPECT, and nine negative, with a degree of accumulation of 31% (4/13).