Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogues of pilocarpine and a hypothetical model for the binding of agonists to the m1 receptor.

Pilocarpine isosteres have been synthesized and characterized with regard to their in vitro muscarinic properties. The results indicate that the carbonyl oxygen of the lactone function of pilocarpine is of primary importance for agonist activity with the ether oxygen being of lesser or secondary importance. An X-ray structure determination for the hydrogen O,O'-ditoluoyltartrate salt of thiolactone pilocarpine isostere 2a has been performed. This compound has an unusual pharmacological profile exhibiting M1-agonist selectivity as well ass presynaptic antagonism. As a result this compound is also viewed as having therapeutic potential for Alzheimer's disease. A model for the binding of pilocarpine and other muscarinic agonists to the third transmembrane helix of the human m1 muscarinic receptor has been developed.     

Inhibition of monocyte esterase activity by organophosphate insecticides

Organophosphate insecticides, such as Vapona, Naled, and Rabon, are highly potent inhibitors of an enzyme found in human monocytes. The enzyme, a specific monocyte esterase, could be inhibited by Vapona in blood samples via airborne contamination at levels easily achieved from commercial slow-release insecticide strips. Fifty percent inhibition (I50)--as measured on the Hemalog D (Technicon Corp.)--occurred at solution concentrations of 0.22, 1.5, and 2.6 X 10(-6) g/liter for Vapona, Rabon, and Naled, respectively. Parathion (a thiophosphate) and Baygon (a carbamate) were less potent, with I50 values of 3.7 X 10(-5) and 1.5 X 10(-4) g/liter, respectively. Dursban (another thiophosphate) and Carbaryl (a carbamate) showed only marginal inhibition. Eserine, malathion, nicotine and pyrethrum had no inhibitory effect up to 0.5 g/liter. The occurrence of this effect in vivo has not yet been shown, nor is it clear what the implications of such an effect would be. The inhibition of this enzyme by airborne contaminants, however, may interfere with the proper functioning of the Hemalog D.     

Dual suppression with oral contraceptives and gonadotrophin releasing- hormone agonists improves in-vitro fertilization outcome in high responder patients

Certain patients have a tendency for high response to gonadotrophin therapy which is often not ameliorated with prior gonadotrophin- releasing hormone agonist (GnRHa) suppression. As a result, these patients are frequently cancelled and often experience ovarian hyperstimulation syndrome (OHSS) episodes during in-vitro fertilization (IVF)-embryo transfer cycles. Patients with polycystic ovarian syndrome (PCOS) have been noted to be particularly sensitive to exogenous gonadotrophin therapy. We have developed a protocol which is effective in improving IVF outcome in high responder patients, including those with PCOS. Oral contraceptive pills (OCP) are taken for 25 days followed by s.c. leuprolide acetate, 1 mg/day, which is overlapped with the final 5 days of oral contraceptive administration. Low-dose gonadotrophin stimulation is then initiated on the third day of withdrawal bleeding in the form of either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone at a dosage of 150 IU/day. Over a 5 year period, we reviewed our experience utilizing this dual method of suppression in 99 cycles obtained in 73 high responder patients. There were only 13 cancellations prior to embryo transfer (13.1%). The clinical and ongoing pregnancy rates per initiated cycle were 46.5 and 40.4% respectively. Only eight patients experienced mild-moderate OHSS following treatment. For those patients who had undergone previous IVF-embryo transfer cycles at our centre, significant improvements were noted in oocyte fertilization rates, embryo implantation rates and clinical/ongoing pregnancy rates with this protocol. Hormonal analyses revealed that the chief mechanism may be through an improved luteinizing hormone/follicle-stimulating hormone ratio following dual suppression. An additional feature of this dual method of suppression is significantly lower serum androgen concentrations, particularly dehydroepiandrosterone sulphate.      

Porous surface replacement of the hip with chamfered-cylinder component

One hundred porous surface replacements (PSR) were performed in 92 patients (63 men and 29 women) with a mean age of 53 (range 17-76). Follow-up times range from 1 to 4 years, with 48 patients having a follow-up of at least 2 years. Preoperative diagnoses were osteoarthritis (OA) 63, osteonecrosis (ON) 13, dysplasia 9, rheumatoid-ankylosing spondylitis 6, and other 9. Seventeen hips had metal-backed acrylic-fixed THARIES acetabular sockets, nine hips had a porous cobalt chrome hemispheric beaded acetabular component with adjuvant fixation screws and externally protruding screw hubs, and 74 hips had a porous chamfered cylinder-design acetabulum. Pain relief had been immediate and more complete than with acrylic-fixed or biologic-ingrowth stem-type replacement with comparable walking and function improvements. There have been no major systemic complications, sepsis, or loosening. There have been two transient peroneal nerve palsies and three trochanteric fibrous unions. There have been three reoperations, one for subluxation, one for "metalosis" due to mesh pad loosening, and one femoral neck fracture. Examination of one removed femoral surface component which has been histologically sectioned revealed excellent (90%) bone in-growth. Circumferential progressive radiolucencies developed at the bone-cement interface by 1 year in all of the 17 acrylic-fixed acetabular components. Reaming or seating defects were noted in 25% of the ingrowth components on postoperative radiographs. Radiographic analysis of immediate postoperative films of the chamfered cylinder design acetabular components frequently demonstrated bone-component interface radiolucencies which represented component seating defects. These initial interface radiolucencies became progressively more narrow over the first six months postoperatively suggesting "healing" of the reamed bone-component interface with trabecular bone around the chamfered cylinder acetabular components. Partial healing of initial interface voids with residual narrow radiolucencies were typical of the nine hemispheric-design acetabula with adjuvant screws and screw hubs. This new porous surface replacement (PSR) of the hip using porous ingrowth fixation avoids the major disadvantages of acrylic-fixed SR: excessive acetabular reaming and difficulty with acetabular revision. (When conversion to stem-type replacement is necessary the modular polyethylene socket liner can be exchanged.) The PSR has the prospect of enhanced fixation and improved longterm durability.