The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors

Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.     

The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study

1. We have studied the effects of muscarinic cholinoceptor agonists and subtype-preferring antagonists on the isometric contraction of smooth muscle strips from dog prostate. 2. Acetylcholine and carbachol induced contraction of prostate strips from the peripheral zone, ('the capsule'). Bethanechol contracted the tissue but not at lower doses. McN-A-343 and oxotremorine-M showed the same effects. 3. Blocking alpha- and beta-adrenoceptors with phentolamine and propranolol, respectively, did not modify carbachol-induced contractions. 4. The nicotinic receptor blocker, hexamethonium (10(-6)-10(-4) M) did not affect the contractile response evoked by a single dose of carbachol (10(-5) M), whilst the muscarinic receptor antagonist, atropine (10(-11)-10(-9) M), inhibited it in a competitive manner. 5. The muscarinic M1 (pirenzepine), M2 [AF-DX 116, himbacine (M2/M4) and methoctramine], M3 (HHSID and f-F-HHSID), and putative M4 (tropicamide) antagonists reduced significantly the carbachol-induced contractions. The pIC50 values were: atropine (10.01) > himbacine (8.3) > methoctramine (7.85) > AF-DX 116 (7.60) > HHSID (7.21) > p-F-HHSID (7.10) > pirenzepine (7.30) > tropicamide (7.00). 6. The antagonist profile indicates that an predominant M2 receptor subtype could mediate the muscarinic contraction in the canine prostate.     

A primary care nurse clinic

A nurse-driven clinic that uses a client-centered approach evolved from an independent ambulatory care program. The clinic operates 4 to 5 hours per day and provides patient counseling, health care maintenance, primary care, patient education, and therapeutic care.     

Indocyanine-green videoangiography of drusen as a possible predictive indicator of exudative maculopathy

OBJECTIVE: Recent studies have shown that indocyanine-green videoangiography (ICG-V) is useful to image occult choroidal neovascularization. The authors studied the ICG-V findings in fellow drusen eyes of patients with unilateral exudative age-related macular degeneration (AMD). The authors also studied the occurrence of exudative changes to determine whether ICG-V is useful in predicting future exudative changes in these eyes with only drusen. DESIGN: Cohort study. PARTICIPANTS: The authors studied 432 consecutive patients diagnosed with unilateral exudative AMD in whom the fellow eye had only drusen by clinical fundus examination and fluorescein angiography. All of these eyes had ICG-V performed. Follow-up data were obtained in all eyes with abnormal indocyanine-green (ICG) angiograms and randomly sampled ICG angiograms of normal eyes. MAIN OUTCOME MEASURES: The initial ICG findings were classified as showing normal or abnormal hyperfluorescence. Abnormal hyperfluorescence eyes were subdivided into focal spots (focal areas of hyperfluorescence < 1 disc area in size) and plaques (areas of hyperfluorescence > 1 disc area). The development of exudative changes in eyes with normal and abnormal hyperfluorescence was compared. RESULTS: Of the 432 fellow eyes, 386 (89%) eyes with drusen had a normal ICG-V study, whereas 46 (10 focal spots and 36 plaques) (11%) eyes had an abnormal ICG-V. Exudative changes occurred in 6 (10%) of 58 normal ICG eyes and 9 (24%) of 38 eyes with abnormal ICG findings during a mean follow-up period of 21.7 months. The difference between drusen eyes with normal ICG angiograms and those with plaques on ICG-V regarding future exudative changes (10% vs. 27%, respectively) was statistically significant (P = 0.038). CONCLUSIONS: Abnormal ICG findings were found in 11% of eyes with clinically and fluorescein angiographically nonsuspicious drusen. The subgroup of patients with plaques on ICG-V had a higher chance of having exudative changes develop. Indocyanine-green videoangiography may be a predictive indicator of future exudative changes in eyes with drusen. A much larger prospective study seems justified.     

Ovarian hyperstimulation following the sole administration of agonistic analogues of gonadotrophin releasing hormone

Ovarian hyperstimulation following the sole administration of gonadotrophin-releasing hormone agonists (GnRHa) is exceedingly rare. We hereby report on two infertile patients undergoing in-vitro fertilization-embryo transfer who developed ovarian hyperstimulation under such circumstances. In both patients, GnRHa were administered using the 'long protocol' regimen. The first patient developed ovarian hyperstimulation on two occasions, with mid-luteal depot administration of triptorelin and with early follicular triptorelin, administered as daily subcutaneous injections. In both cycles, within 2 weeks of triptorelin therapy, massive ovarian multifollicular enlargement occurred, concomitant with high serum oestradiol concentrations, which resolved spontaneously following expectant management. The second patient developed ovarian hyperstimulation following daily injections of leuprolide acetate starting at the mid-luteal phase. The final stage of ovulation was triggered by human chorionic gonadotrophin (HCG) and 11 oocytes were retrieved. In-vitro fertilization resulted in embryo formation, but failed to result in pregnancy. The same phenomenon recurred in a subsequent cycle despite preventive pretreatment with an oral contraceptive. A negative GnRH test, performed just before HCG administration, suggested than an ongoing 'flare-up effect' was unlikely to cause ovarian stimulation. Ovarian hyperstimulation can occur following the sole administration of GnRHa irrespective of the preparation used and the administration protocol. Although spontaneous resolution is the rule, once this condition has developed, HCG administration and oocyte retrieval are feasible. This rare entity probably represents an exaggerated form of ovarian cyst formation following GnRHa administration, the underlying pathophysiology of which remains unresolved.     

SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome

A drug with cationic characteristics such as procaine can be conveyed in a Carbomer hydrogel in two different ways: (i) in the form of salt in solution in the aqueous phase, and (ii) in the base form salified with the same polymer. Introduction of the drug into the hydrogel with different concentrations of polymer produced, in both cases, a reduction in viscosity in relation to drug concentration. The gels with procaine salified with the polymer showed greater viscosity. The drug release rate, in general, diminished with the increase in polymer concentration. Nevertheless, when this concentration was maintained, there was no variation in release rate when the viscosity produced as a consequence of drug concentration was changed. Gels with procaine salified with the carboxyvinylic polymer had a faster release rate than those with procaine in the hydrochloride form dissolved in the aqueous phase. These results have also been confirmed by a simulated absorption test.     

Deoxyribonucleic acid flow cytometry of squamous cell carcinoma of the penis

This article reports 10 cases of cranial base tumors resected by pre-or retro-auricular intratemporal approach. Among them four were neuronomas, two meningiomas, one malignant giant cell tumor of bone, one osteochondnoma, one parotid mixed neoplasm and one poorly-differentiated squamors cell carcinoma. Total resection in 9 cases and one subtotal resection were performed without operative mortality and serious surgical complications. The surgical management of cranial base tumor and indications for selecting operative approaches were discussed.     

Developmental stages in experimental liver metastases: relation to invasiveness

We have previously reported that an invasive morphotype can be evoked in a rat colon carcinoma by transplanting it into pre-induced subcutaneous granulation tissue. We have now studied the interaction of the same tumor with liver tissue, which is extremely poor in connective tissue in comparison with the subcutaneous site. Tumor cells were injected into the portal system and the resulting experimental liver metastases were examined by electron microscopy and immunohistochemistry. Early metastases consisted of well-differentiated acini, fully surrounded by connective tissue that was derived from the periportal stroma. In a later stage, this connective tissue was overgrown by tumor cells and, almost immediately, acinar differentiation was lost. Most metastases eventually reached the liver capsule, which reacted by forming a layer of granulation tissue. Only in this layer, we observed invasion by thin tumor cell strands, which were often intimately associated with fibroblasts or with blood capillaries. The tumor cells remained smooth and rounded during this process. After fully penetrating the granulation tissue, the tumor cell strands reached the liver surface, where they formed poorly structured papillary masses that were nearly devoid of stroma. Our observations indicate that, even in a relatively homogeneous organ like the liver, the tumor-host interaction is highly complex and dynamic. They also confirm the notion that granulation tissue stimulates tumor invasiveness. Finally, they show that tumor cells can actively invade host tissues without exhibiting a "fibroblastic" morphology.     

"En-bloc" vertebrectomy in the mobile lumbar spine

BACKGROUND: Primary tumors of the vertebral bodies have previously been treated with total or subtotal excision in a piecemeal fashion (intralesional excision). Radiation therapy has been used to help control tumor growth. Recurrence rates with an intralesional, piecemeal removal of vertebral tumors have been unacceptably high. This study describes a method to excise a lumbar vertebra "en-bloc," and in the process, to perform a marginal (extralesional) resection of a primary tumor of the mobile lumbar spine that allows for a potential surgical cure. METHODS: A combined posterior-anterior procedure allows for an extralesional, marginal resection of the tumor and the involved vertebra. All posterior bony elements, including the pedicles and the adjacent intervertebral discs, are removed via a posterior approach. An anterior, retroperitoneal approach is then used to remove the vertebral body/tumor as a single specimen. The nerve roots at the involved levels are spared and the spine is instrumented and fused both posteriorly and anteriorly. RESULTS: Three patients successfully had combined posterior-anterior resections of lumbar vertebral chordomas. No permanent neurological complications occurred. Overall morbidity of the procedure was acceptable. At 31-month follow-up, no tumor recurrence has been detected. CONCLUSIONS: "En-bloc" resection of a primary vertebral tumor of the lumbar spine is technically demanding, but potentially curative. The alternative approaches-intralesional excision, radiation therapy, or a combination-are unable to cure these tumors. Long-term, 10-year follow-up will be necessary to confirm whether this en-bloc approach provides a surgical cure.