From cannabis to cannabinergics: new therapeutic opportunities

The molecular basis of cannabinoid activity is better understood since the discovery of the CB(1) receptor in the mammalian brain and the CB(2) receptor in peripheral tissues. Subsequently, an endogenous CB(1) receptor ligand, arachidonylethanolamide (anandamide), was isolated from porcine brain and shown to be metabolized by the enzyme arachidonylethanolamide amidohydrolase or fatty acid amide hydrolase. Recently, we have characterized a reuptake system for the transport of anandamide across the cell membrane, and have shown that selective inhibition of this transporter is associated with analgesia and peripheral vasodilation. The four cannabinoid system proteins, including the CB(1) and CB(2) receptors, fatty acid amide hydrolase, and the anandamide transporter, are excellent targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. During the last decade, numerous selective ligands for each of these proteins were designed and synthesized. Many of these agents serve as important molecular probes, providing structural information about their binding sites, as well as pharmacological tools imparting information about the roles of their targets in physiological and disease states. All of the above compounds that modulate the functions of the endocannabinoid system can be collectively described under the term cannabinergics, regardless of chemical classification or type of resultant pharmacological action.     

Management of mild aortic stenosis during coronary artery bypass surgery: an update, 1992-2001

BACKGROUND: "Prophylactic" aortic valve replacement (AVR) in patients with asymptomatic, mild-to-moderate aortic stenosis (AS) at the time of CABG is controversial. In 1994, we reported our initial experience involving 44 patients and have now updated our series in an attempt to further evaluate outcomes. METHODS: Between January 1992 and July 2001, 100 consecutive patients underwent reoperative AVR following previous CABG. Forty patients had their initial surgery at the Brigham & Women's Hospital (BWH) and 60 patients had their coronary surgery elsewhere. None of the 40 BWH patients had a mean valve gradient greater than 25 mmHg at the time of CABG. RESULTS: The mean time interval from CABG to AVR for the entire group was 9.0 years (range: 1.4-21 years). Overall operative mortality (OM) was 7% including 5 deaths (10.2%) among 49 patients requiring additional CABG at the time of AVR and 2 deaths (3.9%) among 51 patients without additional coronary artery intervention. This OM rate was a notable decrease from our earlier report of 18.2% (P = 0.07). Furthermore, operative mortality decreased progressively from 15.4% in 1992-1993 to 0% in 2000-2001 (P = NS). CONCLUSION: The OM of reoperative AVR following CABG has fallen in recent years. Given the relevance of newer techniques and approaches, it may be reasonable to adopt an expectant management approach in patients with asymptomatic mild-to-moderate AS (i.e., mean systolic gradient less than 25 mmHg) at the time of CABG.     

Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives?

Rheumatoid arthritis (RA) in the elderly may be mild or severe, with features that are similar to those seen in younger patients. As such, the treatment regimen in the elderly is almost the same as in younger patients. Methotrexate is the most popular disease-modifying antirheumatic drug (DMARD) for the treatment of RA in the US and Europe. It has excellent efficacy and an acceptable toxicity profile. However, a number of patients do not tolerate methotrexate and an alternative DMARD should be chosen.In the elderly, choice of an alternative DMARD should be made after careful consideration of several age-related factors including concomitant diseases, existing medication, drug compliance, and altered age-related physiology and pharmacokinetics.In elderly patients with RA who are unable to tolerate methotrexate, the alternatives are hydroxychloroquine or sulfasalazine for mild-to-moderate disease and cyclosporin or leflunomide for severe disease, given in combination with low-dose oral corticosteroids. This is primarily due to their efficacy combined with a relatively low toxicity profile compared with other DMARDs, such as gold compounds, penicillamine, azathioprine and alkylating agents. Where the above DMARDs are contraindicated, anticytokine therapy should be considered.The therapy of RA is a dynamic process and requires a delicate balance of benefits and risks. Experience and familiarity with the currently available agents, and knowledge of the nature of the disease are necessary in order to make better therapeutic decisions.     

Perfluorocarbon liquid utilization in primary vitrectomy repair of retinal detachment with multiple breaks

PURPOSE: To evaluate the efficacy of pars plana vitrectomy in conjunction with intraoperative perfluoro-n-octane (PFO) use as initial treatment of retinal detachment (RD) with multiple breaks located at various distances from the ora serrata. METHODS: Twenty-two consecutive eyes (15 phakic, 2 aphakic, and 5 pseudophakic) presenting with RD with multiple breaks and tears underwent primary pars plana vitrectomy, PFO retinal reattachment, transcleral cryopexy or endolaser treatment of breaks, PFO/air exchange, and final injection of 18% perfluoropropane (C3F8). Scleral buckles were not used. The mean follow-up period was 29 months. RESULTS: Temporary PFO utilization attached the posterior retina and facilitated the safe removal of vitreous at its base and around the retinal tears. Intraoperative complications included new breaks (3 eyes), enlargement of breaks (2 eyes), and a small bubble of subretinal PFO (1 eye). Postoperatively, the retina remained attached during follow-up in 19 eyes. Cataract developed or progressed in 13 phakic eyes. CONCLUSIONS: Pars plana vitrectomy in conjunction with intraoperative PFO utilization is effective as initial treatment of RDs with multiple breaks. The main limitation of this technique is the postoperative progressive cataract formation in phakic eyes.     

Hypertonic saline for cerebral edema

Raised intracranial pressure (ICP) is a major contributor to the mortality of many conditions encountered in a neurologic intensive care unit. Achieving a sustained reduction in ICP in patients with intracranial hypertension remains a challenge. Treatment with hyperosmolar agents is one of the few options that are available, and mannitol is currently the most commonly used agent. However, hypertonic saline solutions have recently emerged as a potentially safer and more efficacious alternative to mannitol.     

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer

PURPOSE: 5-Fluorouracil-based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS: Patients with Stage II-III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. RESULTS: Thirty-one patients were enrolled at the following dose levels: 1000 mg/m(2)/d (3 patients), 1150 mg/m(2)/d (4 patients) 1300 mg/m(2)/d (6 patients), 1400 mg/m(2)/d (6 patients), 1500 mg/m(2)/d (3 patients), 1600 mg/m(2)/d (3 patients), and 1700 mg/m(2)/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m(2)/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m(2)/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m(2)/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. CONCLUSIONS: The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m(2)/d in this study. This dose is recommended for additional use in Phase II-III studies.     

Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer

PURPOSE: Radiochemotherapy (RCT) is an effective treatment for locally advanced non-small-cell lung cancer (NSCLC), but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine, a radioprotector, could reduce the incidence of radiochemotherapy-induced acute and late toxicities. METHODS AND MATERIALS: Between October 1997 and August 1999, 73 patients with previously untreated Stage IIIa-IIIb NSCLC were randomized to treatment with RCT alone (n = 36) or RCT plus amifostine (300 mg/m(2) daily i.v. infusion, n = 37). RCT consisted of either paclitaxel (60 mg/m(2)) or carboplatin (AUC 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy/5 days/week to a total dose of 55 to 60 Gy. Blood cell counts were measured weekly; esophagitis and acute lung toxicity were evaluated during the treatment course. Treatment efficacy was assessed following World Health Organization criteria for response. Late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. RESULTS: A total of 68 patients were evaluable for toxicity analysis (RCT group, n = 32; RCT + amifostine, n = 36). There was no significant difference between treatment arms in patient baseline characteristics. The incidence of Grade >or=3 esophagitis during RCT was significantly lower for patients receiving amifostine than for patients receiving RCT alone (38.9% vs. 84.4%%, p < 0.001). Furthermore, the incidence of Grade >or=3 acute pulmonary toxicity was significantly reduced in patients treated with RCT plus amifostine compared to patients who received RCT alone (19.4% vs. 56.3%, p = 0.002). At 3 months after RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than patients who received RCT alone (p = 0.009). Combined response rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p = 0.498).Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced NSCLC without compromising antitumor efficacy.