Full Therapeutic Doses Research Articles

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen

BACKGROUND Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. AIMS We compared the biochemical and gastrointestinal effects of nimesulide, a...

Gastrointestinal tolerability of nimesulide, a selective cyclooxygenase-2 inhibitor, in experimental animals and man

These studies assessed the gastrointestinal tolerability and cyclooxygenase (COX) selectivity of nimesulide in animals and man. Nimesulide (15 and 30 mg/kg) had no significant 'topical' toxicity in animals as assessed by in vivo mitochondrial morphologcal studies and no increase in small intestinal permeability or inflammation in rats. Similarly, these doses did not affect mucosal prostaglandins significantly and there were no ulcers. At the very high does of 60 mg/kg, nimesulide had some 'topical' toxicity and lost some of its COX-2 selectivity, but this was not associated with inflammation or ulcers. Indomethacin (10 mg/kg, equivalent to 15 mg/kg of nimesulide) altered all of the above parameters and led to small bowel ulcers. This suggests that the gastrointestinal tolerability of nimesulide is not only due to its COX-2 selectivity, but that it is also due to its lack of 'topical' toxicity. Thirty six healthy subjects participated in a randomised, double-blind, double-dummy crossover study (14 day treatment with a washout) of the effect of nimesulide (100 mg bid) and naproxen (500 mg bid) on the gastroduodenal mucosa and small intestine (absorption-permeability and inflammation). An assessment was also made on their COX selectivity. Nimesulide caused significantly less gastric (p = 0.0001) and duodenal (p = 0.0086) damage than naproxen. Naproxen increased intestinal permeability significantly (p = 0.004) and caused intestinal inflammation while nimesulide (p > 0.40) did not. Nimesulide had no significant (p > 0.1) effect on COX-1 dependant platelet aggregation, reduced serum thromboxane B2 levels moderately by 24-34% (p 0.5). By comparison, naproxen had significantly (p < 0.0001) greater effects on these functions: abolished platelet aggregation to arachidonic acid, suppressed serum thromboxane B2 levels by 98% and gastric prostaglandin production by 76-82%. Nimesulide inhibited lipopolysaccharide-induced PGE2 formation in whole blood to a significantly (p < 0.01) greater extent than naproxen. ___TAGSTART___BR___TAGEND___This study shows that nimesulide has a preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses. This selectivity is associated with minimal gastrointestinal damage in the short term.

PAIN MANAGEMENT IN DENTAL PRACTICE: TRAMADOL VS. CODEINE COMBINATIONS

Tramadol hydrochloride is a novel, centrally acting analgesic with two complementary mechanisms of action: opioid and aminergic. First marketed in 1994, tramadol is frequently prescribed by physicians for the management of moderate-to-moderately severe chronic pain. The author evaluates its unique analgesic pharmacology and limited clinical utility for managing acute pain in dentistry. Clinical drug trials in medicine and dentistry were reviewed to assess analgesic efficacy. Postmarketing surveillance studies and reports of adverse drug events were evaluated to determine short- and long-term safety. Tramadol's maximum analgesic efficacy for relieving acute pain after oral surgery appears to be similar to that of 60 milligrams of codeine alone but less than that of a full therapeutic dose of a nonsteroidal anti-inflammatory drug or a codeine combination, such as aspirin/codeine or acetaminophen/codeine. Adverse events reported by patients receiving tramadol therapy since it was approved by the Food and Drug Administration suggest a risk of seizures, drug abuse and anaphylactoid reactions. Tramadol has limited indication for management of acute pain in dentistry, possibly as an alternative analgesic when gastrointestinal side effects contraindicate the use of nonsteroidal anti-inflammatory drugs and when codeine/acetaminophen combination analgesics are not well-tolerated or are contraindicated.

Lymphocytic and Collagenous Colitis: Medical Management.

When possible, patients taking nonsteroidal anti-inflammatory medications should discontinue them when the diagnosis of microscopic colitis is made. Although there is no direct evidence of its efficacy, a trial of elimination of caffeine or lactose or both should be undertaken. Nonspecific antidiarrheal agents (eg, loperamide, diphenoxylate) may be administered, but appear to be largely ineffective in this population. An aminosalicylate should be initiated at full therapeutic dose (2 to 4 g daily) as the first-line therapy. Because sulfasalazine appears to be associated with a high incidence of adverse effects in patients with microscopic colitis, other derivatives of 5-aminosalicylate (5-ASA) are preferred. Bile salt-binding agents such as cholestyramine or colestipol appear to be effective alternatives for patients who are either unresponsive to or intolerant of aminosalicylates. Systemic corticosteroids are an effective treatment for microscopic colitis, but may offer only transient improvement in symptoms. Given their potential adverse effects, corticosteroids should be reserved for patients with refractory disease in whom aminosalicylates and bile salt-binding agents have failed. Other agents that may be effective include antibiotics, bismuth subsalicylate, budesonide, pentoxifylline, octreotide, and methotrexate. Although these agents can be considered in unusual cases, the cumulative clinical experience with them in this setting is relatively limited. Surgical intervention, with either fecal stream diversion or subtotal colectomy, shows promise as an intervention of last resort. In refractory cases of microscopic colitis, strong consideration should be given to excluding a concomitant diagnosis of celiac disease, bacterial overgrowth, or chronic infection.

Predictive value of oral sulfonamide challenge for adverse reactions.

Predictive value of oral sulfonamide challenge for adverse reactions.

Combination paclitaxel (TaxolR)-carboplatin as first-line therapy for advanced ovarian cancer

Data from a recent study conducted by the Gynecologic Oncology Group showed that combination cisplatin–paclitaxel (Taxol®, Bristol-Myers Squibb Company) is superior to standard combination cisplatin–cyclophosphamide in previously untreated patients with ovarian cancer. This dose-finding trial was subsequently initiated to determine whether combination carboplatin–paclitaxel would be as effective as, but less toxic than, cisplatin–paclitaxel in 38 patients with previously untreated ovarian cancer. Paclitaxel was given over 3 h in escalating doses, beginning at a dose of 135 mg m−2 and increasing in 25-mg increments to the maximum tolerated dose. Carboplatin was administered to an area under the concentration–time curve (AUC) of 5; upon reaching the paclitaxel maximum tolerated dose of 185 mg m−2, the carboplatin dose was increased to AUC 6, and then 7.5. All 193 courses administered were evaluable for toxicity. Neutropenia was the principal dose-limiting toxicity encountered, with severe neutropenia observed at every dose level. Nonhematologic toxicity was generally mild and short lasting. It was concluded that paclitaxel and carboplatin can be combined at full therapeutic doses and administered on an outpatient basis with tolerable toxicity and efficacy comparable with that of other active regimens.

Long-term drug treatment of unipolar depression.

Depression is characterized by a recurrent course in many patients, and as a potentially chronic illness. It therefore often requires a long-term treatment strategy. This article proposes answers to the questions involved in devising such a strategy, using the available literature. Cessation of treatment immediately after the observation of a response is associated with a high relapse rate, especially within the following 4 months, and all patients should therefore be treated for at least 3-6 months after the acute response to secure a stable remission. Patients at risk of recurrence should be considered for maintenance therapy thereafter. Such patients include those with prior episodes of depression within the last 5 years, those with a particularly severe or chronic depressive episode, those with residual symptoms scoring HAMD > 8 and also those whose age at onset was < 25 or < 60 years. Those who need maintenance therapy are likely to need it for a number of years, or indefinitely. SSRIs are better tolerated than TCAs or MAOIs and display similar efficacy in acute, continuation and maintenance treatment. They are less likely to be fatally toxic if taken in overdosage. There is growing evidence to support the use of a full therapeutic dose of antidepressant in maintenance treatment.

Maintenance Treatment of Major Depression: A Review of the Literature

This review was undertaken to assess the indications for and efficacy of maintenance treatments for major depression. It was based on a search of the medical literature and a review of randomized clinical trials. The literature shows that antidepressant medications and, to a lesser extent, psychotherapy are both effective in preventing recurrence of major depression. Lithium and carbamazepine may also be effective. Antidepressant medications are probably more effective at full therapeutic doses than at the lower doses initially advised for maintenance treatment. Based on this review, maintenance treatment should be considered for any patient with recurrent major depression. It is clearly indicated in individuals with multiple frequent episodes. Patients with less-severe illness must weight the risks and benefits of treatment in light of their earlier course and symptoms, the current impact of treatment, and the likely future impact of additional episodes.

Long-Term Treatment of Depression

Long-term treatment of depression encompasses two separate phases: relapse and recurrence prevention. Relapse prevention aims to consolidate the response to acute treatment. Some tricyclic antidepressants (TCAs) have been shown to be effective, possibly in lower than standard acute treatment doses. The selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective at the same minimum effective doses used to treat acute depression, or in a lower dose as with citalopram. Recurrence prevention aims to reduce the risk of onset of a new episode of depression in patients with recurrent depression. Imipramine has been thoroughly studied in unipolar depressed patients in full therapeutic doses for up to five years and is clearly effective. Other TCAs have not been adequately tested and may not all be equally effective. The SSRIs fluoxetine, paroxetine and sertraline have also been shown to be effective in reducing the risk of new episodes of depression.

Medical cost savings from pentoxifylline therapy in chronic occlusive arterial disease.

This article assesses the direct medical cost savings associated with therapeutic dosages of pentoxifylline therapy compared with lower dosages in treating chronic occlusive arterial disease (COAD). The savings accrue from elimination of invasive diagnostic measures or a number of surgical procedures received by patients with COAD during hospital admissions. Findings are based on a secondary analysis of results presented in a previously published report of a population based historical cohort study. Patients in this study were severely enough afflicted by the disease that most were under the care of vascular specialists and many underwent surgery to restore normal blood flow. Costs are based on charges from Medicare expenditures in 4 US states in 1989. A case-mix adjustment procedure was applied and a sensitivity analysis was conducted on key assumptions and variables in the cost savings model. Pentoxifylline therapy reduced average hospital costs per patient by $US1173 per year (1989 dollars). After further adjustment for the costs of outpatient visits, other related drugs and the drug acquisition cost, an overall saving of $US965 would still be realised with a patient who received the full therapeutic dose of pentoxifylline. Sensitivity analysis suggests total annual direct medical cost savings between $US69 and $US3090 per patient. Hence, under the most plausible assumptions regarding choice of procedures, study design and patient population, and considering the possibility that diagnostic and surgical costs are delayed but not prevented, pentoxifylline therapy substantially reduces direct medical costs.

Guidelines for treating depressive illness with antidepressants: A statement from the British Association for Psychopharmacology

Depression is a common illness which affects some 3% of the population per year. At least 25% of those with marked depression do not consult their general practitioner and in half of those who do the illness is not detected. Depression is easy to recognize when four or five of the core symptoms have been present for 2 weeks which often coincides with some occupational and social impairment. The core symptoms are depressed mood, loss of interest or pleasure, loss of energy or fatigue, concentration difficulties, appetite disturbance, sleep disturbance, agitation or retardation, worthlessness or self blame and suicidal thoughts. A diagnosis of depression is made when five of these core symptoms, one of which should be depressed mood or loss of interest or pleasure, have been present for 2 weeks. Four core symptoms are probably sufficient. Response to antidepressants is good in those with more than mild symptoms. When there are only few or very mild depressive symptoms evidence of response to antidepressants is more uncertain. Antidepressants are effective, they are not addictive and do not lose efficacy with prolonged use. The newer antidepressants have fewer side effects than the older tricyclics, they are better tolerated and lead to less withdrawals from treatment. They are less cardiotoxic and are safer in overdose. Antidepressants should be used at full therapeutic doses. Treatment failure is often due to too low a dose being used in general practice. It may be difficult to reach the right dose with the older tricyclics because of side effects. To consolidate response, treatment should be continued for at least 4 months after the patient is apparently well. Stopping the treatment before this is ill-advised as the partially treated depression frequently returns. Most depression is recurrent. Long-term antidepressant treatment is effective in reducing the risk of new episodes of depression and should be continued to keep the patient well.

Cyclosporin A, FK506, rapamycin

Potent immunosuppressive agents display toxic complications at full therapeutic doses: cyclosporin A (CsA) produces pleiotropic mesenchymal effects with prominent vasculopathy, whereas FK506 displays severe neurotoxicity associated with a similar range of mesenchymal and possibly vasculitic reactions. The concept of drug synergy seeks to exploit combinations of agents that promote each other's immunosuppressive effects. This article presents a quantitative method to assess synergy in vitro and in vivo--the median-effect analysis. Application of this method revealed synergistic interactions of CsA with steroids, an additive effect with azathioprine, and antagonistic effects with FK506 and enisoprost. Clearly, a synergistic therapeutic combination can be clinically useful only if it is not associated with a similar potentiation of toxic complications. Clinical practice has documented the synergistic relation of CsA plus steroids and the antagonistic relation of CsA with FK506 or enisoprost. Clinical trials of rapamycin, which displays extremely potent synergistic effects with CsA both in vitro with human and in vivo with animal immune responses, may afford important new insights for clinical immunosuppression.

Calcium-channel blocking agents as therapy for amphotericin B nephrotoxicity.

Amphotericin B is a broad-spectrum antifungal agent shown to be effective in the treatment of systemic fungal infections. Unfortunately, therapeutic doses are often associated with a variety of adverse effects, including nephrotoxicity. Studies of the deleterious effects of amphotericin B on the renal microvasculature are yielding clues to sparing kidney function. In selected patients, concomitant use of a calcium-channel blocker may prevent the nephrotoxic effects of amphotericin B and allow full therapeutic doses to be used.

Sensitive, Selective Detection and Differentiation of Salicylates and Metabolites in Urine by a Simple HPTLC Method

We present a method for salicylates which is slightly more labor intensive than the usual manual Trinder's test, but is much more sensitive and able to identify individual drugs or metabolites. A 2-mL acidified urine aliquot is briefly extracted with 5 mL ether, and the residue from evaporating the ether under nitrogen is chromatographed on a 250-microns silica gel HPTLC plate using benzene-acetic acid-diethylether-methanol (60:9:30:5) as mobile phase and 5% aqueous ferric chloride as chromogen. The hardiness of the method is evidenced by the Rf values, which vary by no more than 3% over a four-month period. The Rf values are 0.70 for salicylic acid and diflunisal, 0.67 for aspirin and methyl salicylate, 0.60 for gentisic acid, 0.57 for p-aminosalicyclic acid, and 0.40 for salicyluric acid. Detection limits of 1 ppm or less for all the analytes compared favorably to limits of more than 20 ppm for Trinder's test. Separations and spot shapes are sufficiently good to make instrumental quantitation potentially applicable. Sensitivity is sufficient to give clearcut, positive test results 48 h after a single 80-mg dose of ASA by mouth or a 100-mg dose of methyl salicylate by skin injection with a muscle rub, and more than 96 h after a 660-mg oral aspirin dose. Thus, the test is useful for detection and a good degree of differentiation, even in patients using subtherapeutic doses of these salicylates or in those with trace residues from significantly remote full therapeutic or larger doses prior to specimen collections.

Evaluation of the policy of empiric treatment of suspected Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome

purpose: This study was designed to measure response rates and survival in patients with acquired immunodeficiency syndrome (AIDS) and suspected Toxoplasma encephalitis treated empirically and in AIDS patients treated for biopsy-proven toxoplasmosis. patients and methods: AIDS patients identified at Bellevue Hospital between August 1985 and May 1986, who had abnormal computed tomographic scans of the brain and who received empiric treatment for toxoplasmosis, constitute the empirically treated cohort. A cohort with biopsy-proven toxoplasmosis was identified from Bellevue Hospital neuropathology records spanning 1981 through 1986. Patient records were reviewed with a standardized data form, and tomograms were evaluated by neuroradiologists unaware of the identity of the scans. Survival analysis was performed by the product limit method. results: Of 38 empirically treated patients, 26 responded clinically and radiographically within four weeks of initiation of therapy. Four of nine patients who underwent biopsy responded to treatment. There was no difference in these response rates (68% versus 44%, p = 0.24). The median survival of the empirically treated responders, from first diagnosis of AIDS to last follow-up, was 422 days. Among the 30 responders, five patients discontinued therapy and four of them had relapses. No relapses occurred in the 25 patients who continued full-dose therapy indefinitely (p = 0.0004). Sixteen of 30 patients (53%) receiving continuous therapy developed toxicity, which required a change in medication. There was no difference in the survival of patients who continued to receive sulfadiazine and pyrimethamine compared with those in whom clindamycin was substituted for sulfadiazine (median, 311 days versus 422 days, p = 0.25). conclusion: A policy of empiric treatment of suspected Toxoplasma encephalitis is satisfactory, and patients who respond to such therapy and continue to take full therapeutic doses of anti- Toxoplasma drugs have relatively long survivals.

Omeprazole: Inhibiting the Final Common Pathway to Acid Secretion - The Acid Pump

Omeprazole is the first agent in a new therapeutic advance class the proton or acid pump inhibitors which represents a significant therapeutic advance in the treatment of acid related diseases. Omeprazole reduces gastric acid secretion at its source – the acid pump of the parietal cell, thereby offering precise and consistent clinical effects. Omeprazole once daily has been shown to heal over 80% of duodenal ulcers within two weeks and over 95% within four weeks In gastric ulcer, the healing rates are up to 80% within four weeks and 96% within eight weeks. More patients are free from symptoms earlier on omeprazole therapy than with the H2receptor antagonists. Omeprazole is also effective in healing and symptom relief even where prolonged H2receptor antagonist therapy has been unsuccessful. Omeprnzole has been shown in clinical trials to be the first consistently effective treatment of erosive/ulcerative reflux esophagitis. Complete healing is achieved in the majority of patients and symptom relief is rapid. In clinical trials with 20 mg once daily, over 70% of patients healed within four weeks and up to 85% healed within eight weeks. Also. patients with erosive/ulcerative reflux esophagitis resistant to three months or more of treatment with full therapeutic doses of H2receptor antagonists have shown significant benefit, with healing rates of 49% within four weeks and 73% within eight weeks of therapy with omcprazole. The rare Zollinger-Ellison syndrome has been difficult to treat in the past due to the massive hypersecretion of gastric acid Omeprazole has proved highly effective in this syndrome, being well tolerated by patients who have received more than five years of continuous treatment with daily oral doses up to 160 mg. In summary, in extensive clinical trials omeprazole has been shown to be highly effective in the treatment of duodenal and gastric ulcers, erosive/ulcerative reflux esophagitis and Zollinger-Ellison syndrome. Omeprazole is well tolerated and is without any established side effects when used for short periods. It remains to be established whether H2blockers still represent the best available therapy for acute treatment of peptic disorders, and whether maintenance therapy is best achieved with H2blockers or with proton pump blockers.

Treatment of Massive Acute Pulmonary Embolism: The Use of Low Doses of Intrapulmonary Arterial Streptokinase Combined with Full Doses of Systemic Heparin

The efficacy of low-dose, locally administered streptokinase (SK) combined with full therapeutic systemic doses of heparin was investigated. Seven patients with angiographically proven massive acute pulmonary embolism were treated. Streptokinase, 10,000-20,000 units/hour, was administered directly into the left or right pulmonary artery for 9 to 24 hours. Heparin was administered concurrently. The number of unperfused segments of the infused lung shown on the lung scan decreased from 5 +/- 2 to 2 +/- 1 after 12-24 hours (p less than .01). No change was shown in the contralateral lung. The angiographic index of severity score in the infused lung decreased from 16 +/- 1 to 9 +/- 4 (p less than .01). The partial pressure of oxygen in arterial blood improved within four hours. In spite of the low doses of streptokinase, however, two major bleeding episodes occurred that required blood transfusion. In conclusion, low dose intrapulmonary streptokinase, combined with intravenous heparin, may provide a therapeutic option in patients with life-threatening massive acute pulmonary embolism in whom full dose lytic therapy may be hazardous, although even low dose lytic therapy was associated with risk.

Mandibular reconstruction in the radiated patient: the role of osteocutaneous free tissue transfers.

This paper discusses our experience with the second metatarsal and iliac crest osteocutaneous transfers for mandibular reconstruction. The prime indication for this type of reconstruction was for anterior mandibular defects when the patient had been previously resected. Midbody to midbody defects were reconstructed with the metatarsal and larger defects with the iliac crest. In most cases, an osteotomy was done to create a mental angle. The evaluation of speech, oral continence, and swallowing revealed good results in all patients unless lip or tongue resection compromised function. Facial contour was excellent in metatarsal reconstructions. The iliac crest cutaneous flap provided a generous supply of skin for both intraoral reconstruction and external skin coverage but tended to be bulky, particularly when used in the submental area. Thirty three of 36 flaps survived completely. Flap losses were due to anastomosis thrombosis (1), pedicle compression (1), and pedicle destruction during exploration for suspected carotid blowout (1). Ninety three percent of bone junctions developed a solid bony union despite the mandible having had a full therapeutic dose of preoperative radiation. Despite wound infections in 8 patients, and intraoral dehiscence with bone exposure in 12 patients, all but one of these transfers went on to good bony union without infection in the bone graft.

Overview of efficacy of fenbufen in rheumatoid arthritis and osteoarthritis

Fenbufen (Cinopal) has been evaluated extensively in 155 clinical trials, including 102 in rheumatoid arthritis and 53 in osteoarthritis. Forty-nine of these trials involving 12 protocols have been identified as pivotal. All 12 protocols (six rheumatoid arthritis and six osteoarthritis) were double-blind and controlled, with the duration of treatment ranging from four weeks to one year, and included sufficient patient populations to detect important differences in efficacy between fenbufen and the reference agents. Evaluation of the efficacy results was based on the standard parameters commonly measured for rheumatoid arthritis and osteoarthritis. The primary evaluation point was the end of four weeks of therapy. Results of the 49 studies employing the 12 pivotal protocols, demonstrated that fenbufen, given in divided daily doses of 600 to 1,000 mg, provided significant anti-inflammatory effects. These effects were superior to placebo and comparable to those attained with full therapeutic doses of aspirin, indomethacin, phenylbutazone, and ozyphenbutazone. Long-term trials provided important information as to the relative effectiveness and tolerance of fenbufen in the management of patients with rheumatoid arthritis and osteoarthritis. The proportion of fenbufen-treated patients able to continue long-term therapy was substantially greater than the proportion of aspirin-, indomethacin-, or placebo-treated patients. Results from these trials indicate that fenbufen provides a more favorable ratio of benefit to risk than either aspirin or indomethacin.

Desensitization of patients allergic to penicillin using orally administered β-lactam antibiotics

When patients allergic to penicillin develop life-endangering infections that require treatment with beta-lactam antibiotics, they face a fatal infection or the possibility of a fatal allergic reaction. We have approached this situation by using an oral desensitization procedure before full-dose antibiotic therapy. Thirty consecutive patients with histories of allergic reactions to penicillin, positive immediate wheal and flare skin-test reactions to penicillin determinants, and life-threatening infections were studied. Bacterial endocarditis requiring penicillin G therapy led to desensitization of 19 patients, Pseudomonas sepsis of pneumonia requiring treatment led to desensitization of nine subjects, and staphylococcal infections requiring therapy with a penicillinase-resistant penicillin led to desensitization of two patients. Penicillin G or carbenicillin were administered orally, beginning with 100 U or 60 microgram, respectively. At 15-min intervals, progressively doubled doses were given during continuous monitoring for the appearance of allergic reactions. Within 5 hr, full therapeutic doses were administered intravenously. Skin-test reactions disappeared or diminished in all 23 subjects who were retested after desensitization. Full courses of antibiotic therapy and cure of the infections were accomplished in 30 of 30 patients. No deaths, anaphylaxis, or severe acute allergic reactions occurred. Pruritic cutaneous eruptions appeared in nine patients (30%) 6 to 48 hr after the onset of therapy. One patient developed reversible nephritis 3 wk into therapy with penicillin G. The results of this study suggest that oral desensitization is an effective, relatively safe approach to administering beta-lactam antibiotics to penicillin-allergic patients with life-threatening infections.