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Methylxanthines are at present widely prescribed for obstructive airway-diseases. However, the exact therapeutic role of these drugs is not clear in 1990. In this short review, we discuss what we think to be a rational use of xanthines in asthma and in COPD patients: shortly speaking, we propose that the drugs are not first-line therapeutic tools and should be only prescribed in selected situations.
The pathophysiology, diagnosis, and treatment of diabetic gastroparesis are reviewed, and the mechanisms of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage of metoclopramide, domperidone, and cisapride are described. Diabetic gastroparesis is a state of delayed gastric emptying that reportedly affects 20-30% of diabetic patients. Symptoms include nausea, early satiety, postprandial bloating and fullness, and vomiting. Diabetic gastroparesis has been managed most successfully with drugs that stimulate gastric emptying. Of the three agents studied--metoclopramide, domperidone, and cisapride--only metoclopramide is commercially available in the United States. The clinical efficacy of metoclopramide, domperidone, and cisapride has been well documented in several placebo-controlled trials. Metoclopramide effectively decreases mean gastric emptying time, although tolerance to this stimulation of gastric emptying may develop with long-term therapy. However, symptomatic relief persists with long-term therapy because of metoclopramide's antiemetic properties. Domperidone, which has also been shown to stimulate gastric motility and to possess antiemetic properties, improves symptoms in patients suffering from diabetic gastroparesis. Cisapride appears to have continued beneficial effects on gastric motility with long-term therapy. All three agents have favorable adverse-effect profiles. Although metoclopramide is currently the first-line agent for the management of gastroparesis, domperidone and cisapride both possess properties that may make them useful alternatives in patients who are unresponsive to or cannot tolerate metoclopramide therapy.
The National Heart, Lung, and Blood Institute (NHLBI) has recommended intensive dietary treatment as first-line therapy for patients with high cholesterol levels. The NHLBI has also encouraged research into the effectiveness and safety of alternative diets and further study of human behavior as it relates to adherence to diets. Based on these recommendations and previous studies suggesting a hypocholesterolemic effect of oat bran dietary supplementation, 16 family practice outpatients with elevated cholesterol levels were enrolled in a 12 week study designed to assess the practicality and effectiveness of adding four oat bran muffins per day to the diet. Subjects were randomized into immediate intervention and delayed intervention groups. The combined group had a significant decrease in total cholesterol of 7.9 percent (p less than .03) and in LDL-cholesterol of 10.1 percent (p less than .03) but there was no significant difference with respect to lipid changes between the immediate group and the delay group when the delay group was serving as a control for the immediate group. The results taken in conjunction with evidence in the literature indicate that the simple addition of oat bran muffins to the diet of certain family practice outpatients is well tolerated and probably effective in lowering serum total and low density lipoprotein cholesterol.
The diagnosis of syphilis is dependent mainly on serological tests. In primary syphilis there is a seronegative period when the diagnosis is dependent on demonstration of Treponema pallidum in lesional exudate. The most widely used screening tests for syphilis are the VDRL and the rapid plasma reagin (RPR) and for confirmation the fluorescent treponemal antibody (FTA) and the treponema pallidum hemagglutination (TPHA) tests. The nonvenereal treponematoses have the same serological response as in syphilis. For the diagnosis of neurosyphilis, the cerebrospinal fluid (CSF) parameters available are insufficient. The albumin quotient for estimation of the blood-brain barrier function is recommended as well as the IgG index, which is a measure of intrathecal immunoglobulin production. Treponemal antibodies in CSF have high sensitivity for neurosyphilis, although the specificity is low. Although penicillin has been used as first-line therapy in syphilis for more than 40 years, T pallidum has not shown any signs of decreased sensitivity. T pallidum is still one of the most penicillin-sensitive microorganisms known. The standard treatment is depot preparations (benzathine penicillin and procaine penicillin) giving a continuous low penicillinaemia. Treatment failures in early syphilis have been exceedingly rare, although in neurosyphilis there have been several reports indicating that low-dose therapy is insufficient. With recommended treatment regimens, treponemicidal levels of penicillin in CSF are not achieved. Failure of therapy and rapid progression to neurosyphilis has recently been reported in patients coinfected with human immunodeficiency virus (HIV). It has been proposed that neurosyphilis and patients coinfected with syphilis and HIV should be treated with high intravenous doses of benzylpenicillin.
Eighty-three patients with intermediate- or high-grade non-Hodgkin's lymphoma were treated with CEPP(B) (cyclophosphamide, etoposide [VP-16], procarbazine, and prednisone with or without bleomycin) chemotherapy at Stanford University Medical Center (Stanford, CA) from January 1982 through June 1989. Sixty-nine received CEPP(B) as second-line or subsequent therapy after relapse from previous combination chemotherapy, and 14 patients received CEPP(B) as first-line therapy. Of 75 patients evaluable for response, 30 patients (40%) achieved a complete response (CR) and 24 patients (32%) achieved a partial response (PR), providing an overall response rate of 72%. Complete responses were recorded on 21 of 61 (34%) patients with recurrent disease and 9 of the 14 patients who received CEPP(B) as first line therapy (64%). Myelosuppression was the major side effect of treatment, resulting in eight neutropenic-febrile episodes from a total of 253 courses. A single fatal toxic event occurred on a patient who developed adult respiratory distress syndrome. Overall, CEPP(B) was well-tolerated and proved to be effective palliative therapy for patients with non-Hodgkin's lymphoma after relapse. As such, CEPP(B) may be considered for cytoreduction before ablative therapy and bone marrow transplantation. CEPP(B) may also be considered for initial therapy in selected patients who cannot tolerate doxorubicin-containing regimens.
Clinical and genetic studies have allowed the limits of Tourette syndrome to be broadened. There is now strong evidence that chronic motor tics and Tourette syndrome are different manifestations of an autosomal dominant gene with high penetrance. A genetic link with obsessive-compulsive disorder also appears to have been established. Up to 10% of cases of Tourette syndrome may be nongenetic phenocopies, however. There is also an association between Tourette syndrome and attention deficit hyperactivity disorder. This complicates therapy, as psychostimulant drugs may precipitate or exacerbate tics in some individuals. A high proportion of patients with Tourette syndrome also has neuropsychological deficits and learning disabilities. The pathophysiology is incompletely understood. The best supported hypothesis is that there is dopamine receptor supersensitivity, although there are strong suggestions of abnormalities in serotonin metabolism. The possibility of abnormalities in neuropeptide systems is being explored. Treatment of tics relies primarily on neuroleptics with dopamine receptor blocking activity. Clonidine may be useful in some patients, especially those with behavior problems. Obsessive-compulsive symptoms can be treated using appropriate pharmacologic agents. The treatment of attention deficit disorder in patients with tics should begin with behavioral strategies. Clonidine can be tried as the first-line drug, and psychostimulants should be used only if necessary and with great caution. In rare instances it may be necessary to combine a psychostimulant and a neuroleptic.
Twenty-one strictures following uretero-digestive anastomoses were treated by percutaneous transrenal dilatation. In 20 cases, an Olbert type angioplasty balloon on a guidewire was used. Rigid coaxial dilators were used in one patient after failure of the preceding technique and an electroincision was performed prior to dilatation in the remaining case. Overall, percutaneous transrenal dilatation was successful in nine patients, whereas ten dilatations failed and two patients are undergoing continued modeling with a mean follow-up of 16 months (range 1-42 months). Success rates by type of anastomosis were as follows: Bricker 5/12; Coffey 1/4; enterocystoplasty 2/4 and ureteroileovesical anastomosis 1/1. The date of development of the stricture, duration of modeling, and caliber of the indwelling catheter were apparently without influence on results. Because morbidity is low with percutaneous transrenal dilatation, this technique is advocated as first-line treatment, with surgery being reserved to failures.
Recombinant interferon alpha-C is a new strain of the alpha interferon family. It was given to 33 patients with measurable metastatic renal cell carcinoma of whom 31 were evaluable. Protocol consisted of 3 million U/d for 2 weeks, then 3 million U/m2 every other day until progression. No complete response was observed. Three patients (9.7%) had partial response for a mean duration of 5.6 months and eight patients (25.8%) were stabilized for a mean of 4.3 months. Responsive sites were mainly lung, bone, and kidney, while side effects were generally mild. better results were observed in previously nephrectomized patients who had not received chemotherapy or hormonotherapy for recurrent or metastatic disease (p less than 0.05), and also in patients with a brief disease-free interval and short delay from presenting symptoms of the primary tumor until interferon treatment (p less than 0.05). Median survival was significantly longer in responders than in progressors (p less than 0.05). We suggest that the efficacy of recombinant interferon alpha-C in a low-dose regime versus other types of interferon as first-line therapy for inoperable, metastatic, or locally recurrent renal cell carcinoma should be investigated in a prospective, controlled, randomized study.
Primary carcinoma of the fallopian tube is uncommon and is often treated using regimens active in ovarian carcinoma. Evidence is scant that such therapies benefit patients with fallopian tube carcinoma. Between December 1979 and July 1988, we treated 18 patients who had adenocarcinoma of the fallopian tube with the combination of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) administered intravenously on 1 day every 28 days. Histologic confirmation of fallopian tube carcinoma was obtained before entry in the study. Three patients had stage I disease, five had stage II, nine had stage III, and one had stage IV. Sixteen patients received the combination therapy as first-line treatment after cytoreductive surgery, and two patients received it for recurrent carcinoma. Seven patients had clinically measurable disease at the start of therapy. Two of these patients had a complete clinical response, two had stable disease, and three had progressive disease. Eight of the 15 patients with stages II-IV disease underwent second-look laparotomy; four had a complete response to therapy and four had a partial response, making the overall response rate 53%. The toxicity of the regimen was moderate. The median survival was 81 months. Patients with stages II-IV disease had a median survival of 43.9 months and a progression-free survival of 22.5 months. This regimen appears to be active in fallopian tube carcinoma and can result in response rates comparable to those reported for epithelial ovarian cancer.
Excessive vaginal bleeding, or menorrhagia, is one of the most common presenting symptoms for gynecologic patients. Although this disorder has many possible etiologies, it is generally possible to approach its diagnosis and management in an orderly fashion. When evaluating the menorrhagic patient, it important to gear the work-up toward a differential diagnosis that includes pregnancy-related causes, hormonal problems, iatrogenic etiologies, mechanical intrauterine disorders, infections of the lower genital tract, and gynecologic cancers (PHIMIC). This differential approach can guide the types of historical data obtained from the patient, focus the physical examination, and alert the practitioner to the most appropriate laboratory and radiologic evaluation. Therapy can differ widely, depending on the cause of the bleeding. Most types of menorrhagia respond to medical therapy with oral contraceptives, oral synthetic estrogens or progestins, and long-acting intramuscular progestins or GnRH agonists. Surgical approaches, such as dilatation and curettage or hysterectomy, are less and less a first-line therapy; but innovative surgical techniques such as hysteroscopy and laparoscopic surgery are becoming increasingly important. With rapid, goal-directed diagnosis and specific therapy, the medical complications, anxiety, and discomfort suffered by the woman with menorrhagia can be alleviated quickly.
Several important points regarding the treatment of urinary tract infections should be made. Single-dose and short-course antibiotic therapy is appropriate only for women with acute bacterial cystitis due to E. coli. Studies comparing single-dose to full-course therapy have not been sufficiently designed to draw valid statistical conclusions, and only TMP/SMX is recommended at this time. Recurrent UTI in women is almost always due to reinfection, which is best managed by prophylactic antibiotics. Acute bronchitis and acute exacerbations of chronic bronchitis are often due to viral infections, and therefore antibiotic therapy is not always needed. In acute exacerbations of chronic bronchitis, the clearest success rates for antibiotic therapy have been in patients, who have all three of the following symptoms: increased dyspnea, increased sputum production, and sputum purulence. Mupirocin is an important addition to the agents used to treat bacterial skin infections due to streptococcal and staphylococcal strains. In impetigo, mupirocin has been demonstrated to be as effective or superior to oral erythromycin. In prostatitis, data on the fluoroquinolones appears impressive, but further comparative trials are needed. They may become first-line, empiric therapy. The newer oral antibiotics are not recommended as initial, empiric therapy in the outpatient management of common infections, with the possible exception of the treatment of prostatitis. These newer agents may be more important in the treatment of recurrent or resistant infections.
The pathophysiology, clinical manifestations, monitoring techniques, and management of elevated intracranial pressure (ICP) are reviewed. The use of barbiturate coma to treat ICP is discussed in detail. Elevated ICP can be associated with severe head injuries and diseases of the central nervous system such as brain tumors and stroke. Symptoms of elevated ICP may be difficult to distinguish from symptoms of other disease states. ICP monitoring techniques such as the intraventricular catheter and the Camino fiber optic system are useful for determination of ICP elevations before any changes in vital signs or neurological status occur. Conventional treatment and control of ICP elevations includes general and physiologic management (cerebrospinal fluid removal, fluid restriction, controlled hyperventilation, sedation, and elevating the patient's head) and pharmacologic management. Osmotic diuretics, (e.g., urea, mannitol, glycerol) and loop diuretics (e.g., furosemide, ethacrynic acid) are first-line pharmacologic agents used to lower elevated ICP. Corticosteroids may be beneficial in some patients. Patients with elevated ICP refractory to conventional treatment may benefit from therapy with high-dose barbiturates. Pentobarbital has been used in the majority of the clinical studies. Pentobarbital serum concentrations should be determined every 24-48 hours when a patient is in a barbiturate coma because pentobarbital clearance increases with continued high-dose therapy. The treatment of elevated ICP requires aggressive therapy and intensive monitoring. In patients whose ICP is refractory to conventional therapies alone, survival rates have been improved by combining high-dose barbiturates with conventional therapies.
The results of percutaneous automated lumbar nucleotomy in the treatment of lumbar disc herniation were assessed in a series of 39 patients. The technique consists of mechanical decompression of the herniated intervertebral disc without total excision. Only one-space discs were treated by this method. Sciatica was the predominant clinical symptom in 30 cases, and lumbar pain in 9 cases. Good to very good results were obtained in 70% of patients with sciatica and in 55% of patients with lumbar pain. After 4 cases of nucleotomy performed after failure of nucleolysis were excluded, the proportion of very good results rose to 77% in sciatica. Conversely, it seems that a number of failed nucleotomies can be treated by nucleolysis. Nucleotomy is very well tolerated and deserves to be used as first-line treatment of single and radiologically well documented lumbar disc herniations.
Megestrol acetate was administered as first-line therapy to 152 patients with advanced breast cancer. Forty-three of 136 evaluable patients (32%) obtained an objective response (95% confidence interval, 24% to 40%). Toxicity was minimal, with only 4 patients requiring dose reduction. Megestrol acetate is an effective, well-tolerated agent in previously untreated patients with advanced breast cancer.
Hypertension frequently coexists with hyperlipidaemia and it has been suggested that the potential benefits of blood pressure reduction may be compromised if lipid levels are not concurrently reduced. In addition, conventional first line antihypertensive drugs (thiazide diuretics and beta-blockers) produce adverse changes in blood lipids which are most apparent in the short-term but do not entirely disappear during chronic treatment. Of the alternative first-line antihypertensive agents, the calcium antagonist and ACE inhibitor drugs are lipid 'neutral' but only the alpha 1-blockers have been associated with favourable effects on the lipid profile.
Angiotensin-converting enzyme inhibitors are mixed vasodilators with a prolonged sustained effect in chronic heart failure. They also act on the reactivity of peripheral circulation, on ventricular remodelling after myocardial infarction, on myocardial hypertrophy in arterial hypertension and on ventricular hyperexcitability. They alleviate the symptoms of symptomatic heart failure, and they constitute the only treatment that has been able to improve the survival of patients with the most severe heart failure. Several studies are in progress to determine whether these drugs should be used as first-line therapy.
The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.
In order to investigate the impact of detailed fetal echocardiography on perinatal care at a tertiary health care centre, the records of all 29 cases referred for fetal echocardiography during the years 1987-88 were reviewed. All patients had risk factors for offspring with congenital heart disease. A family history of congenital heart disease led to fetal echocardiography in about two-thirds of the cases, while the remainder were referred on the basis of abnormal cardiac screening examinations during fetal assessment. Forty examinations were performed on patients at gestational ages of 16 to 37 weeks. Detailed fetal echocardiography did not alter the perceived severity of major structural cardiac defects previously identified by an experienced fetal assessment unit and did not change or influence intrapartum care. The value of fetal echocardiography in the diagnosis and treatment of fetal tachyarrhythmias was confirmed. Also, fetal echocardiography provided reassurance of cardiac normality in cases with familial and maternal risk factors for congenital heart disease. Fetal echocardiography appears to be an inappropriate screening tool in view of its limited availability and focus. Comprehensive fetal assessment with four chamber cardiac imaging is the appropriate first-line screening test for patients with risk factors for offspring with congenital heart disease.