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A comparative trial of flunarizine and propranolol in the prevention of migraine.

The calcium-entry blocker flunarizine (Sibelium; Janssen) was compared with the beta-adrenoreceptor-blocking agent propranolol in the prophylaxis of migraine. Fifty-eight patients were entered into a double-blind 4-month treatment trial. Patients in whom beta-blockers were contraindicated were excluded from the trial. At the end of the trial 28 patients had received 10 mg flunarizine at night during the study, 29 patients had received 60 mg propranolol 3 times a day and 1 patient was withdrawn. Both groups responded well; and there was a 4-fold drop in frequency of attacks. There was no significant difference between the two groups in terms of patient profile, onset of response to therapy, final response to therapy, incidence of dropout from the trial or incidence of side-effects. Side-effects for flunarizine were weight gain (9 patients) and tiredness (6), and for propranolol sleep disturbances including nightmares (6), tiredness (8), mental changes (e.g. irritability) (3) and weight gain (4). Both flunarizine and propranolol are useful drugs for migraine prophylaxis and can be used effectively as first-line drugs. The low incidence of generally mild side-effects with flunarizine may make it preferable to many of the agents at present in use for migraine prophylaxis.

Adolescent↗

Evaluation of a new antihypertensive agent ketanserin versus methyldopa in the treatment of essential hypertension in older patients: an international multicenter trial.

The serotonergic antagonist ketanserin (K) was compared to methyldopa (M) in a four-center international study in 119 hypertensive patients over 50 years of age. After a 4-week placebo run-in period, patients randomly received K (20-40 mg b.i.d.) or M (250-500 mg b.i.d.) for 3 months. The drugs were given in monotherapy for at least 1 month, then a diuretic could be added if blood pressure remained abnormally high. For the patients on monotherapy, active drug was replaced by placebo at the end of the 3-month period until the patients were hypertensive again. K and M had a similar effect on systolic blood pressure, but diastolic blood pressure was reduced significantly more by K than by M. Significantly more patients had their blood pressure normalized in the K group (75%) than in the M group (49%). The twice daily dosage schedule caused trough blood pressure control with both drugs. No rebound hypertension occurred at discontinuation of treatment. Monotherapy with K caused a decrease in heart rate (-5 beats/min) while M produced no change. Body weight decreased with K (-0.5 kg) and increased with M (+ 0.4 kg). No important hematological or biochemical changes were seen with either drug. Slightly fewer patients reported adverse reactions during K monotherapy (40%) than with M (45%). In the latter group mainly central side effects were observed. The data confirm K to be an effective first-line antihypertensive agent with a favorable side-effect profile.

Blood Pressure↗

Is first salvage chemotherapy the last-line chemotherapy in children with Hodgkin's disease? A tentative answer based on long observation of two patients.

In 82 children affected with Hodgkin's disease, in whom a complete remission was obtained, the first relapses occurred in 13 patients, their outcome was a follows: one child died of relapse and in 12 others second complete remissions were achieved. They were durable in 10 children (median, 65.5 months). Two remaining children had further relapses, their treatment consisted of four successive salvage chemotherapies. Both patients are now in their fifth complete remission. The third-line chemotherapy was already introduced 78+ months and 39+ months ago respectively. We believe that it is not possible to determine exactly the end-stage of Hodgkin's disease in those children and adolescents who have failed the first-line salvage chemotherapy.

Adolescent↗

Carvedilol for systemic hypertension.

Twenty-four hour profiles of intraarterial ambulatory blood pressure (BP) and heart rate were significantly reduced by administration of carvedilol, a new beta-blocker with vasodilating properties. Twelve patients were given carvedilol, 25 mg twice daily for 2 weeks; the dose was then increased to 50 mg twice daily if the target BP was not achieved. After 4 weeks of therapy, mean daytime reduction in BP was 25 +/- 3 mm Hg systolic and 19 +/- 3 mm Hg diastolic, and mean reduction in heart rate was 22 +/- 3 beats/min. BP at the peak of isometric exercise and during dynamic exercise was also significantly reduced. Radionuclide measurements showed that left ventricular ejection fraction was not affected by treatment, but there was a significant reduction in systolic and diastolic volumes. The drug was well tolerated. This clinical trial suggests that carvedilol will be a useful first-line drug for treatment of essential hypertension, and its vasodilating action may have a more favorable effect on left ventricular function than conventional beta-blocking drugs.

Adrenergic beta-Antagonists↗

Long-term hypotensive treatment with nitrendipine in mild to moderate essential hypertension: preliminary results of a placebo-controlled study versus atenolol.

Nitrendipine is a dihydropyridine calcium antagonist suggested to be a new drug for first-line antihypertensive therapy, possibly active in once-daily administration. In the present study the acute and long-term hypotensive effects of nitrendipine have been evaluated in comparison with those of atenolol in a randomized, double-blind, clinical trial. Twenty-four patients have been studied, and the effects of treatment have been evaluated both at rest and during psychological and physiological stresses. Hemodynamic noninvasive parameters have also been obtained, at rest and during mental arithmetic tests, by a continuous-wave Doppler technique. Preliminary results about the first 13 consecutive patients are reported here. Nitrendipine induced a highly significant acute hypotensive effect (2 h after drug administration), whereas no effect was observed for atenolol except for heart rate. During chronic treatment (5 weeks), nitrendipine showed less hypotensive effect than atenolol when BP values 24 h after the last administration were analyzed, but significantly more effect when values obtained 2 h after drug administration were evaluated. These findings confirm that nitrendipine is effective in decreasing blood pressure, but the once-daily administration may not bring about the maximum effect in all patients. Interesting aspects of this drug, which make the clinical use of this compound safe, are represented by apparent lack in tolerance and rebound, and by the moderate increase in cardiac output associated with the treatment.

Adult↗

European experience with ifosfamide in lymphomas.

In malignant lymphomas, ifosfamide-containing regimens were at first used mainly in second-line therapy and response-adapted protocols. Currently, in combination with other drugs, ifosfamide is being used in several phase-III trials. As salvage therapy in non-Hodgkin's lymphoma (NHL), IMV-Bleo (ifosfamide, methotrexate, etoposide, bleomycin) produced a complete remission (CR) rate of 41% and seemed to be particularly effective in patients with suboptimal response to first-line treatment. IBEP (ifosfamide, bleomycin, etoposide, procarbazine), in combination with procarbazine and bleomycin was an effective non-cross-resistant alternative in CHOP (cyclophosphamide, hydroxydauomycin/doxorubicin, vincristine, prednisone)-refractory NHL. In a trial of response-oriented therapy in high-grade malignant lymphoma patients, the investigators concluded that consolidation therapy was necessary even in patients with rapid response to CHOP. Patients with NHL resistant to or relapsing from conventional chemotherapy or with MOPP-ABVD (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, decarbazine)-resistant Hodgkin's disease (HD) were treated with BMV-VIP [bleomycin, plus high-dose methylprednisolone plus ifosfamide, etoposide, plus methylprednisolone]. In high-grade malignant NHL, patients received three cycles of COP-BLAM (cyclophosphamide, vincristine, procarbazine, prednisone, bleomycin, doxorubicin). Those who achieved CR received two more cycles of COP-BLAM and IMV (ifosfamide, methotrexate, etoposide) as consolidation therapy. Patients in partial remission (PR) or with less of a response to COP-BLAM were switched to IMV. After reaching CR, patients received two additional cycles as consolidation therapy. After the second restaging, patients were randomized to observation v additional radiotherapy. Of 191 patients, 148 have passed first restaging with 51% in CR; 85 went through the second restaging with 61% in CR. Of 32 patients who only reached PR after the first restaging, 15 (47%) achieved CR with IMV. For primary treatment of HD, the German Hodgkin Study Group added a third non-cross-resistant regimen, IMEP (ifosfamide, methotrexate, etoposide, prednisone), to supplement COPP (cyclophosphamide, vincristine, procarbazine, prednisone) and ABV in the primary treatment of HD. In a pilot study, 87% of 63 evaluable patients reached CR. The current phase-III protocol is comparing COPP/ABVD with fast alternating cycles of COPP/ABV/IMEP.

Antineoplastic Combined Chemotherapy Protocols↗

Age-related effects of antihypertensive therapy with alpha-blockers.

Currently, the most important alpha-blockers used in treating hypertension are prazosin and its long-acting congeners, doxazosin and terazosin. Although there are minor age-related changes in the pharmacokinetics of these compounds, they result in no appreciable alteration in dose requirements. Overall, published evidence does not indicate any loss of responsiveness to alpha-blockade in the elderly. Despite the potential risks of first-dose hypotension and of postural hypotension, long-acting alpha-blockers may warrant further consideration as possible first-line therapy in elderly hypertensive patients. These agents allow the simplicity of once-daily dosing, and their cardiac and metabolic effects offer potential advantages.

Adrenergic alpha-Antagonists↗

An overview of integration of therapy for congestive heart failure.

Patients with symptoms of congestive heart failure look to treatment to relieve symptoms, improve the quality of life, and prolong life. They prefer a convenient dosing schedule, with minimal side effects and low cost. A wide variety of agents are available to treat patients with congestive heart failure. The three major classes of drugs that improve heart failure include the diuretics, inotropic drugs, and vasodilators. It appears that any one of these three classes are potential first-line candidates for treating patients with congestive heart failure. Patients with edema usually require long-term therapy with diuretic agents. Since the vasodilators are the only class of drugs which have been shown to prolong life, they should be used routinely in the management of patients with congestive heart failure. Since all three classes of drugs have additive beneficial hemodynamic effects, it makes sense to consider the use of all three in patients with at least moderate to severe heart failure. At the moment unanswered questions include the role of antiarrhythmic agents in reducing the incidence of sudden death, and the use of potent new inotropic vasodilators. Overall, the current therapeutic approach to patients with heart failure is effective in relieving symptoms, improving exercise tolerance and in prolonging life.

Heart Failure↗

The effect of dihydropyridine calcium antagonists in hypertensive patients with impaired renal function.

Dihydropyridine calcium antagonists play an important role in the treatment of arterial hypertension. In many centers, they are used as first-line treatment. Since impaired renal function can be a complication of long-standing blood pressure elevation, the usefulness of dihydropyridine calcium antagonists in hypertensive patients with reduced glomerular filtration rate is an important clinical issue. Several studies of the pharmacokinetics of calcium antagonists, such as nifedipine and related compounds, clearly show that the important pharmacokinetic variables are not affected by impaired renal function. Moreover, the antihypertensive efficacy is not reduced in patients with reduced glomerular filtration rate. A matter of potentially great clinical importance is the fact that several studies have shown that treatment with dihydropyridine calcium antagonists in patients with impaired renal function has reduced the rate of deterioration in filtration rate, leading to a preservation of renal function. It can therefore be concluded that dihydropyridine calcium antagonists are useful in the treatment of hypertensive patients with impaired renal function, that the major pharmacokinetic and pharmacodynamic variables are not negatively affected, in particular that the antihypertensive effect is maintained in such patients, and that there is no retention of metabolites. Finally, the observation that the decline in renal function can be slowed down suggests that dihydropyridine calcium antagonists may be the preferential treatment in hypertensive patients with reduced renal function.

Aged↗

The polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifaceted clinical entity the hallmark of which is ovulatory dysfunction associated with a relative luteinizing hormone excess and follicle-stimulating hormone (FSH) deficiency. Clomiphene citrate has been the first-line drug for ovulation induction in women with PCOS: because it is an attenuated estrogen, its action blocks the acyclic estrone effect in PCOS. However, many women fail to ovulate or conceive on clomiphene, and an appropriate agent for them was unavailable until relatively recently. The use of a "pure" FSH preparation, Metrodin, provides physiologic replacement of the deficient gonadotropin in PCOS; thus, Metrodin is the ideal second-line drug. Its use with a low-dose regimen should avoid the hyperstimulation seen with human menopausal gonadotropin in PCOS; spontaneous ovulation is an end point. Thus, PCOS patients who do not achieve pregnancy with clomiphene citrate have available a new, more physiologic approach to ovulation induction.

Clomiphene↗

[Implantation of endoprostheses in aortocoronary bypass. Preliminary experience at the Thoraxcenter of Rotterdam].

An intraluminal stent was implanted in 5 patients after dilatation of an aorto-coronary venous graft. In the first 4 patients the procedure was motivated by restenosis after angioplasty. In the 5th patient the stent was implanted as a first-line measure in a case of dilated venous bypass stenosis. Stent implantation carries a risk of thrombosis and requires effective anticoagulation. Thus, one of our patients had to be reoperated upon for prosthetic thrombosis facilitated by the withdrawal of anticoagulants owing to a gastrointestinal haemorrhage. After a 3-month follow-up, the results seem to be encouraging in spite of a case of restenosis located at the proximal end of the tutor. However, more time will be needed to determine precisely the effectiveness of stents in the prevention of restenosis after venous graft dilatation.

Aged↗

Percutaneous transluminal angioplasty of failing arteriovenous dialysis fistulae.

Percutaneous transluminal angioplasty (PTA), a method combining diagnostic and therapeutic procedures, was studied prospectively in 40 patients with clinically failing a-v fistulae. Forty-seven procedures were performed in 40 patients with a variety of a-v fistulae (26 Cimino, five saphenous loops, five goretex grafts, and four upper-arm fistulae). In 43 cases the procedure was initially successful. The mean time of fistula patency after first PTA was 10.06 +/- 2.10 months. Primary failures were due either to technical inability to pass the stenosis (two patients) or to vessel perforation during the attempt (two patients). Surgical intervention had to follow both perforations. Restenosis at the dilatation site occurred in six patients, and in one a new stenosis at a different site occurred; the mean time of fistula patency in these patients was 5.8 months. Our results suggest that PTA is a highly effective therapy for the majority of cases of shunt stenosis. The success rate of the method is excellent and the complication rate low. The combination of this interventional approach with the mandatory angiographic procedure if stenosis of a fistula is suspected makes PTA a favourable first-line treatment and appears to save a considerable number of surgical interventions.

Adult↗

[Treatment of achalasia by pneumatic dilatation].

Between 1979 and 1988, 60 patients with achalasia were treated by pneumatic dilatation under general anaesthesia, using the Rider-Moeller apparatus. The diagnosis rested on clinical, radiological, manometric and endoscopic criteria. These 60 patients underwent a total of 99 dilatations: 63.3 per cent were dilated once and 37.7 per cent were dilated several times. Forty seven of the 60 patients were followed up for more than 12 months (mean: 44 months): 2 of them (4.2 per cent) had to be operated upon, while 45 (95.7 per cent) are asymptomatic. Immediate complications were perforation in one case and cardial fissure in another; both were treated medically and cured. There was no oesophagitis or peptic stenosis, and no patient died. These results are compared with those found in the literature. The authors underline the simplicity, safety and effectiveness of pneumatic dilatation and suggest that it should be used as first-line treatment of achalasia, surgery being performed only when dilatation fails.

Adolescent↗

Therapeutic focus. Minocycline in the treatment of acne.

Minocycline has an established place in the oral therapy of acne. Prolonged courses of therapy have an acceptable safety profile. Where therapy with oxytetracycline has failed, minocycline is still likely to prove effective. The twice-daily dosage and ease of absorption from the gastrointestinal tract offer significant advantages over other tetracyclines. The simpler minocycline regime and early onset of clinical improvement are likely to result in better patient compliance, and hence optimise therapeutic response. There is therefore justification for the use of minocycline as first-line oral therapy, but, whether as a first- or second-line therapy, minocycline is a valuable drug in the treatment of this very distressing disorder. The earlier effective therapy is used in a patient with acne, the less physical and psychological scarring will remain thereafter.

Acne Vulgaris↗

Percutaneous automated lumbar nucleotomy.

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.

Adult↗

Ifosfamide in small cell lung cancer.

Ifosfamide, an analogue of cyclophosphamide, has been proven to be of value in numerous malignancies, including testicular cancer, sarcoma, and lymphoma. Furthermore, ifosfamide is more suitable for combination chemotherapy than its parent compound because it causes less myelosuppression than cyclophosphamide. There have been only a few studies evaluating single-agent ifosfamide in small cell lung cancer (SCLC). In patients who have had little or no prior chemotherapy, ifosfamide appears as active as any single agent. Combination chemotherapy regimens employing cisplatin (or carboplatin) plus etoposide plus ifosfamide are currently under way on both sides of the Atlantic. A Hoosier Oncology Group (HOG) study will evaluate this three-drug regimen v cisplatin plus etoposide, and this protocol will establish or refute the value of ifosfamide as first-line therapy in extensive SCLC.

Antineoplastic Combined Chemotherapy Protocols↗

[Recent trends of chemotherapy in small cell lung cancer: a slow but steady progress].

The author reviewed some distinct findings concerning chemotherapy of small cell lung cancer (SCLC) which had appeared recently in the articles of journals and proceedings. Of new drugs, teniposide and carboplatin have a significant activity against SCLC, however, the usefulness of these drugs must be determined in the comparative fashion with their mother compounds. Cisplatin plus etoposide (PVP), which was demonstrated to have a distinct activity in previously treated SCLC and to be not fully cross-resistant to CAV, has recently been incorporated into the first-line treatment. PVP has been evaluated as either induction chemotherapy or consolidation therapy, as alternating chemotherapy with CAV and as a chemotherapy regimen in the combined modality treatment with chest irradiation. The data obtained provide results comparable or rather superior to those achieved with CAV or other conventional regimens when used as induction chemotherapy, and provide some encouraging results when used as consolidation chemotherapy and in combination with chest irradiation. Four trials have been conducted to test the usefulness of CAV-PVP alternation, however, the results is still controversial. Recently, two institutions reported the results of pilot study of an intensive weekly chemotherapy. Although the complete response rate of the weekly regimens appears superior to that of conventional regimens, the survival benefit is still obscure because of an inadequate follow-up time. The pace of therapeutic advances in SCLC has slowed and appears to reach a plateau, however, recent articles indicate a slow but steady progress in the treatment of SCLC.

Antineoplastic Combined Chemotherapy Protocols↗

Drug prescribing in rheumatoid arthritis in Otago.

The drug therapy prescribed for a group of 50 patients with rheumatoid arthritis in Otago prior to specialist referral was examined. Thirty-two patients were receiving some first-line anti-inflammatory drugs and six were receiving no therapy at the time of their first hospital clinic visit. Salicylates had been prescribed first in only 16 of the 50 patients while this drug had been withdrawn because of side effects in about one-third of the patients who had been treated with it prior to specialist referral. Seven patients had received phenylbutazone and six corticosteroids as the first treatment for their rheumatoid arthritis. About one-third of the patients were receiving more than one anti-inflammatory drug at the time of their initial clinic visit.

Adult↗