Modest Side Effects Research Articles

Oseltamivir: a clinical and pharmacological perspective

Oseltamivir is the ethyl ester prodrug of the antiviral molecule, oseltamivir carboxylate, a potent and selective inhibitor of influenza A and B neuraminidase (NA) (sialidase). It is highly bioavailable in capsule and suspension formulations and, after conversion to the active metabolite in the liver, distributes throughout the body, including the upper and lower respiratory tract. Oseltamivir carboxylate is 3% bound to human plasma proteins and eliminated through the kidneys by a first-order process as unchanged drug by glomerular filtration and tubular secretion by an anionic transporter system. Given these characteristics, its potential for adverse interactions with other drugs appears limited to those arising from competitive inhibition of excretion by the renal tubular epithelial cell anionic transporter. The terminal plasma elimination half-life is 1.8 h in healthy adults. Renal clearance is inversely related to renal function and averages 23 h after oral administration in individuals with creatinine clearance < 30 ml/min. In vitro studies have demonstrated potent antiviral activity against all strains of influenza A and B tested including avian H5N1 and H9N2 strains recently implicated in human cases in Hong Kong. Studies of both experimental and naturally-occurring influenza in humans have demonstrated efficacy in both the prevention and treatment of influenza A and B infection. The drug is well-tolerated with the only clinically important side effect being mild gastrointestinal upset. Resistance has been uncommonly seen after clinical use; the highest incidence was 5.5% in children treated for influenza A infection for 5 days. Viruses that develop resistance appear to be less virulent in laboratory animals and to replicate less efficiently than parent strains. Although oseltamivir and the M2 ion channel inhibitors, amantadine and rimantadine, have not been directly compared in clinical trials, the greater breadth of spectrum of oseltamivir, its modest side effect profile compared to amantadine and its lesser propensity to engender the emergence of transmissible drug-resistant strains all suggest strongly that oseltamivir is a significant new agent for the prevention and treatment of influenza. A series of controlled trials comparing M2 ion channel inhibitor drugs and the new neuraminidase (NA) inhibitor agents are now needed to test this hypothesis and thereby to further advance the science of antiviral drug use to control influenza.

Therapy with somatostatin analogs in patient with orbitopathy and positive Octreoscan

We prospectively evaluated 28 persons with active endocrine ophthalmopathy and positive sonographic criteria (A-mode) on extraocular eye muscles. To evaluate somatostatin-receptor status SPECT of the orbits was performed with a double-headed rotating gamma camera after application of 110 MBq 111-In-Pentreotide. 9 patients (12/56 eyes respectively) showed a marked uptake ratio (> 2 in circular ROIs by semiquantitative calculation) and were selected for lanreotide (30 mg i.m. every 14 d) treatment. 5 individuals had control scan after clinical progression which became positive in two of them. All but one tolerated modest side-effects of lanreotide treatment (diarrhea). Therapy was discontinued after 3-10 months when thyroid eye disease had lead to fibrotic stage. This subgroup, with the exception of two women, who received corticosteroids additionally, presented stable disease. One of those had to be sent to surgery because of endangered optical nerve. Clinical ophthalmological control showed promising results in patients receiving somatostatin analogues at early stage when positive on octreo-scan.

Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer

The protracted continuous infusion (PCI) of 5-fluorouracil (5-FU) has proven in several studies an active and well tolerated treatment for advanced, pretreated breast cancer. Navelbine has also activity in this setting. Heavily pretreated patients with metastatic breast carcinoma were eligible for the study. Treatment consisted of 5-FU 250 mg/m2 given as a PCI by an elastomeric pump and navelbine 20 mg/m2 on days 1 and 8, every four weeks. Eighty-three patients (median age 54 years; range 32-82 years) entered the study. The median number of metastatic tumour sites was 2, with visceral involvement in 56 patients. Apart from five patients with contraindications, all patients had been pretreated with anthracyclines. Thirty-one patients had received taxanes and seventy-four bolus 5-FU. A median of 5 cycles (range 1-14) per patient was administered. The median duration of 5-FU infusion was 17 weeks (range, 4-90). In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and 24 partial remissions occurred (response rate, 45%). Median duration of response was 9 months. Toxicity was mild. Median survival was 20 months. PCI-5-FU combined with navelbine offers a reasonable chance of tumour regression with modest side effects in patients with heavily pretreated breast cancer.

Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy

Previous studies have shown that short-term treatment with adrenocorticotrophic hormone (ACTH) has a strong and rapid lipid-lowering effect. In this long-term study of nephrotic patients with idiopathic membranous nephropathy, the influence of ACTH on the serum lipoprotein profile and glomerular function as well as the dose-effect relationship was investigated. Fourteen patients received ACTH intramuscularly at increasing doses during 56 days. Serum concentrations of lipids, lipoproteins, and apolipoproteins as well as variables of glomerular function were analyzed, and the side-effects were recorded. ACTH treatment, in the estimated optimal dosage, was then continued in five patients with severe steroid-resistant nephrotic syndrome. In these five patients, the total treatment period was 12 months, and the follow-up time after discontinuing treatment was 18 months. Taking both the statistically significant therapeutic effects and the modest side-effects into consideration, the optimal dosage of ACTH was estimated to be 1 mg twice per week. At that dose, reductions by 30 to 60% in the serum concentrations of cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a) were observed, whereas the serum concentrations of high-density lipoprotein cholesterol and apolipoprotein AI rose by 30 to 40%. In addition, the urinary albumin excretion decreased by 90%, and the glomerular filtration rate increased by 25%. Deterioration was observed in all cases when ACTH was discontinued after a treatment duration of 56 days. However, the five patients in whom ACTH therapy was resumed were still in remission 18 months after discontinuance of treatment. In nephrotic patients with idiopathic membranous nephropathy, treatment with ACTH 1 mg twice per week was associated with significant long-term improvements in serum lipoprotein pattern and glomerular function.

Pharmacology of G-1-64, a new nondepolarizing neuromuscular blocking agent with rapid onset and short duration of action.

Chances are slim that a clinically useful ultra-short-acting neuromuscular blocking agent of rapid onset will emerge from the benzylisoquinolinium or the aminosteroid series to which all currently popular relaxants belong. G-1-64 is a promising prototype of a new series of bis-quaternary ammonium salt of bistropinyl diester derivatives we have synthesized and studied in the laboratory. Neuromuscular block (NMB) and autonomic and cardiovascular side effects were studied on appropriate preparations of anesthetized rats, rabbits, cats, ferrets, pigs and monkeys. Neuromuscular blocking characteristics, cumulativeness, and pharmacological reversibility were determined. Cardiac vagal block was evaluated by the inhibition of the bradycardic response to stimulation of the vagus in the cat, rat, ferret, and pig. Sympathetic ganglion block was evaluated on the cat's superior cervical ganglion/nictitating membrane preparation. Arterial blood pressure and heart rate were determined in all species. G-1-64 produced nondepolarizing NMB with train-of-four (TOF) and tetanic fades, and reversible with anticholinesterases. Its ED50 ranged between 60 and 800 microg/kg in these species. It showed a significantly faster onset (0.9-2.1 min) and/or shorter duration of action (5-12 min) than either atracurium or mivacurium. It did not show cumulativeness on repeated doses or infusion. A varying degree of cardiac vagal block was present, dependent on the species at doses exceeding the ED80 for NMB. Cardiovascular changes, ganglion block or signs suggesting histamine release were absent. With favorable neuromuscular blocking characteristics and modest side effects, G-1-64 and similar derivatives may have clinical potential.

Nitrazepam for refractory infantile spasms and the Lennox-Gastaut syndrome.

Infantile spasms and the Lennox-Gastaut syndrome are considered to be age-specific pediatric epileptic syndromes and together constitute a significant percentage of medically resistant seizures in childhood. Twenty children, ages 4 to 28 months (median, 12 months), with medically refractory infantile spasms or the Lennox-Gastaut syndrome, were treated with the investigational benzodiazepine nitrazepam in an open-label study. Daily dosage of nitrazepam ranged from 0.5 to 3.5 mg/kg, with a median dosage of 1.5 mg/kg, divided into two doses per day. Side effects included pooling of oral secretions (12 children) and sedation (six children); however, no serious side effects were seen. Responses to nitrazepam were as follows: five complete responses (cessation of all seizures), seven partial responses (greater than 50% reduction of seizures), and eight with no response. Median duration of response was 9 months (range, 4 to 16 months) in children with infantile spasms and 14 months (range, 8 to 26 months) in children with the Lennox-Gastaut syndrome. Nitrazepam is an effective anticonvulsant in this small cohort of children with medically refractory infantile spasms and the Lennox-Gastaut syndrome, resulting in a 25% response rate and only modest side effects.

1064 Gemcitabine-cisplatin combination in non-small cell lung cancer (NSCLC). A phase II study

The clinical efficacy and safety profile of a gemcitabine-cisplatin combination was investigated in a 12-centre phase II trial. 48 consecutive previously untreated NSCLC patients were entered. Median age was 60 years (range 37–70); performance status 0–1; 21 patients had locally advanced unresectable stage IIIb disease and 27 disseminated stage IV disease. Gemcitabine 1000 mg/m2 was administered weekly (days 1, 8, 15) followed by one week rest and cisplatin 100 mg/m2 monthly (day 2) of each 28-day cycle. This schedule was chosen because of experimental and clinical evidence of synergy when the 2 drugs are given in close sequence, and to assess separately acute side effects. Forty-six patients were evaluable for response and toxicity (≥ 1 measurable lesion and ≥ 2 cycles). 1 complete response and 26 partial responses were observed for an overall response rate of 58% (95% CI 44–72%), 11 stage IIIb (52%, CI 3l–73%) and 16 in stage IV (59%, CI 41–77%). Thrombocytopenia was the main side effect with 51% grade 3–4 toxicity, usually short-lived and responsible for the omission of gemcitabine administration on day IS in 90 courses of chemotherapy, and no serious bleeding episodes. Nonhaematological toxicity was usually mild with one acute but reversible renal failure. The combination of gemcitabine and cisplatin induced a significant response rate both in stage IlIb and IV NSCLC with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial. The clinical efficacy and safety profile of a gemcitabine-cisplatin combination was investigated in a 12-centre phase II trial. 48 consecutive previously untreated NSCLC patients were entered. Median age was 60 years (range 37–70); performance status 0–1; 21 patients had locally advanced unresectable stage IIIb disease and 27 disseminated stage IV disease. Gemcitabine 1000 mg/m2 was administered weekly (days 1, 8, 15) followed by one week rest and cisplatin 100 mg/m2 monthly (day 2) of each 28-day cycle. This schedule was chosen because of experimental and clinical evidence of synergy when the 2 drugs are given in close sequence, and to assess separately acute side effects. Forty-six patients were evaluable for response and toxicity (≥ 1 measurable lesion and ≥ 2 cycles). 1 complete response and 26 partial responses were observed for an overall response rate of 58% (95% CI 44–72%), 11 stage IIIb (52%, CI 3l–73%) and 16 in stage IV (59%, CI 41–77%). Thrombocytopenia was the main side effect with 51% grade 3–4 toxicity, usually short-lived and responsible for the omission of gemcitabine administration on day IS in 90 courses of chemotherapy, and no serious bleeding episodes. Nonhaematological toxicity was usually mild with one acute but reversible renal failure. The combination of gemcitabine and cisplatin induced a significant response rate both in stage IlIb and IV NSCLC with modest side effects. The regimen deserves further careful evaluation in a phase III prospective randomized trial.

Goserelin (Zoladex) in premenopausal advanced breast cancer: duration of response and survival

In premenopausal women with advanced breast cancer the luteinising hormone-releasing hormone agonist goserelin (Zoladex, ICI plc) will produce serum levels of oestradiol equivalent to those following surgical oophorectomy or the menopause. This paper reports our further experience of using this drug in 75 premenopausal patients with advanced breast cancer. In addition to response rates, duration of response is reported. An objective response was seen in 25 patients (33%), the median duration of which was in excess of 15 months. Seven patients (9%) showed a complete response to therapy; median duration greater than 37 months. There was no significant difference in time to disease progression (Lee-Desu statistic 18.26, 1 d.f., P = 0.43) and probability of survival (Lee-Desu statistic 3.41, 1 d.f., P = 0.07) between those patients assessed as having either static disease, or those showing a partial response at six months. Response to therapy correlates significantly with the oestrogen receptor status of the primary tumour (X2 = 20.59, 6 d.f., P less than 0.005). The modest side-effects, ease of administration and reversibility make this approach to therapy very attractive. This is to be remembered in that 53% of patients had disease progression whilst receiving goserelin. These patients thus avoided the unnecessary and irreversible morbidity associated with surgical oophorectomy. With the proven efficacy and minimal morbidity associated with goserelin we believe there is no current role for surgical oophorectomy in the management of premenopausal patients with advanced breast cancer.

Phase II study of 10-ethyl-10-deaza-aminopterin (10-EdAM; CGP 30 694) for stage IIIB or IV non-small cell lung cancer

Thirty-one patients with stage IIIB or IV non-small cell lung cancer (NSCLC) were treated with intravenous 10-EdAM on a weekly basis. The starting dose was 80 mg/m2, with subsequent doses adjusted depending on evidence of toxicity. There were 20 men and 11 women with a median age of 58 years (range, 33-75). Response was evaluated in 30 patients, 5 with evaluable but not measurable tumors and 25 with measurable indicator lesions. There were no complete remissions; 3 patients achieved partial remission. Nine patients had a minor response, 6 showed no change, and 12 had progressive disease. Median survival for all 31 patients was 43 weeks (range, 12-65+). During the first 3-week period, the 10-EdAM dose was reduced or withheld in 19 patients (because of stomatitis in 12, SGPT elevation in 3, skin rash in 2, and granulocytopenia in 2), escalated in 11 patients, and unchanged in 1 patient. A mean of 34-88 mg/m2 of 10-EdAM (median, 50) was given per week during the first 5-week period. Myelotoxicity was infrequent and there was no significant nephrotoxicity. Considering the modest side effects of this treatment and the conservative dose-modification schedule which mandated substantial dose reductions, we conclude that 10-EdAM is a promising antitumor agent for NSCLC.

Review of the Endocrine Actions of Luteinising Hormone-Releasing Hormone Analogues in Premenopausal Women with Breast Cancer

The endocrinological actions of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex (goserelin) in premenopausal women with advanced breast cancer are reviewed. LHRH analogues are an interesting addition to the currently available treatments for hormone-sensitive breast cancer in premenopausal women. Their modest side effects and ease of administration are in contrast to the risks and morbidity of surgical endocrine therapy.