Immunopotentiation with levamisole in resectable bronchogenic carcinoma: a double-blind controlled trial; Study Group for Bronchogenic Carcinoma.

A long-term multicentre double-blind study was designed to test the immunotropic effects of levamisole in patients undergoing operation for primary bronchial carcinoma. They received levamisole 50 mg three times a day by mouth or placebo for three days every fortnight, starting three days before surgery. Unless there was clinical evidence of recurrence, cytostatic drugs, corticosteroids, and radiotherapy were prohibited. In the 111 patients who have been followed up for one year the incidence of side effects was similar in both groups. Recurrences occurred in 10 out of 51 patients (seven deaths) receiving levamisole and in 20 out of 60 (12 deaths) receiving placebo. Further analysis showed that there were fewer recurrences on levamisole in patients with squamous cell carcinomas and medium and large primary tumours and fewer suspected and proved recurrences and deaths from metastases on levamisole in patients with extended tumours. Distant recurrences tended to be less common with levamisole, whereas the disease-free interval in relapsing patients was almost identical in the two groups. These interim results show that levamisole seems to exert its beneficial effect by preventing immunosuppression due to surgery.     

Chronic recurrent aphthous stomatitis: oral treatment with low-dose interferon alpha

Recombinant human interferon alfa-2a (HuIFN alpha) was administered orally once daily in a low concentration (1,200 IU/day) to nine patients with chronic recurrent aphthous stomatitis (RAS), and a placebo solution was given to 10 control chronic RAS patients in a double-blind study. All HuIFN alpha-treated patients had total remission of their aphthae within a 2-week period, while placebo control patients had no change in their condition. The 10 placebo control patients were then treated with HuIFN alpha in a manner identical to that used for the initial principal group. Within a 2-week period, all original placebo patients had complete remission of their aphthae. Eleven of the patients did not have a recurrence of RAS during a subsequent 6-month observation period. Eight patients had recurring aphthae; however, the lesions were resolved by retreating with oral HuIFN alpha for less than 1 week.     

THIORIDAZINE (MELLARIL?) IN PSYCHIATRIC PATIENTS

Thioridazine (Mellaril®) was given to 104 psychiatric patients with a variety of illnesses, chiefly schizophrenic reactions. Of 14 patients treated in a double-blind study with successive one-month courses of drug or placebo, nine improved most on the drug and only one on placebo. These results, although limited, confirm a definite therapeutic action for this compound.Nine of 24 patients were significantly improved after treatment with thioridazine for an average of four months following previous treatwith other phenothiazine tranquilizers. Of ten patients treated intensively with thioridazine after they had not responded to other phenothiazine drugs, two were definitely improved and three were slightly improved. Twenty-eight of 56 patients treated from the outset with thioridazine were significantly improved after an average of six months. Most patients received from 100 to 400 mg. daily. These results were comparable to those obtained from other potent phenothiazine tranquilizers. The drug is particularly advantageous for a group of schizophrenic patients who are sometimes made worse by other phenothiazine derivatives or rauwolfia alkaloids. It should also be suitable for treating patients with psychoneuroses and chronic brain syndromes.Only minimal side reactions were observed, chiefly drowsiness, dizziness and nasal stuffiness. Weight gain occurred frequently during treatment.     

Adjuvant immunotherapy with levamisole in resectable lung cancer

Summary Levamisole (1.1–3.8 mg/kg daily) or a placebo was given in a randomized, double-blind study to 211 patients undergoing curative surgery for primary lung cancer. The treatment, in a fixed dose of one tablet (containing 50 mg or a placebo) t.i.d., was given for 3 days before the operation, and such 3-day courses were repeated every 2 weeks thereafter for 2 years.A significant reduction of the cancer mortality was observed at 18 and 21 months post surgery in the levamisole group. There was also a nonsignificant increase of the disease-free interval.In patients who had received more than 2 mg/kg (or more than 80 mg/m²) daily, the crude recurrence rates had been halved and the death rates reduced to one-third. No beneficial effect could be observed in the patients who had been given a lower dose. In the former, adequately dosed patients, the beneficial effect was more marked if the tumor had been more advanced at the time of surgery. In addition, the incidence of hematogenous secondaries was significantly reduced in the same group of patients.Professor Swierenga died in late 1977, shortly before completion of the work     

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.

OBJECTIVE--To determine whether alfacalcidol--used in management of overt renal bone disease--may safely prevent renal bone disease when used earlier in course of renal failure. DESIGN--Double blind, prospective, randomised, placebo controlled study. SETTING--17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. SUBJECTS--176 patients aged 18-81 with mild to moderate chronic renal failure (creatinine clearance 15-50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. INTERVENTIONS--Alfacalcidol 0.25 micrograms (titrated according to serum calcium concentration) or placebo given for two years. MAIN OUTCOME MEASURES--Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. RESULTS--132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P < 0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P < 0.001). There was no difference in rate of progression of renal failure between the two groups. CONCLUSION--Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure.     

Does the order of second-line treatment in rheumatoid arthritis matter?

In a prospective study 88 patients, with rheumatoid arthritis who had stopped taking gold, penicillamine, or levamisole were randomly allocated to one of the alternative drugs and followed up for a minimum of one year. Concurrent studies of the effects of gold, penicillamine, and levamisole prescribed in 123 patients as the first second-line drug were used for comparison. No difference in toxicity or efficacy between primary and secondary use of gold or penicillamine was identified. Variation in the toxicity of levamisole could in part be accounted for by changes in the dose regimen over the four years of study. The length of the treatment-free interval between drugs did not influence subsequent development of toxicity. These results suggest that an adverse reaction to one of the three second-line drugs studied should not prejudice the selection of another.     

Effect of phosphate supplementation on oxygen delivery at high altitude

In the present communication, effect of low doses of phosphate supplementation on short-term high altitude adaptation has been examined. Studies were carried out in 36 healthy, male, sea-level residents divided in a double blind fashion into drug and placebo treated groups. 3.2 mmol of phosphate were given orally to each subject of the drug treated group once a day for 4 days on arrival at an altitude of 3,500 m. Sequential studies were done in the subjects in both groups on the 3rd, 7th, 14th and 21st day of their altitude stay. Haemoglobin, haematocrit, erythrocyte and reticulocyte counts increased to the similar extent in both groups. Blood pH, pO₂ and adenosine tri-phosphate (ATP) did not differ between the two groups. On 3rd day of the altitude stay, inorganic phosphate and 2,3-diphosphoglycerate (2,3 DPG) levels in the drug treated group increased significantly as compared to the placebo group. No significant difference in inorganic phosphate and 2,3 DPG was observed later on in the two groups. Psychological and clinical tests also indicated that the drug treated subjects felt better as compared to the placebo treated subjects. The present study suggests that low doses of phosphate increases circulating 2,3-DPG concentration which in turn brings about beneficial effect towards short term high altitude adaptation.     

Stimulating effect of serum from tumor-bearing mice on lymphocyte response to mitogenic stimulation associated with protein increase in serum

Summary Twenty levamisole-treated and 14 placebo-treated lung cancer patients were studied sequentially in assays of lymphocyte proliferation. Prior to treatment, the patients as a group had significantly depressed proliferative responses to mitogens and allogeneic cells (MLC), and this immunosuppression was especially noticeable in patients with clinically detectable tumor burdens. Following treatment, responses in both levamisole and placebo groups tended to increase slightly, although the increases were more consistent and persistent in the levamisole group. Increases within the levamisole group were similar for patients with and without detectable tumor burdens. Proportions of E and EAC rosette-forming cells were stable throughout treatment for all groups. No consistent response pattern was observed in patients crossed-over from placebo to levamisole treatments. Although these results do not contradict the concept that levamisole can reverse malignancy-induced immunosuppression, levamisole treatment clearly did not result in normalization of lymphocyte-proliferative capacity in these lung cancer patients. The usefulness of a placebo-treated group was apparent, as some increased responsiveness was commonly found with placebo treatment.     

Safety of treatment for subclinical osteomalacia in the elderly.

Forty one elderly patients admitted to hospital for acute illnesses were also found to have subclinical osteomalacia. Immediately before discharge, therefore, all were randomised to receive either vitamin D2 25 micrograms daily, alfacalcidol 0.5 micrograms daily, or placebo. Treatment was given for at least three months, those allocated to placebo then being switched to an active drug. Within the first three months of treatment with either of the active drugs most patients had exhibited a fall to normal in osteoid values. In only four treatment periods was there a mild increase in serum calcium concentration, and in no patient was this accompanied by deterioration in renal function. Any increase in serum creatinine concentration was invariably attributable to the underlying disease for which the patient had been admitted in the first place. Subclinical osteomalacia in the elderly may be corrected by relatively low doses of alfacalcidol (0.5 micrograms daily) or vitamin D2 (25 micrograms daily) given for three months. Such treatment is safe and not accompanied by a serious risk of hypercalcaemia or renal impairment.     

Effect of salcatonin given intranasally on early postmenopausal bone loss.

OBJECTIVE--To study the effect of salmon calcitonin (salcatonin) given intranasally on calcium and bone metabolism in early postmenopausal women. DESIGN--Double blind, placebo controlled, randomised group comparison. SETTING--Outpatient clinic for research into osteoporosis. SUBJECTS--52 Healthy women who had had a natural menopause two and a half to five years previously. INTERVENTIONS--The 52 women were allocated randomly to two years of treatment with either salcatonin 100IU given intranasally (n = 26) or placebo (n = 26). Both groups received a calcium supplement of 500 mg daily. Seven of the women receiving salcatonin and six of those receiving placebo left the study before its end. MAIN OUTCOME MEASURES--Bone mineral content in the spine, the total skeleton, and the forearms after two years of treatment. RESULTS--Bone mineral content in the spine was significantly higher in the women who had received salcatonin than in those who had received placebo both after one year and after two years of treatment. After one year the difference was 3.8% (95% confidence interval 0.0 to 7.6%) and after two years it was 8.2% (3.8 to 12.6%). In contrast, the bone mineral content in the distal and proximal forearms and in the total skeleton declined similarly in both groups by about 2% each year, and after two years of treatment the differences between the groups were not significant. Biochemical estimates of bone turnover were not affected by salcatonin. CONCLUSION--The results suggest that salcatonin given intranasally in the dose used prevents bone loss in the spine of early post menopausal women but does not affect the peripheral skeleton.     

Oral poliovirus vaccine in management of recurrent aphthous stomatitis

Oral poliovirus vaccine (OPV) is reported to be effective in treatment of recurrent herpes simplex (RHS). According to our observation during recent years, OPV was not only effective in management of RHS but also in some patients with concomitant recurrent aphthous stomatitis (RAS) reducing its severity and frequency. The purpose of this study was to evaluate the efficacy of OPV in the management of RAS. In a longitudinal, case--control study 48 patients with RAS were recruited. Twenty patients received OPV and 28 patients received placebo. OPV was administered in a dose of 4 drops at monthly intervals for 3 months to the study group while the control group received placebo. The results were registered in 3 months after the last dose. Eight cases (40%) in the OPV group showed significant reduction in the duration of the ulcers, while no change was seen in the control group (P = 0.048). The frequency of recurrence of RAS was reduced in 13 cases (65%) in the OPV group, and in 6 cases (21.4%) of the placebo group (P = 0.006). The severity of attacks was reduced in 12 cases (60%) in the OPV group and in 4 cases (14.3%) in the placebo group (P = 0.008). In conclusion OPV appeared to be effective in the management of RAS.     

Peppermint oil in irritable bowel syndrome

In a literature search 16 clinical trials investigating 180-200 mg enteric-coated peppermint oil (PO) in irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651 patients enrolled were identified. Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods, five had a randomized double blind parallel group design and two were open labeled studies. Placebo served in 12 and anticholinergics in three studies as comparator. Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range 10-52%) for placebo. The three studies versus smooth muscle relaxants did not show differences between treatments hinting for equivalence of treatments. Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI effects like heartburn and anal/perianal burning or discomfort sensations, whereas the anticholinergics caused dry mouth and blurred vision. Anticholinergics and 5HT3/4-ant/agonists do not offer superior improvement rates, placebo responses cover the range as in PO trials. Taking into account the currently available drug treatments for IBS PO (1-2 capsules t.i.d. over 24 weeks) may be the drug of first choice in IBS patients with non-serious constipation or diarrhea to alleviate general symptoms and to improve quality of life.     

Long-term therapy of essential tremor with propranolol.

In a double-blind crossover study 12 patients with essential tremor were treated with propranolol and a placebo; 8 improved with propranolol and 3 with the placebo; the degree of improvement with propranolol was greater. In a similar study with diazepam 5 of 12 improved with diazepam and 4 of 12 with the placebo; the degree of improvement was less than that achieved with propranolol. Response in 21 patients to treatment with propranolol for 2 to 4 years was excellent in 4, good in 4 and fair in 10; the condition of 1 was unchanged and that of 2, worse. Excellent response was maintained for as long as 4 years, but response tended to deteriorate with time if initially it was less than excellent. Response decreased with increasing age. No patient 60 years of age or older had an excellent response, and the four with an excellent response were under age 55, three being under age 35; all four had had their tremor less than 12 years. Patients with essential tremor should be given a 3-month trial of propranolol at 120 mg/d; if no significant response is seen the dose should be decreased, then the drug discontinued.     

The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide.

In a double blind placebo controlled randomised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug. After a four week placebo washout period 53 patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to 50, 125, or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment. Blood pressure was measured in the patients'' homes by the same observer every two weeks. Serum urea, electrolytes, urate, and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods. After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo. The decrement in serum potassium concentration (0.6 mmol/l) and increase in serum urate concentration 0.06 mmol/l) were greatest with the 500 micrograms dose, the increase in serum urate concentration alone being significant. No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide. Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity (1.8 (95% confidence interval 0.2 to 3.4)-5.4 (3.9 to 6.8) nmol angiotensin I/l/h); the other doses like the placebo had no effect. Cyclopenthiazide 125 micrograms, a dose lower than is currently marketed, produced a similar hypotensive response to 500 micrograms of the drug without upsetting the biochemical profile.     

Changes in anthelmintic resistance status of Haemonchus contortus and Trichostrongylus colubriformis exposed to different anthelmintic selection pressures in grazing sheep

This experiment was designed to study, over a 5-year-period, the effect of different frequencies of treatment with three different anthelmintic groups, namely, benzimidazoles, levamisole and ivermectin, and different frequencies of alternation between them, on existing levels of anthelmintic resistance in the nematode parasites Haemonchus contortus and Trichostrongylus colubriformis of grazing sheep. No evidence of ivermectin resistance emerged, even in suppressively treated groups. Likewise, H. contortus failed to develop resistance to levamisole under a similar selection regimen. Thiabendazole was shown to select positively against levamisole resistance in T. colubriformis resulting in significantly greater susceptibility to this drug than for the natural reversion which occurred in the untreated control. There was no evidence that an anthelmintic treatment combined with a movement of sheep to pastures of low infectivity selected more rapidly for resistance than where the same number of treatments were given to set-stocked sheep. Rotation between anthelmintic groups at yearly intervals appeared to be more beneficial in delaying resistance than rotation of drugs with each treatment.     

Selection studies on anthelmintic resistant and susceptible populations of Trichostrongylus colubriformis of sheep

Waller P. J., Dobson R. J., Donald A. D., Griffiths D. A. and Smith E.F. 1985. Selection studies on anthelmintic resistant and susceptible populations of Trichostrongylus colubriformis of sheep. International Journal for Parasitology15: 669–676. A T. colubriformis population (BCK), formerly resistant to benzimidazole anthelmintics, but now highly resistant to levamisole after 6 years exposure to this drug alone in the field, was passed through 12 generations in the laboratory in three separate lines exposed either to selection with thiabendazole or levamisole, or to no selection. Another population (McM) not previously exposed to these anthelmintics was treated similarly in two lines, selected with thiabendazole or not selected.Selection with thiabendazole resulted in a return of benzimidazole resistance in the BCK line which occurred faster than in the McM line, but a similar level of resistance was reached in each by the twelfth generation. Resistance ratios in both selected lines compared with the unselected McM line were less than 20: 1, and only 1.5 times the recommended dose rate of thiabendazole was required to remove more than half of the resistant population. This suggests that a polygenic vigour tolerance rather than a specific resistance had been selected.In the case of levamisole resistance, the BCK population was found to contain two distinct subpopulations, one susceptible and the other highly resistant. Resistance ratios for the highly resistant subpopulation were greater than 4000: 1, implying a specific resistance controlled by a major gene. During the 12 generations of levamisole selection, the proportion of resistant phenotypes fluctuated about an average level of 70%, suggesting that susceptibility alleles were being maintained in the population through superior heterozygote fitness. This conclusion is supported by a significant decline in levamisole resistance in the absence of levamisole selection. Moreover, thiabendazole selection hastened the reversion to levamisole suceptibility.The results provide support for the reintroduction of a benzimidazole anthelmintic to control this helminth population, and for a slow rotation in the use of drugs with different modes of action.     

Arthroscopic surgery compared with supervised exercises in patients with rotator cuff disease (stage II impingement syndrome)

OBJECTIVE--To compare the effectiveness of arthroscopic surgery, a supervised exercise regimen, and placebo soft laser treatment in patients with rotator cuff disease (stage II impingement syndrome). DESIGN--Randomised clinical trial. SETTING--Hospital departments of orthopaedics and of physical medicine and rehabilitation. PATIENTS--125 patients aged 18-66 who had had rotator cuff disease for at least three months and whose condition was resistant to treatment. INTERVENTIONS--Arthroscopic subacromial decompression performed by two experienced surgeons; exercise regimen over three to six months supervised by one experienced physiotherapist; or 12 sessions of detuned soft laser treatment over six weeks. MAIN OUTCOME MEASURES--Change in the overall Neer shoulder score (pain during previous week and blinded evaluation of function and range of movement by one clinician) after six months. RESULTS--No differences were found between the three groups in duration of sick leave and daily intake of analgesics. After six months the difference in improvement in overall Neer score between surgery and supervised exercises was 4.0 (95% confidence interval -2 to 11) and 2.0 (-1.4 to 5.4) after adjustment for sex. The condition improved significantly compared with placebo in both groups given the active treatments. Treatment costs were higher for those given surgery (720 pounds v 390 pounds). CONCLUSIONS--Surgery or a supervised exercise regimen significantly, and equally, improved rotator cuff disease compared with placebo.     

Lack of Potentiation by Chlordiazepoxide (Librium) of Depression or Excitation due to Alcohol

A double-blind study was completed comparing the interaction of chlordiazepoxide (Librium), 10 mg. given three times for one day, and 6 oz. of Canadian rye whiskey given over a three-hour period in the evening of the same day. The comparison drug was a placebo. Four evening experiments were conducted using the same six normal subjects and two observers. At the end of the evening, the observers were unable to detect which subjects had had placebo or chlordiazepoxide. It was concluded that chlordiazepoxide, given in this recommended daily dose, did not potentiate what was considered a social quantity of alcohol.     

A case report of the successful treatment of recurrent aphthous stomatitis with some preparations of orally administered transfer factor

A patient with severe disabling recurrent aphthous stomatitis (RAS) was treated with four different preparations of oral human transfer factor (TF), as well as placebo, following a double-blind protocol. Two of the TF preparations had a significant effect upon the course of the patient's illness by prolonging the interval between attacks and decreasing the severity of attacks. No side effects attributable to any of the preparations were noted by the patient. Thus, some but not all preparations of human transfer factor given orally are an effective therapy for RAS.     

The effect of levamisole and levamisole + vitamin C on oxidative damage in rats naturally infected with Syphacia muris

This study was performed to determine the effects of levamisole and levamisole + vitamin C against Syphacia muris naturally infection in rats and to detect its effect on the oxidative parameters in blood and tissues of host. For this purpose, natural infection was diagnosed using the cellophane tape method on the perianal region of rats. Infected rats (total 18) were divided into three groups. On the other hand six without helminth rats were used in this study as negative control group. Group 2 was given an orally levamisole HCl treatment with gastric gavage at a dose level of 20 mg/kg body weight in distilled water, every alternate day. Group 3 was given levamisole HCl via gastric gavage at a dose level of 20 mg/kg and vitamin C was given 1 g/L added to the drinking water. All the treatments continued for a period of 7 days. As a result; levamisole administered to rats at dose of 20 mg/kg orally 98.34% was found to be effective against adult S. muris in the rats. In addition to levamisole + vitamin C is effective to alleviate the oxidative damage in rats infected with S. muris.