Economic losses caused by the use of low-efficacy anthelmintic drugs in growing heifers.

The aim of this study was to compare the economic revenue related to the use of low- or high-efficacy anthelmintic drugs within suppressive or strategic schemes of treatment in growing heifers. Heifers raised in a semi-intensive grazing system in southern Brazil were used. Levamisole and ivermectin were selected as the high- and the low-efficacy drugs, respectively, based on a previous efficacy test. Subsequently, these drugs were used within strategic (Strat; four times per year) or suppressive (Supp; once a month) treatment regimens in the heifers, and their liveweight and eggs per gram of feces counts were monthly evaluated during a 13-month period. The total costs of the treatments and their cost-benefit ratio in regard to liveweight gain were calculated. Final mean liveweight gains (kg) observed were 126.7 (Strat-Low), 133.6 (Supp-Low), 141.3 (Strat-High), 142.9 (Supp-High), and 125.8 (Control). Treatments with a high-efficacy drug resulted in monetary gains of US$ 19.56 (Strat-High) and US$ 14.98 (Supp-High), but Supp-Low and Strat-Low treatments caused economic losses. Total cost of the efficacy test (US$ 374.79) could be paid by the additional liveweight gain of 20 heifers from the Strat-High group. These results showed that it would be preferable not to treat the heifers against GIN if compared with treating them with a low-efficacy drug. In addition, we showed that the use of four treatments per year with a high-efficacy drug-selected by efficacy test-resulted in a profitable management to control GIN in growing heifers raised in a semi-intensive gazing system in southern Brazil.

Economic viability of anthelmintic treatment in naturally infected beef cattle under different nutritional strategies after weaning.

The aim of the present study was to evaluate the effects of treatment with different anthelmintic compounds on the productivity of naturally infected calves and the economic viability of these treatments within extensive breeding systems employing different nutritional strategies after weaning. For this purpose, 4 farms with 42-60 calves naturally infected with gastrointestinal nematodes were selected. The calves were distributed into 6 groups (7-10 animals each) per farm and treated with ivermectin 1%, ivermectin 3.15%, eprinomectin 5%, levamisole 7.5%, albendazole 15%, and control group (no treatment). These animals were evaluated over an experimental period of 150 days. Levamisole 7.5% presented the best capacity for the reduction of eggs per gram (EPG) of feces in all herds evaluated, followed by albendazole 15% and eprinomectin 5%. Parasite resistance to multiple drugs was found in all herds, especially those of Cooperia, Haemonchus, Oesophagostomum, and Trichostrongylus. For farm 1, differences in weight gain and EPG reduction percentages led to a difference of US$285.06 between the levamisole and ivermectin 3.15% groups. Similar findings were noted for the levamisole and ivermectin 1% groups of farm 3, with a difference of US$399.37 because of the final weight gain in these groups. For farms 2 and 4, the ivermectin 3.15% and control groups, respectively, were the most profitable; these unexpected results were possibly influenced by variables not measured during the experimental period. This study suggested that anthelmintic treatments should always precede an efficacy test, once they are demonstrated to be most profitable under adequate breeding conditions, to ensure adequate control of gastrointestinal nematode infection.

Anthelmintic Drugs: Their Efficacy and Cost-Effectiveness in Different Parity Cattle.

Gastrointestinal nematodes are responsible for economic losses in bovines and are characterized by reduced milk production, decreased working efficiency, and even death. In our study, the effect of different anthelmintic treatments on nematode control in different parity cattle (Friesian crossbreds) at calving and their effect on milk yield were evaluated. The economics of anthelmintics and farm benefits in terms of increased milk production after deworming was also calculated. We screened cattle of first and second parity for nematodes. Animals were randomly selected in each group. In first parity animals, there were 23 positive cattle found, which were divided into 3 different groups, while in second parity animals there were 20 positive cattle which were also divided into 3 groups. For treatment of gastrointestinal nematodes, we used albendazole (velbazine) at 10 mg/kg body weight and levamisole (Nilverm®) at 7.5 mg/kg. In this study, both drugs were found effective in controlling nematode infections in cattle. Percentage reduction of eggs per gram (EPG) by albendazole was 48.20, 85.34, and 93.90% and 51.54, 81.43, 91.74% on day 7, 14, and 21 in first and second parity animals, respectively. Percentage reduction of EPG by levamisole was 44.45, 76.92, and 88.03% and 46.60, 73.78, 85.43% on day 7, 14, and 21 in first and second parity animals, respectively. The average increase in milk production in albendazole-treated groups was 0.39 and 0.92 L per day while increases in levamisole treated groups were 0.27 and 0.55 L per day in first and second parity cattle, respectively. After treatment, albendazole increased the milk fat by 0.07 and 0.1% while levamisole decreased by 0.02 and 0.05% in first and second parity cattle, respectively. It is concluded that anthelmintic treatments of recently calved cattle have a significant effect on milk production due to the nematode control. Milk production increased significantly in second parity cattle following anthelmintic treatment as compared to first parity animals. Levamisole had a negative effect on fat concentration in cattle while albendazole-treated cattle showed a positive effect. Albendazole has been found more efficient in reducing EPG of helminths in both parity animals as compared to levamisole-treated animals while the cost-benefit ratio of levamisole was greater than albendazole.

Assessment of serum interleukin-8 as a sensitive serological marker in monitoring the therapeutic effect of levamisole in recurrent aphthous ulcers: a randomized control study.

AIM: The study was designed to evaluate the serum interleukin-8 (IL-8) levels in patients with recurrent aphthous ulcer (RAU) and monitor the immunomodulation and altered IL-8 levels by levamisole before therapy and after levamisole therapy. MATERIALS AND METHODS: This study was carried as a randomized case-control study involving a study group of 30 patients diagnosed as RAUs and given levamisole (vermisole 150 mg, od for 1 st 3 days of 3 weeks in a month and for 3 months with a gap of 1 week) and these patients were recalled after 3 months and were subjected for estimation of serum IL-8 levels. Control group had 20 age and sex matched individuals with no systemic illness and were not given any levamisole. Good compliance was reported at the end of the study. RESULTS: Mild gastric irritation was reported and when severe it was managed by H1 blocker. Patients were reviewed after 3 months. The follow-up data at each visit with respect to each other and to base-line values was calibrated using a Students t-test. Highly significant comparisons were obtained in the serum IL-8 between study and control groups before the onset of levamisole (t = 6.53, P ≤ 0.001). IL-8 levels reduced by 72% after levamisole was instituted in RAU patients and comparison was highly significant for before and after levamisole onset (t = 5.54, P ≤ 0.001). CONCLUSION: This study points to the effectiveness of levamisole as an effective adjunct therapy in the routine management of RAU.

Experimental assessment of the effects of gastrointestinal parasites on offspring quality in chinstrap penguins (Pygoscelis antarctica).

Parasites reduce host fitness and consequently impose strong selection pressures on their hosts. It has been hypothesized that parasites are scarcer and their overall effect on hosts is weaker at higher latitudes. Although Antarctic birds have relatively low numbers of parasites, their effect on host fitness has rarely been investigated. The effect of helminth parasitism on growth rate was experimentally studied in chinstrap penguin (Pygoscelis antarctica) nestlings. In a total of 22 two-nestling broods, 1 nestling was treated with anthelminthics (for cestodes and nematodes) while its sibling was left as a control. Increased growth rate was predicted in de-wormed nestlings compared to their siblings. As expected, 15 days after treatment, the experimental nestlings had increased body mass more than their siblings. These results show a non-negligible negative effect of helminth parasites on nestling body condition that would presumably affect future survival and thus fitness, and it has been suggested there is a strong relationship between body mass and mortality in chinstrap penguins.

Cost effectiveness of adding folinic acid to fluorouracil plus levamisole as adjuvant chemotherapy in patients with colon cancer in Germany.

OBJECTIVE: To assess the cost effectiveness of the addition of folinic acid to fluorouracil plus levamisole in patients with colon cancer from the perspective of the German Social Health Insurance. STUDY DESIGN AND METHODS: Patients with International Union Against Cancer (Union International Contre Cancer; UICC) II/T(4) or UICC III colon cancer enrolled in an open-label randomised clinical trial in Germany (Forschungsgruppe Onkologie Gastrointestinaler Tumoren-1 [FOGT-1]) received either fluorouracil plus levamisole (A, standard) or fluorouracil plus levamisole and folinic acid (B) for 12 months as adjuvant chemotherapy after curative intended surgery. Outcome measures for economic evaluation were disease-free life-years gained (df-LYG) and overall life-years gained (LYG) derived from the respective Kaplan-Meier survival curves. Direct medical costs from the perspective of the German Social Health Insurance were estimated retrospectively (2000 values) and incremental cost-effectiveness ratios (ICERs) were calculated. A Markov model was used to project the trial results beyond 5 years for the patients' remaining life expectancy. RESULTS: Adding folinic acid to the fluorouracil/levamisole regimen results in an increase in time to progression and survival in patients with locally advanced colon cancer. Within the trial period of 5 years ICERs (B versus A) were 33,008 Euro per df-LYG and 51,225 Euro per LYG (costs and effects discounted at 5%). The Markov model yielded ICERs of 11,176 Euro per df-LYG and 11,020 Euro per LYG (costs and effects discounted at 5%). The model was robust for variations of key variables in the sensitivity analysis. CONCLUSIONS: Results of this cost-effectiveness analysis suggest that the addition of folinic acid offers clinical benefits at additional costs which are likely to be acceptable for decision makers in the long term. Cost-effectiveness ratios calculated within the clinical trial period were just above 50,000 Euro/LYG. Because treatment benefits, i.e. prolonged survival, are sustained beyond 5 years whereas incremental costs are mainly incurred in the first year, results of the Markov model yielded cost-effectiveness ratios that compare more favourably with other published ICERs.

Levamisole vs. cyclophosphamide for frequently-relapsing steroid-dependent nephrotic syndrome.

A retrospective analysis comparing the first-time use of levamisole (L) or cyclophosphamide (C) as second-line therapy for children with frequently relapsing, steroid-dependent (FR/SD) nephrotic syndrome, was conducted at our center. The relapse rate and the total cumulative dose of prednisone during the year prior to L/C therapy was compared to that during the year following the institution of therapy with L or C in 51 patients, between July 1992 and June 1997. An analysis of covariance was used to adjust the outcome for differences between the 2 groups of treatment in the year prior to second-line drug initiation. In the L group the mean relapse rate was lowered by 0.28 relapses/patient/month and the mean cumulative dose of prednisone was reduced by 336 mg/m2/month versus 0.32 relapses/patient/month and 387 mg/m2/month in the C group (p = 0.395. p = 0.577). No significant difference in the effectiveness of L vs. C for therapy of FR/SD nephrotic syndrome could be identified in our patients. We conclude that L may be considered an alternative for C as a first second-line agent for these patients.

Response shift in the perception of health for utility evaluation. an explorative investigation.

We previously showed that patients with newly diagnosed colon cancer change the internal standards on which they base their quality of life estimation. In the present investigation, we explored whether this response shift similarly affects the perception of health for utility evaluation in cancer clinical trials. After radical resection of adenocarcinoma of the colon (pT1-4 pN>0 M0 and pT3-4 pN0 M0) and perioperative chemotherapy, patients were randomised to three treatment arms: observation only (A), 5-fluorouracil (5-FU) 450 mg/m(2) plus levamisol (B), or 5-FU 600 mg/m(2) (C). Subjective health was assessed by a linear analogue self-assessment (LASA) scale anchored at 'perfect health-worst health' developed for serial assessment of utility values (Hürny C, van Wegberg B, Bacchi M, et al. Subjective health estimations (SHE) in patients with advanced breast cancer: an adapted utility concept for clinical trials. Br J Cancer 1998, 77, 985-991). Patients estimated their pre-surgery health among various quality of life indicators both before surgery and retrospectively thereafter, and their pre-adjuvant health both at the beginning of randomly assigned chemotherapy or observation and retrospectively approximately 2 months later. Thereafter, current subjective health was assessed. Paired t-tests were used to test the hypotheses of no change. Patients' estimated pre-surgery health was worse after surgery than before (n=127, mean change=-6.7, standard deviation (S.D.)=30, P=0.01), and their estimated pre-adjuvant health was worse under treatment or observation than at the beginning (n=132, mean change=-7.1, S.D.=23.8, P=0.001), in agreement with the quality of life indicators. Chemotherapy had no impact on these changes attributed to a response shift. Conventionally assessed changes between the beginning of adjuvant treatment or observation and 2 months later indicated no change in subjective health. Change scores relative to patients' retrospective estimation revealed an improvement (n=122, mean change=6.6, S.D.=24.8, P=0.004) in this period. Patients with colon cancer substantially reframe their internal standard of health as they do for quality of life. This explorative finding questions the assumption, generally made in decision models, that health estimates for utility evaluation are independent of time. Given that patients may change their standards, comparisons of health estimates across different populations and clinical situations are to be interpreted with caution.

Levamisole: a safe and economical weapon against pediculosis.

Twenty-eight patients with pediculosis capitis, defined as the presence of pruritus, living eggs, and/or lice in the hair, were enrolled in an uncontrolled open pilot study. The subjects were school-age girls (7-12 years old), apparently free of other diseases, and not treated for pediculosis for 4 weeks prior to this study. Family contacts were not treated for pediculosis. The mothers of the patients, who had given informed consent, were asked not to use any topical pediculocide on the girls during the drug trial. Other than the drug administered in the study, the subjects did not take any oral medicine, including cotrimoxazole and ivermectin, during the trial. Treatment consisted of 3.5 mg/kg once daily oral administration of levamisole for 10 successive days, which was given to the subjects in their school by health personnel. A 10-day course was chosen because the subjects lived in unhygienic and overcrowded conditions in a poor village where head lice infestation was hyperendemic. Therefore, two treatment courses spaced 10 days apart could not preclude new infestations from other affected persons and fomites and might have led to a false deduction of drug ineffectiveness. Substituting "N" for the grade of living nits and "L" for adult lice, three forms of response based on the meticulous examination of the entire scalp with the use of a lens with high magnification and a powerful light source were considered: (i) total responsiveness, defined as N2 = 0 and L2 = 0; (ii) partial responsiveness, defined as 0 not equal N2 < N1 and 0 not equal L2 < L1; and (iii) complete unresponsiveness, defined as N2 > or = N1 or L2 > or = L1. The detection of unhatched nits which were operculated and generally located within one-quarter of an inch of the scalp was used to indicate the presence of lice infestation and also to judge the clinical response. For those small nits whose opercula were difficult to see with a hand lens, a low power microscopic study was performed to determine whether the nits were unhatched or not. Of the 28 girls enrolled in the study, one patient refused to take the drug after 2 days of treatment. No adverse reactions were noted in any of the 28 subjects. On the 11th day, meticulous hair examination showed that 23 patients had responded to treatment (85%; 95% confidence interval (CI): 66-94%). Of these, 18 showed complete responsiveness (67%; 95% CI: 48-82%). More complete information is given in Table 1. Confidence intervals were calculated using the likelihood method. This study suggests that levamisole is effective against pediculosis with a dose of 3.5 mg/kg administered for 10 days.

Economic evaluation of three anthelmintic strategies for lamb flocks affected by benzimidazole-resistant nematodes.

OBJECTIVE: To compare the profitability of three anthelmintic strategies in growing lambs in flocks with nematodes resistant to benzimidazole anthelmintics. METHOD: A partial-budgeting analysis was carried out by means of a stochastic simulation model, which allows inputs to be described as distributions rather than as fixed values, and hence permits variation between farms to be considered in the analysis. RESULTS: The results show that control of nematode parasites by use of an effective anthelmintic provides the highest net returns, yielding a margin over ineffectively treated lambs of A$114 per 100 lambs on average. Suppressive treatment based on the administration of two controlled-release capsules and monthly with moxidectin resulted in an average loss of A$131 per 100 lambs in comparison with animals treated with an ineffective anthelmintic. Analysis of the results from capsule-treated lambs did not take into account the unmeasured benefits associated with less contamination of pastures. Sensitivity analysis using a stochastic model indicates that apart from the effect of treatment on weight gain variation in carcase price greatly influences the profitability of all the parasite control programs examined. CONCLUSION: The results suggest that it is economically important for farmers to adjust their strategy in the presence of anthelmintic resistance. But as a result of uncertainty in the factors influencing economic return, the expected economic benefit is likely to vary substantially.

A cost-effectiveness analysis of anthelminthic intervention for community control of soil-transmitted helminth infection: levamisole and Ascaris lumbricoides.

A study to compare effects of mass, targeted, and selective chemotherapy with levamisole as an intervention for the control of Ascaris lumbricoides was carried out in 3 communities in rural Oyo State, Nigeria. Selective treatment was applied in 1 village by treating the most heavily infected 20% of the inhabitants, targeted treatment in the second village involved children aged 2-15 yr, whereas mass treatment was offered to all inhabitants in the third village, excluding infants under 1 yr and pregnant women. Intensity (eggs per gram,) of A. lumbricoides infection was determined immediately before and 3 mo after the period of intervention as a means of assessing the relative efficacy of the treatment regimes. During the field study, information on resource use was also collected for a retrospective cost analysis of the 3 strategies Resources used included manpower, materials, drugs, and transport. The results of the parasitological evaluation on the effect of treatment on egg intensity were then combined with the cost analysis to provide an overall measure of the cost-effectiveness of mass, targeted, and selective interventions. The results were expressed in terms of the cost per 1,000 egg reduction in intensity and the cost per person treated. The results showed the mass and targeted approach to be considerably more cost effective than the selective approach.

Avaliaçäo da reaçäo de Mitsuda em pacientes virchovianos inativos antes e após imunoterapia / Assessment of the Mitsuda reaction in lepromatous patients inactive before and after immunotherapy

Neste estudo investigou-se o potencial imunomodulador do levamisole e da mistura BCG/Mycobacterium leprae em pacientes virchovianos inativos, utilizando como parâmetro a reaçao de Mitsuda. Vinte pacientes, classificados como Mitsuda histologicamente negativos há 10 anos, foram divididos em três grupos: cinco pacientes que foram somente reavaliados frente a mitsudina: oito pacientes que receberam levamisole e, sete que receberam a mistura de BCG vivo mais M. leprae morto. Os resultados mostraram que: 1) o levamisole nao alterou a reatividade à mitsudina em nenhum dos casos estudados; 2) as modificaçoes da reatividade verificadas com o uso da mistura (tres casos) ou aquelas que ocorreram espontaneamente (tres casos) foram sempre de pequena amplitude e refletiram variaçoes próprias de pacientes com algum grau de resistência ao Mycobacterium leprae.

[Assessment of the Mitsuda reaction in lepromatous patients inactive before and after immunotherapy]. / Avaliação da reação de Mitsuda em pacientes virchovianos inativos antes eapós imunoterapia.

In this study the immunopotentiator levamisole as well as a mixture of BCG/Mycobacterium leprae were investigated in inactive lepromatous leprosy patients by using the Mitsuda reaction as a parameter. Twenty lepromatous patients ten years ago classified as histologically negative for Mitsuda's test were divided into three groups: five patients that were only retested with Mitsuda antigen; eight patients that received oral levamisol and seven patients that received a mixture of alive BCG plus autoclaved M. leprae. The results indicated that: 1) the levamisole did not alter the reactivity to lepromin in any of the patients studied; 2) neither the changes in the reactivity to lepromin by using the mixture (3 cases) nor those that occurred spontaneously (3 cases) were clear. They properly reflected the natural variation of patients with some degree of resistance to Mycobacterium leprae.

Cox regression analysis of multivariate failure time data: the marginal approach.

Multivariate failure time data are commonly encountered in scientific investigations because each study subject may experience multiple events or because there exists clustering of subjects such that failure times within the same cluster are correlated. In this paper, I present a general methodology for analysing such data, which is analogous to that of Liang and Zeger for longitudinal data analysis. This approach formulates the marginal distributions of multivariate failure times with the familiar Cox proportional hazards models while leaving the nature of dependence among related failure times completely unspecified. The baseline hazard functions for the marginal models may be identical or different. Simple estimating equations for the regression parameters are developed which yield consistent and asymptotically normal estimators, and robust variance-covariance estimators are constructed to account for the intra-class correlation. Simulation results demonstrate that the large-sample approximations are adequate for practical use and that ignoring the intra-class correlation could yield rather misleading variance estimators. The proposed methodology has been fully implemented in a simple computer program which also incorporates several alternative approaches. Detailed illustrations with data from four clinical or epidemiologic studies are provided.

An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer.

OBJECTIVE: To determine the effectiveness of carcinoembryonic antigen (CEA) monitoring in detecting surgically curable recurrence of colon cancer. DESIGN: Clinical data were collected from a national surgical adjuvant trial in which CEA monitoring was elective. SETTING: Cancer centers, universities, and community clinics. PATIENTS: A total of 1216 patients with resected colon cancer, 1017 (84%) of whom had CEA monitoring. MAIN OUTCOME MEASURES: Sensitivity and specificity of CEA testing for cancer recurrence and CEA-motivated diagnostic and surgical interventions and their end results. RESULTS: Among 417 monitored patients with recurrence, 59% had a preceding elevation of CEA concentration. Sixteen percent of 600 patients without recurrence showed a false-positive test result. Carcinoembryonic antigen testing was most sensitive for hepatic or retroperitoneal metastasis and relatively insensitive for local, pulmonary, or peritoneal involvement. Surgical explorations were performed in 115 patients with CEA elevations, and 47 recurrences, usually hepatic, were resected with curative intent. On the other hand, 38 patients with normal CEA concentrations and 23 patients not monitored also underwent such resections--usually for pulmonary or local recurrence. Of all CEA-monitored patients, 2.3% are alive and disease free more than 1 year after salvage surgery (2.9% of those with CEA elevations and 1.9% of those with no elevations). Of patients with no CEA monitoring, 2.0% are also alive and disease free more than 1 year after salvage surgery. CONCLUSIONS: Cancer cures attributable to CEA monitoring are, at best, infrequent. It is questionable whether this small gain justifies the substantial cost in dollars and physical and emotional stress that this intervention may cause for patients.

Scintimetric assessment of synovitis activity during treatment with disease modifying antirheumatic drugs.

In a double blind trial of 36 patients with rheumatoid arthritis a new scintimetric method was applied to three comparable patient groups before and after eight months' treatment with levamisole, penicillamine, or azathioprine. Technetium-99m pyrophosphate scintigraphy of both hands was performed on a gammacamera with a computer attached, immediately after the administration of the tracer. The uptake ratio of each proximal interphalangeal (PIP) joint and the mid-half of the adjacent proximal phalanx was calculated from the activity counted for one minute. A scintimetric index was expressed as the sum of eight uptake ratios. This index was higher for each of the three patient groups before start of treatment than that for 10 age matched controls. After eight months of treatment the index, the number of PIP joints with clinical signs of synovitis, and the total circumference of the PIP joints decreased in the penicillamine and azathioprine groups. The scintimetric method reliably reflected local synovitis activity and its changes but, like grip strength and PIP circumference, was not a representative measure of the overall activity of the disease.