Respiratory muscle endurance training reduces chronic neck pain: A pilot study.

BACKGROUND: Patients with chronic neck pain show also respiratory dysfunctions. OBJECTIVE: To investigate the effects of respiratory muscle endurance training (RMET) on chronic neck pain. METHODS: In this pilot study (single-subject design: 3 baseline measurements, 4 measurements during RMET), 15 neck patients (49.3 ± 13.7 years; 13 females) conducted 20 sessions of home-based RMET using a SpiroTiger® (normocapnic hyperpnoea). Maximal voluntary ventilation (MVV), maximal inspiratory (Pimax) and expiratory (Pemax) pressure were measured before and after RMET. Neck flexor endurance, cervical and thoracic mobility, forward head posture, chest wall expansion and self-assessed neck disability [Neck Disability Index (NDI), Bournemouth questionnaire] were weekly assessed. Repeated measure ANOVA (Bonferroni correction) compared the first and last baseline and the last measurement after RMET. RESULTS: RMET significantly increased MVV (p= 0.025), Pimax (p= 0.001) and Pemax (p< 0.001). During RMET, neck disability significantly decreased (NDI: p= 0.001; Bournemouth questionnaire: p= 0.002), while neck flexor endurance (p< 0.001) and chest wall expansion (p< 0.001) increased. The changes in respiratory and musculoskeletal parameters did not correlate. CONCLUSIONS: RMET emerged from this pilot study as a feasible and effective therapy for reducing disability in patients with chronic neck pain. The underlying mechanisms, including blood gas analyses, need further investigation in a randomized controlled study.

Arteflene compared with mefloquine for treating Plasmodium falciparum malaria in children.

Arteflene is a synthetic peroxide recently developed from an indication of antimalarial activity found in the Chinese plant Artabotrys uncinatus. The new antimalarial was compared against mefloquine in a phase 3, open-labeled, randomized trial in children with uncomplicated Plasmodium falciparum malaria in Gabon. Patients received single oral doses of either 25 mg/kg of arteflene suspension or 15 mg/kg of mefloquine tablets. High-grade (RII and RIII) resistance was observed in eight (40%) of the 20 patients receiving the single dose of arteflene, but in none of the 21 mefloquine-treated patients (P < 0.005). At day 28, only one patient in the arteflene group, compared with all 21 patients in the mefloquine group, was cured (P < 0.001). Arteflene cleared fever slightly but not significantly faster than mefloquine and the 50% and 90% parasite clearance times were comparable in both treatment groups. In vitro results in the arteflene group suggest an increase of arteflene resistance when comparing sensitivity of paired parasite isolates before treatment and at recrudescence. Both treatment regimens were well-tolerated. In conclusion, single dose monotherapy with arteflene was not effective in curing children suffering from uncomplicated P. falciparum malaria in Gabon, while mefloquine proved to be highly effective for this purpose.

How frequent are notified severe cutaneous adverse reactions to Fansidar?

An attempt was made to estimate the risk of severe cutaneous adverse reactions (SCARs) to Fansidar (sulfadoxine plus pyrimethamine). Cases were identified through a spontaneous reporting system. Persons exposed were estimated using sales data of 27 countries reporting one SCAR case for either Fansidar or a related product, Bactrim (cotrimoxazole; sulfamethoxazole plus trimethoprim). Between 1974 and 1989, 126 cases were notified for Fansidar: 87 cases of erythema multiforme or Stevens-Johnson syndrome, and 39 cases of toxic epidermic necrolysis. 86% of cases were reported in Europe or North America. In 116 cases with use known, prophylaxis was the reason in 103, and treatment in 13. Toxic epidermolysis and erythema multiforme/Stevens-Johnson syndrome had case fatalities of 36 (95% confidence intervals 21 to 53%) and 9% (4 to 18%), respectively. Fansidar users were estimated at 117 million, and the overall SCAR risk to be 1.1 (0.9 to 1.3) per million. For developing countries with mainly single dose use, the risk was estimated to 0.1 (0.0 to 0.1) per million. For Europe and North America with mainly prophylactic use, the risk was 10 (8 to 12) and 36 (23 to 48) per million, respectively. Prophylactic use had a 40 times higher risk than single dose therapeutic use. The aggregated risk peaked in 1984-1985, with global and North American SCAR frequencies of 3.4 (2.4 to 4.3) and 72 (41 to 102) per million, respectively. After 1985, North America reported only one further case despite continued use by an estimated 0.3 million persons.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of Plasmodium falciparum malaria by Fansimef and Lariam in the northeastern part of Thailand.

Two studies were conduct in Thailand in order to find appropriate falciparum malaria prophylactic drug regimens. The first study was done during June - September 1987 with 363 soldiers who received Fansimef (MSP) 1 tab/week (group 1), 337 soldiers who received MSP 1 tab/2 week (group 2) and 165 soldiers who received chloroquine 300 mg base weekly plus Fansidar 1 tab/week (group 3). At the end of the study there were 9 and 13 falciparum malaria episodes in groups 1 and 2, respectively, with incidence rates of 0.8 and 1.8 cases/100 person-months (P-M). In group 3, the corresponding values were 30 episodes and an incidence of 7.2/100 P-M. For the second study which lasted from October 1987 - January 1988 in the same area, 498 soldiers were given Fansimef 1/2 tab/week (group 4), 499 soldiers were given Lariam 1/2 tab/week (group 5) and 247 soldiers were given chloroquine plus Fansidar (group 6). Thirty malaria episodes were found in group 4, for an incidence of 2.0/100 P-M. In group 5, 23 episodes were found, for an incidence of 1.6/100 P-M. In group 6, 74 episodes occurred, ie an incidence of 12.2/100 P-M. The incidence rates of malaria among Fansimef 1 tab weekly, Fansimef half dose weekly or Lariam half dose weekly were not significantly different but were different from chloroquine plus Fansidar groups. Adverse events in each group were mild.

Fansimef for prophylaxis of malaria: a double-blind randomized placebo controlled trial.

At a time when Fansimef, the fixed combination of mefloquine, sulfadoxine and pyrimethamine was considered for prophylaxis of falciparum malaria, a randomized double-blind study comparing the efficacy and tolerability of Fansimef with that of Lariam (mefloquine), Fansidar, chloroquine and placebo in malaria prophylaxis was performed in Thailand from July 1987 to January 1988. The study population of 602 adult males was recruited in Pak Tongchai District, some 360 km North-East of Bangkok, where multiresistant P. falciparum is endemic. All active treatments and placebo were given once weekly for 24 weeks with doses as follows: Fansimef: 125 mg mefloquine + 250 mg sulfadoxine + 12.5 mg pyrimethamine (1 half-strength tablet); Lariam: 125 mg mefloquine (1 half-strength tablet); Fansidar: 500 mg sulfadoxine + 25 mg pyrimethamine; chloroquine; 300 mg. A loading dose of 2 half-strength tablets was given in the Fansimef group in weeks 1 and 2 and in the Lariam group in weeks 1 to 4. The incidence of acute episodes of P. falciparum per 100 person months of prophylaxis was 0.17 each in the Fansimef and the Lariam groups, 1.18 in the Fansidar group, 0.69 in the chloroquine group and 0.64 in the placebo group (differences statistically not significant). Clinically adverse events were reported by 170 subjects (Fansimef 28, Lariam 29, Fansidar 41, choroquine 43, placebo 29; differences statistically not significant). The most frequent adverse events in all groups were headache, sleepiness, dizziness and weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

[Emergency treatment of malaria during travel]. / Notfallmässige Behandlung der Malaria auf Reisen.

Stand-by therapy is the first treatment of a presumptive malaria by the traveller. Goals and possible indications are listed and the mode of application described. Information of the traveller by the physician is time consuming but very important for the correct use of stand-by therapy. The central message is the instruction to visit a doctor within 12 to 25 hours after intake of stand-by therapy, to avoid the risk of missing other diseases with similar symptoms. Fansimef and Lariam, recommended in Switzerland for stand-by therapy of malaria, are shortly reviewed.

[Current drugs for the treatment of tropical malaria]. / Neue Medikamente für die Behandlung der Malaria tropica.

The occurrence in the early 60's of stable resistance to chloroquine among Plasmodium falciparum strains in the Amazonas and on the Thai-Cambodian border has been a shock for all malariologists. This led to the search for new antimalarials without cross resistance with chloroquine. For each new drug, one of the major concerns was to define how rapidly parasites would develop resistance to this compound. Drug combinations were taken into consideration so as to achieve a delay in the appearance of resistance. The decision to test a triple combination has led to the development of Fansimef, a fixed combination with tablets containing 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimethamine. A very relevant delay in the development of resistance was found both in-vivo--in the P. berghei model--and in-vitro using P. falciparum. Fansimef has also been under investigations for malaria. Controlled clinical trials were performed in Africa, South America and South East Asia. The documentation for this new indication will be submitted to registration authorities in 1991. A preference alternative to continuous chemoprophylaxis is stand-by malaria treatment for travellers to regions where the malaria risk is relatively low. Stand-by treatment is under investigations in France and in Switzerland. In the search for alternative remedies against drug resistant P. falciparum malaria our attention was directed to Yingzhaosu, a new sesquiterpene peroxide of plant origin from traditional Chinese medicine. A short and convenient synthesis of this ring system gave access to a variety of structural analogues of Yingzhaosu.(ABSTRACT TRUNCATED AT 250 WORDS)

Commitment of Roche in malaria and other tropical diseases.

In the absence of a suitable malaria case definition, reliable surveillance data on the impact of malaria are not available. Determinants of case loads, including population movements, environmental changes, lack of political commitment and resources, and resistance to antimalarials and residual insecticides, work towards global deterioration. Some 90% of the Plasmodium falciparum burden is carried by Africa south of the Sahara. There, in 1992, the number of children under five years of age and exposed to high risk was about 106 million. Assuming a malaria attack rate of 0.5-1.5 per child per year, and a case fatality rate of 2%, annual clinical cases and malaria deaths in this population alone come to 53-160 million and 1-3 million, respectively. Roche, a pharmaceutical company with major research efforts in tropical medicine, in collaboration with research centers and international institutions, has recently set up a tropical medicine unit that coordinates and concentrates corporate efforts in this field. The unit aims to make affordable and innovative products available which are effective against major tropical diseases. A commercial product of the unit is Lariam, a major antimalarial used alone or in simultaneous or sequential combinations. The single dose combination of Lariam plus Fansidar (Fansimef) is particularly useful for stand-by or emergency oral therapy. Artemisinine, or its derivatives, followed by one to two doses of Lariam are effective against severe and multiresistant P. falciparum malaria. A new Roche peroxide antimalarial is currently in phase II clinical trials. The unit is also involved in research and development of malaria sporozoite and asexual blood stage vaccine candidates.

Comparative tolerability and kinetics during long-term intake of Lariam and Fansidar for malaria prophylaxis in nonimmune volunteers.

One hundred and five healthy nonimmunes in Colombia took part in a randomize, double-blind comparison of 250 mg of Lariam (L) (active ingredient: mefloquine) on alternate weeks or one tablet of Fansidar (F) (active ingredients: sulfadoxine and pyrimethamine) weekly for malaria prophylaxis during at least six months. Volunteers also gave blood for determination of drug concentrations after six months and/or 24-27 months of prophylaxis. Twenty-five volunteers withdrew involuntarily when they lost their jobs in the company. Two who took L withdrew due to moderate diarrhea and mild nausea or headache, weakness, drowsiness and anxiety. One volunteer stopped taking F due to severe unilateral hypostatic eczema and slight S-T depressions on the ECG. The rest completed at least six (range 6-36) months of prophylaxis. The mean half-life for L was 26 days. The AUCs in the time interval 0-14 days for L varied between 19.3-31.5 mumol x days/l. For the main metabolite, the corresponding range was 28.8-81.3 mumol x days/l. The range of trough concentrations at day 0 and 14 were 0.95-2.01 mumol/l for L and 1.69-5.62 mumol/l for the metabolite. No differences in tolerability and efficacy were noted between L and F. Our kinetic results do not indicate that enzymatic induction or inhibition would be important during long-term prophylaxis with mefloquine. This favors a continued use of the drug for very long periods of time (= years).

Ro 42-1611 in the treatment of patients with mild malaria: a clinical trial in Nigeria and Burkina Faso.

An open, non-comparative clinical trial was carried out in Nigeria and Burkina Faso to investigate the safety and efficacy of the novel antimalarial arteflene in patients with mild malaria. Patients were males aged 12 to 16 years, with a Plasmodium falciparum count of 10(4) to 10(5) parasites/microliters and a body temperature of 37.5 to 38.5 degrees C. Twenty-three patients received a single dose of Ro 42-1611 (arteflene), corresponding to 25 +/- 2.5 mg/kg bodyweight. Nineteen patients were evaluable for standard efficacy. Efficacy was assessed at 6, 9, 12, 24, 36, 48 and 72 hours, and at seven days, by: reduction in parasitaemia and time to parasite clearance; resolution of fever; and clinical cure (defined as the absence of signs and symptoms of malaria). Adverse events were reported at each assessment point, and laboratory tests were carried out at baseline and at 2 and 7 days. The parasite count was reduced by 50% or more in 89.5% of patients after 48 hours, and 52.6% were completely free of parasites at the same time. Normal temperature was achieved in 89.5% of patients and clinical cure in 75%, after 48 hours. One patient reported mild vertigo and mild pruritus. The lower than expected effect was thought to be due to inadequate storage of the arteflene suspension. There were no withdrawals due to adverse events and no deaths. A single dose of 25 mg/kg arteflene was found to be an effective and well-tolerated treatment for mild P. falciparum malaria.

Efficacy of Ro 42-1611 (arteflene) in the treatment of patients with mild malaria: a clinical trial in Cameroon.

The novel antimalarial Ro 42-1611 (arteflene) was evaluated for safety and efficacy in an open, non-comparative study of patients with mild malaria in the south of Cameroon. Thirty male patients aged 12 to 42 years, with an initial Plasmodium falciparum count of > 5000 (mean: 21,406) parasites/microliters and a body temperature of 37.7% to 39.8 degrees C, were selected to receive a single dose of arteflene, corresponding to 25 +/- 2.5 mg/kg bodyweight. Efficacy was assessed at 6, 9, 12, 24, 36, 48 and 72 hours, and at seven days by: reduction in parasitaemia and time to parasite clearance; resolution of fever and clinical cure (defined as the absence of signs and symptoms of malaria). Adverse events were reported at baseline and at each assessment point, and laboratory tests were carried out at 2 and 7 days. The mean number of parasites/microliter fell from 21,406 at baseline to 157 after 48 hours, at which point 80% of patients were completely free of parasites. Mean body temperature was reduced from 38.9 degrees C at baseline to 37.3 degrees C 12 hours after arteflene administration, and by this time 80% of patients had a normal temperature. Clinical cure rates were also high, with 70% of patients free of all signs and symptoms after 24 hours. However, by day 7, 6/30 (20%) presented with smears positive for P. falciparum. There were no adverse events considered to be related to treatment. A single dose of 25 mg/kg arteflene was found to be an effective and well-tolerated treatment for mild P. falciparum malaria.

The chemotherapy of rodent malaria. LII. Response of Plasmodium yoelii ssp. NS to mefloquine and its enantiomers.

A comparison was made between the blood schizontocidal action in mice of racemic mefloquine hydrochloride and the free bases of its (+)- and (-)-enantiomers (Ro 13-7224 and Ro 13-7225) against chloroquine-resistant Plasmodium yoelii ssp. NS. The racemic hydrochloride was two to three times as active against this parasite in mice as either of the enantiomer free bases, which were of similar activity to each other. Under drug selection pressure, the parasites acquired resistance in approximately the same time for each of the three compounds.

Behavioural aspects of travellers in their use of malaria presumptive treatment.

The use of stand-by treatment for malaria by travellers depends on their knowledge, attitudes and behaviour. We examined the behavioural aspects of a cohort of travellers from Switzerland to low-risk malarial areas who, on recruitment, were provided with a kit containing medication for stand-by treatment, guidelines on the diagnosis of malaria, and materials for collection of blood samples for later confirmation of malaria. All subjects were urged to seek medical advice at the first signs of possible malarial symptoms. Illness (fever as the main indicator) was reported by 123 of the 1187 participants, often accompanied by shivering/chills (36.6%), headache (35.0%), gastrointestinal symptoms (69.9%), and myalgia and/or arthralgia (41.5%). Two-thirds of those ill failed to seek medical attention despite their symptoms and pretravel advice. Only 9 (7.3%) were actually beyond the reach of medical attention. The stand-by treatment was self-administered by 6 travellers, only one of whom had confirmed malaria. Two non-serious adverse events were reported. All users consulted a physician after administering the presumptive treatment. This stand-by approach is limited by inappropriate behaviour and poor malaria awareness among travellers. These negative factors can be mitigated by development of an improved kit containing a simple test for self-diagnosis.

Mefloquine-sulphadoxine-pyrimethamine (Fansimef, Roche) in the prophylaxis of Plasmodium falciparum malaria: a double-blind, comparative, placebo-controlled study.

From July 1987 to June 1988 a randomized, double-blind, comparative placebo-controlled field trial was conducted in a group of villages near Ibadan, Nigeria. The aim of the study was to assess the suppressive tolerability and efficacy of four antimalarials (Fansimef, Lariam, Fansidar, chloroquine) given for 24 weeks. Fansimef and Lariam were given with loading and maintenance doses, Fansidar and chloroquine as one tablet per week for 24 weeks. Of 567 enrolled subjects, 114 (20%) had parasitaemia on entry. Eight episodes of symptomatic falciparum malaria occurred during the trial, seven in the placebo group, and one in the Fansimef group. Compared with placebo, parasitaemia was effectively suppressed by all four drug regimens. Adverse event data were not significantly different between groups: six adverse events per 114 participants in the Fansimef group, six/113 in the mefloquine group, five/111 in the Fansidar group, 17/115 in the chloroquine group and eight/114 in the placebo group. Safety of Fansimef for 24 weeks in endemic areas was comparable for standard antimalarials in this trial and provides support for the use of this drug for the treatment of resistant malaria in indigenous African populations.