Aims The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg x1 on day 0 and 1.6 mg kg x1 on days 1-4 (treatment A), 1.6 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment B), 3.2 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment R).Results Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentrationtime profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokineticpharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.

To determine whether expression of class II major histocompatibility complex antigens on alveolar epithelium is relevant to the pathogenesis of idiopathic pulmonary fibrosis (IPF) lung biopsy specimens were investigated from nine patients with IPF with or without connective tissue disease, four patients with sarcoidosis, eight patients with lung disease of presumably infectious origin, and five controls. The alveolar epithelium stained strongly with anti-Ia (HLA-DR) or Leu 10 (HLA-DS) monoclonal antibodies, in eight of nine biopsy specimens from patients with IPF, in three of four biopsy specimens from patients with sarcoidosis, in all six biopsy specimens from patients with presumably viral, mycobacterial, or pneumocystic lung disease, but not in control lung tissue, nor in two biopsy specimens from patients with bacterial pneumonia. Mononuclear cell infiltrates consisted of T4 positive (helper/inducer) lymphocytes, predominantly present in a nodular arrangement in the interstitium, and T8 positive (cytotoxic/suppressor) cells, distributed equally in the interstitium and subepithelially or intraepithelially. T8 cells outnumbered T4 cells in six of nine biopsy specimens from patients with IPF, but in none of the biopsy specimens from patients with sarcoidosis or interstitial lung disease of infectious origin. Although the expression of class II antigens on the alveolar epithelium which is infiltrated by T8 cells in IPF is consistent with local presentation of autoantigens and an ensuing local immune response, class II expression is also present in interstitial lung disease of sarcoidosis and microbial infections: its role in the pathogenesis of IPF must therefore remain speculative.

SUMMARYActivation of human B cells in vitro either by cross-linking of surface immunoglobulins (sIg) or by triggering CD40 antigen, in the presence of interleukin-10 (IL-10) and interleukin-2 (IL-2), may result in high levels of immunoglobulin secretion in vitro. We studied the combined effects of ligation of the B-cell receptor (BCR) and CD40 [with anti-CD40 monoclonal antibody (mAb)] on B-cell proliferation and production of human immunoglobulin. For this purpose highly purified splenic B cells were cultured with various combinations of anti-CD40 and IL-10/IL-2 or IL-4 in the presence of CD32-transfected L cells. Simultaneous cross-linking of the BCR was achieved by mAb held on CD32-L cells or Staphylococcus aureus (SA). We found that dual BCR and CD40 ligation with IL-10/IL-2 leads to reduced immunoglobulin G (IgG) secretion compared with B cells stimulated with either anti-CD40 and IL-10/IL-2, or compared with B cells stimulated with SA or anti-BCR mAb and IL-10/IL-2. Dual BCR and CD40 ligation with anti-immunoglobulin mAb (anti-k+anti-l light chains) but not with SA induced a similar reduction in IgM production. The reduced immunoglobulin secretion found during dual ligation is accompanied by increased proliferation. This was independent of cytokine stimulation but SA/CD40-induced proliferation was increased in the presence of IL-10/IL-2, although not with IL-4. The combination anti-k and anti-l with anti-CD40 showed a long-term suppression of IgG and IgM production (at least 14 days), while anti-k or anti-l alone, or SA, allowed a moderate recovery of immunoglobulin production by day 14. These results suggest that simultaneous B-cell antigen receptor cross-linking and CD40 engagement via CD40L on T cells induces strong initial proliferation. This may be followed later by antibody production depending on the strength of the BCR signal and the presence of the appropriate cytokines.

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