Near normalization of final height with adapted doses of growth hormone in Turner's syndrome.

An adapted GH dose regimen was evaluated in 14 untreated patients with Turner's syndrome. The initial GH dose (0.7 U/kg.BW) was increased by 0.7 U/kg.BW, up to a maximum of 2.1 U/kg.BW, when growth velocity (GV) declined to less than 200% of the pretreatment level. These patients were compared to a group of 17 patients with similar initial characteristics, who received a fixed dose of 0.9 U/kg.BW GH. Tolerance to both GH regimens was excellent. The adapted GH doses only partially prevented the waning effect observed with conventional doses of GH, and the initial goal of doubling GV was only achieved in 42% of the 112 patient-semesters. Doubling the GH dose from 0.7 to 1.4 U/kg.BW increased the GV by 1.6 +/- 1.8 cm/yr (P < 0.006); increasing the GH dose from 1.4 to 2.1 U/kg.BW increased GV by 0.8 +/- 1.3 cm/yr (P = NS). The overall height gain during the 4-yr trial was 25.6 +/- 3.9 cm in the adapted dose group and 21.8 +/- 3.9 cm in the conventional group (P < 0.02). Final height (FH) results were obtained in 12 of 14 patients in the adapted dose group and all 17 patients in the conventional group and compared to the predicted FH using Lyon's method. The estimated height benefit was 10.6 +/- 3.8 cm in the adapted dose group compared to 5.2 +/- 3.7 cm in the conventional group (P < 0.01). Eighty-three percent of the patients in the adapted dose group had an FH superior or equal to -2 SD score for the general population compared to 29% in the conventional group. In conclusion, a marked increment in the GH dose in girls with Turner's syndrome associated with a relatively late age at introduction of estrogen therapy brought 83% of the patients into the lower range of the normal height distribution of the general population.

Dose-dependent catch-up growth after 2 years of growth hormone treatment in intrauterine growth-retarded children. Belgian and French Pediatric Clinics and Sanofi-Choay (France).

This study reports the results of a 2-yr clinical trial with GH in 95 short prepubertal children with non-GH-deficient intrauterine growth retardation. This randomized, double blind, controlled study compared the effects of placebo (restricted to the first 6 months) and two doses of GH (0.4 and 1.2 IU/kg.week) given sc 6 days/week for 2 yr. A significant GH dose-dependent growth acceleration was observed. Mean height gain (SDS/CA) was 0.66 +/- 0.07 in group I (low dose, 0.4 IU/kg.week) compared to 1.25 +/- 0.07 in group II (high dose, 1.2 IU/kg.week). Mean bone maturation progression (expressed in months) was 26.2 +/- 1.7 and 30.2 +/- 1.5 over 24 months in groups I and II, respectively. Onset of puberty was observed in some patients of both groups. Whether chronic use of a high GH dose will advance the onset of puberty remains to be established. A great variability of growth acceleration was seen among GH dose groups, suggesting that factors in addition to GH dose might modulate individual responses to treatment. In conclusion, it is suggested that in these patients, dose-dependent catch-up growth could be induced by GH treatment.

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC.

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.

Adult height in children with prepubertal short stature secondary to intrauterine growth retardation.

In a retrospective study of 47 children seen before puberty for growth retardation secondary to intrauterine growth retardation (IUGR), 23 boys had a final height of 161.9 +/- 8.0 cm and 24 girls a final height of 147.6 +/- 7.2 cm, values that were significantly lower than the target heights of these patients (p < 0.001). This reduction in adult height indicates the possible usefulness of growth hormone therapy in children with IUGR.

[Treatment of metastatic renal cancer in adults with elliptinium acetate]. / Traitement des cancers du rein métastasés de l'adulte par l'acétate d'elliptinium.

The results obtained with N-methyl-hydroxy-elliptinium acetate (NMHE) in the treatment of 22 assessable adult patients with metastatic renal cancer are reported. According to the WHO criteria, there were 10 responses, including 7 stabilizations, 2 partial remissions (greater than 50%) and one complete and durable remission. Since there is no other effective medical treatment for this type of tumour, and since the protocol used so far appears to have low toxicity and makes it possible to evaluate the value of the drug within 4 to 6 weeks, the trial will be extended in order to determine more precisely (+/- 5%) the degree of effectiveness of NMHE.

Positioning, labelling and control of medical information: artesunate strategy and Arsumax development story.

Sanofi decided, some years ago, to help developing a molecule of a new type called artesunate, a semisynthetic derivative from Qinghaosu, or artemisinine, a sesquiterpenic lactone extracted from the leaves of a world wide spread plant: Artemisia annua. After having signed a secrecy agreement with a local pharmaceutical company in China manufacturing artesunate, Sanofi started, in 1993, the assessment of all the data transmitted as well as the plant involved in the artesunate tablet manufacturing. As conclusions of the whole audit performed on this project were judged satisfactory, Sanofi signed a cooperation agreement with this Chinese pharmaceutical firm in order to be allowed to start further development work required to guarantee quality and safety of artesunate 50 mg tablets called Arsumax, and to complete a registration dossier acceptable for Health Authorities in French-speaking Africa. Pharmaceutical, pharmacotoxicological and clinical documentation were widely completed, and entirely reformated according to European guidelines. The registration dossier was submitted in all French speaking African countries. The approval has been obtained in 13 countries. Due to its fast efficacy, its absence of undesirable effects, its presentation in tablets, its quite simple dosage (one box for a treatment), Arsumax positioned itself as an accurate second line antimalaric treatment.

[African Quin: results of a pragmatic study on the diagnosis of uncomplicated malaria attacks and treatment using quinine in French-speaking Africa]. / African-Quin: résultats d'une étude pragmatique sur le diagnostic de l'accès palustre simple et son traitement par la quinine en Afrique francophone.

Management and treatment of disease do not always conform with official recommendations. African-quin is a pragmatic multicentric study carried out in 13 African countries to evaluate non-conformities in the management and treatment of uncomplicated malarial attacks using quinine. This study involved a total of 3,981 patients with documented uncomplicated malarial attacks diagnosed by 500 clinical physicians. Physicians were supplied with quinine tablets (125 mg et 500 mg Quinimax containing 125 mg and 500 mg of quinine base respectively) to allow treatment according to the dose recommendations of the WHO (24 mg/kg/day of quinine base). In 38% of the 3,981 patients, diagnosis was based on clinical findings without measurement of parasitemia. The median dose of Quinimax was 15.4 mg/kg/day in 3 intakes in 67% and 2 intakes in 33%. The dose was 23.2 mg/kg/day for patients under 12 years and 14.7 mg/kg/day for patients over 18 years (p < 0.001). Treatment lasted for at least 5 days in 62% of patients. Fever control was achieved within a mean delay of 3.9 +/- 1.5 days and was followed by a rapid decrease in clinical symptoms. Clinical control (normal temperature) was obtained in 96% of patients. The dose of Quinimax was the same regardless of whether treatment was a success or failure. The results of this study demonstrate the gap between official recommendations and everyday clinical practice and raise several important questions concerning the basis for decision-making, treatment goals, drug dosage, and treatment duration.

[Rapid resolution of Plasmodium ovale malarial attacks using artesunate (Arsumax)]. / Resolution rapide des acces palustres à Plasmodium ovale par l'artésunate (Arsumax).

This randomized, non-comparative clinical trial without placebo was carried out to assess the efficacy and tolerance of artesunate for treatment of acute Plasmodium ovale malarial attacks. Thirty Cameroonese patients were included. All presented acute Plasmodium ovale malarial attacks with parasitemia in excess of 500 asexual forms per mm3. Four days after treatment with artesunate, all 30 patients were asymptomatic with no parasitemia. Reduction rates were 93.9 p. 100 for asexual forms and 75.4 p. 100 for gametocytes. Parasite clearance was achieved within 38.8 hours and fever disappeared within 36.6 hours. Tolerance was excellent in 29 patients. The remaining patient briefly complained of mild vertigo. A transient decrease in reticulocyte levels was observed in one patient initially presenting anemia. Artesunate appears to achieve rapid and complete resolution of acute Plasmodium ovale malarial attacks. Since artesunate eliminates both asexual forms and gametocytes, it also acts on transmission by limiting the duration of survival of asexual forms.

Growth response to growth-hormone administration during the decelerating phase of the pubertal growth spurt in short normal children.

In order to investigate the value of growth hormone (GH) treatment during late puberty, we studied the effect of human GH (hGH) administration (0.85 +/- 0.30 IU/kg/week; range: 0.44-1.28) on height velocity (HV) after the peak of the pubertal growth spurt in a group of 10 (4 girls and 6 boys) short normal children (GH peak after pharmacological stimulation: 15.5 +/- 2.3 ng/ml) with growth retardation (height: 2.6 +/- 0.3 SD) and puberty Tanner stage 4. A group of 10 untreated children, observed prior to the study, served as controls. The children were regularly measured during their pubertal growth spurt, and HV (cm/year) was calculated every 6 months. The pretreatment evaluation consisted of 2 consecutive 6-month periods characterized by a decrease in HV of at least 25%. In the group of selected children, hGH administration was then initiated and growth variables were evaluated after 6 and 12 months of therapy. Skeletal maturation was evaluated at the beginning as well as after 6 months and 12 months of hGH therapy. In the controls, HV (mean +/- SD) had decreased from 8.8 +/- 1.8 to 4.9 +/- 1.4 cm/year during the pretreatment period (in girls from 7.9 +/- 1.4 to 4.1 +/- 0.6 cm/year and in boys from 9.6 +/- 1.6 to 5.8 +/- 1.2 cm/year). During the following semester, HV was 3.3 +/- 0.8 cm/year (girls: 3.4 +/- 1.0 and boys: 3.2 +/- 0.2 cm/year).(ABSTRACT TRUNCATED AT 250 WORDS)

[Management of pulmonary metastases from osteosarcomas]. / Le traitement des métastases pulmonaires des ostéosarcomes.

The management of pulmonary metastases from osteosarcomas rests at present on thoracic surgery combined with chemotherapy. Until the beginning of the seventies chemotherapy proved very disappointing. With adriamycin, methotrexate in high doses followed by folinic acid and, more recently, platinum cis-dichlorodiamine, remissions, which are usually partial, are obtained in a significant proportion of patients (at least 30%). The addition of less active agents such as vincristine, cyclophosphamide, actinomycin D and bleomycin is helpful. Among 31 patients with pulmonary metastases from treated osteosarcomas seen at the Gustave Roussy Institute, 18 underwent thoracic surgery as the first treatment; in 10, surgery was followed by chemotherapy with adriamycin, vincristine, methotrexate in high doses + folinic acid + cyclophosphamide. Five patients are in complete remission 27, 30, 49, 50 and 77 months after the surgical procedure. 12 patients were initially treated with a similar chemotherapeutic regimen; a subsequent thoracic surgical procedure was undertaken in two patients who died 18 and 30 months after the pulmonary metastases had appeared. In one patient, the metastases were treated by irradiation. These results are compared to previous reports in the medical literature.

A phase I clinical tolerance study of polyadenylic-polyuridylic acid in cancer patients.

Polyadenylic-polyuridylic acid [poly(A) X poly(U)], an immunomodulator, has been shown to have antitumor effects in rodents and in a randomized clinical trial as an adjuvant to surgery in patients with operable breast cancer. The purpose of the present study was to determine the following: (a) clinical tolerance and safety of poly(A) X poly(U) in 13 patients with advanced cancer receiving a single dose of this duplex, using increasing amounts per intravenous injection of 90, 180, 300, and 450 mg; (b) if such high doses increased the level of interferon-mediated protein kinase and enhanced natural killer (NK) cell activity as observed previously with lower doses; and (c) if circulating interferon could be detected. No toxicity was observed in the 13 patients by close observation of clinical parameters, hemogram, and renal and liver functions. Increases of interferon-mediated protein kinase and of NK cell activity were observed, but there was no correlation between the magnitude of the responses and the dose of poly(A) X poly(U). No circulating interferon was detected. We conclude that poly(A) X poly(U) is not toxic in humans, at least up to a dose of 450 mg.

Phase II trial of elliptinium in advanced renal cell carcinoma.

Forty patients with advanced renal cell carcinoma were treated with elliptinium by a weekly infusion of 100 mg/m2. Of 38 evaluable patients, five had an objective response (13.2%). Average response duration was 8 months (range, 5-11). The major dose-limiting toxic effect was induction of antielliptinium antibodies, with the risk of intravascular hemolysis. Elliptinium has modest activity in advanced renal cell cancer and does not produce myelosuppression.

Follow-up of three years of treatment with growth hormone and of one post-treatment year, in children with severe growth retardation of intrauterine onset.

Seventy-eight prepubertal, non-GH-deficient children aged 8.1 +/- 0.2 y, with very short stature (mean, -3.2 SD) of intrauterine onset, were treated for 3 y with GH [0.4 (dose D1) or 1.2 (dose D2) IU/kg/wk] and 66 were followed during a 4th y without GH therapy. A 2-y intermediary report had demonstrated a GH dose-dependent acceleration of growth. During the 3rd y on GH, patients D2 (1.2 IU/kg/wk) continued with the same dose, whereas patients D1 (0.4 IU/kg/wk) were randomized to either continue on D1 (group D1) or be increased to D2 (group D1D2). After 3 y on GH, patients' mean height (SD) reached -2.37 (D1), -2.17 (D1D2), and -1.58 (D2) with a total mean height gain of 0.77 (D1), 0.93 (D1D2) (difference NS), and 1.61 SD (D2 significantly higher than D1 and D1D2, p < or = 0.0001). During the off-treatment year, mean growth rate (cm/y) decreased to 3.4 in patients D1, 3.7 in D1D2, and 4.1 in D2 (NS). During the 4 y, bone age advanced of 4.6, 4.6, and 5.3 y in D1, D1D2, and D2, respectively, and puberty started in 34 patients (10 during the off-treatment year). Age at onset of puberty, apparently within normal range, did not relate either to the dose or the duration of treatment. Clinical and biologic tolerance of treatment was good. In conclusion this study demonstrates a GH dose-dependent effect on growth acceleration in persistent postnatal severe growth retardation of intrauterine onset. This effect was sustained for 3 y at 1.2 IU/kg/wk followed by a peculiar growth deceleration at treatment discontinuation. Additional studies are necessary to optimize long-term GH treatment regimen and to document its effects on final height.