Low plasma insulin-like growth factor (IGF)-I despite high circulating growth hormone (GH) in insulin-dependent diabetes mellitus (IDDM) indicate a hepatic GH resistance. This state may be reflected by the reduction of the circulating GH binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, and the reduction of insulin-like growth factor binding protein (IGFBP)-3, major IGF-I binding protein, upregulated by GH. We carried out two studies. In the first, plasma GHBP activity was compared in patients with IDDM on continuous subcutaneous insulin infusion (CSII) or on conventional therapy and in healthy subjects. In the second study, the 18 patients on CSII at baseline were then treated by continuous intraperitoneal insulin infusion with an implantable pump (CPII) and prospectively studied for GH-IGF-I axis. Although HbA1c was lower in patients on CSII than in those on conventional therapy, GHBP was similarly reduced in both when compared to control subjects (10.2 +/- 0.8 and 11.6 +/- 0.9% vs 21.0 +/- 1.3, p < 0.01). CPII for 12 months resulted in: a slight and transient improvement in HbA1c (Time (T)0: 7.6 +/- 0.2%, T3: 7.1 +/- 0.2%, T12: 7.5 +/- 0.2%, p < 0.02), improvement in GHBP (T0: 10.2 +/- 0.8%, T12: 15.5 +/- 1.5, p < 0.0001), near-normalization of IGF-I (T0: 89.4 +/- 8.8 ng/ml, T12: 146.9 +/- 15.6, p < 0.002) and normalization of IGFBP-3 (T0: 1974 +/- 121 ng/ml, T12: 3534 +/- 305, p < 0.0001). The hepatic GH resistance profile in IDDM does not seem to be related to glycaemic control, but partly to insufficient portal insulinization. Intraperitoneal insulin delivery, allowing primary portal venous absorption, may influence GH sensitivity, and improve hepatic IGF-I and IGFBP-3 generation.

Baclofen, the most effective drug for treating spasticity, is a specific agonist of gamma-aminobutyric acid-B receptors, and is very abundant in the superficial layers of the spinal cord. Given orally, baclofen does not easily penetrate the blood-brain barrier, and is distributed equally to the brain and spinal cord. Direct intrathecal administration was given in order to change the distribution of the drug by preferentially perfusing the spinal cord. Eighteen patients presenting a severe spastic syndrome were treated with chronic intrathecal infusion of baclofen in the lumbar cerebrospinal fluid. After clinical preselection, 38 patients were implanted with a lumbar access port allowing long-term trials in order to determine the efficacy of baclofen therapy and the effective 12-hour dose. The 18 patients selected for chronic administration were implanted with a programmable pump. The pathology in these cases was: multiple sclerosis (6 cases), posttrauma spastic syndrome (eight cases), and (one case each) cerebral palsy, ischemic cerebral lesion, spinal ischemia, and transverse myelitis. The mean follow-up period was 18 months (range 4 to 43 months). The clinical results were evaluated according to muscular hypertony on Ashworth's scale (changed for occurrence of painful spasms) and functional improvement. Results were better for spastic syndrome secondary to traumatic medullary lesion than for demyelinating disease. Hypertonia was improved in all cases as confirmed by the registration of the Hoffman (H) reflex. Painful muscular spasms disappeared in 14 of the 16 affected patients. Significant functional improvement was noted in nine patients and was considerable in three. The risk of side effects secondary to overdose (such as excessive hypotonia or central depression) and the absence of a specific baclofen antagonist stresses the necessity for accurate determination of the efficient dose. After an initial titration period and adjustment of the therapeutic dose, the individual doses were from 21 to 500 micrograms/24 hrs (mean 160 micrograms/24 hrs). This new conservative method is very effective, perfectly reversible, and safe when administered in conditions favorable to its use.

The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l.h-1. In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).

The requirement for a moderate increase in intrathecal opioid doses reflects the development of tolerance but did not limit the patients' ability to obtain adequate analgesia during the course of their painful disease.

Serum GH-binding protein (GHBP) was evaluated in 2 randomly divided groups of prepubertal children presenting with idiopathic GH deficiency and receiving recombinant human GH, either continuously by sc infusion (group 1) or as 1 daily sc injection (group 2). After the first 6 months, group 1 switched from continuous infusion to daily injections for the following 6 months. There was no significant difference in clinical data, GH values, or GHBP levels between the 2 groups before treatment. During the first 6 months, GHBP levels increased in all except 1 of the 8 children in group 1 from 8.6% to 16.9% after 3 months and 22.5% after 6 months. The increment factor ranged from 1.1-7.9, with wide individual variations. In group 2, the mean variation in GHBP was from 8.3-8.2% after 3 months and 10.7% after 6 months. Only 2 of the 10 children in this group showed a significant increase in GHBP levels. During the second period, group 1 maintained their GHBP levels, whereas the 2 children in group 2 tended to a continued increase in their GHBP levels. There was no correlation with the increase in growth velocity, as children in both groups grew equally well, but higher insulin-like growth factor-I levels were found in group 1, although the difference between the two groups was not significant. These data show that GH can increase GHBP levels and that there is a differential effect depending on the mode of GH administration, although the reason for and the role of such regulation remains to be explained.

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Journal of Liquid ChromatographyPublication details, including instructions for authors and subscription information:Un iversiti Paul Sa batier 31400 Toulouse Cedex, France 2Lab orato ire de Neuro ech irurg-ee et Neuro b io logie A ppliq uie ABSTRACT Baclofen (4-aminc+3pchlorophenylbutyric acid) is used clinically for the treatment of multiple sclerosis and other spastic conditions. The intrathecal route Df abinistration is now prefered to the o r a l route. To optimize efficacy, the levels of the drug in CSF need to be monitored after intrathecal ahministration. In this paper, the authors describe a sensitive reverse phase high performance liquid chromatographic method for the determination of baclofen in human CSF. This =say employed cation exchange extraction, precolumn derivatization with PITC, and ultra-violet detection 1753

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