Recent advances on chitosan-based micro- and nanoparticles in drug delivery.

SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action.

https://dipbsf.uninsubria.it/monti/BFPN%202009/bloodIM.pdf

The development of imatinib as a therapeutic agent for chronic myeloid leukemia

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Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles.

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [14C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2 R )-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (−/−) knockout mice that were orally administered 25 mg/kg [14C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1–3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (−/−) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (−/−) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.

https://jpet.aspetjournals.org/content/jpet/early/2002/12/13/jpet.102.045260.full.pdf

Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux

A detection cell (2) which is used as a component of an optical biosensor comprises a transparent base plate (8) and a sample plate (4) on the base plate. The sample plate has a matrix of wells (6) extending through it to each receive a sample. The base plate includes a waveguiding film and a diffraction grating means to incouple an incident light field into the waveguiding film beneath a well to generate a diffracted light field to enable the detection of a change in the effective refractive index of the waveguiding film.

Optical biosensor matrix

We have evaluated the long term effects and safety of Sandostatin LAR, a long acting formulation of octreotide, during 18 subsequent injections given every fourth week to 14 octreotide-sensitive acromegalic patients. The dosages (20, 30, or 40 mg) were adjusted according to GH response, side-effects, or symptom relief and assessed on day 28 after each injection. We found a stable and consistent suppression of GH and insulin-like growth factor (IGF-I) during the entire study period. Daily mean GH levels were suppressed below 2 micrograms/L in 9, to between 2-5 micrograms/L in 3, and to between 5-10 micrograms/L in 2 patients. The corresponding IGF-I values were suppressed to below 500 micrograms/L in 9 patients and to between 500-1000 micrograms/L in the remaining 5 patients. Increasing the dosage of Sandostatin LAR from 20 to 30 mg had no obvious additional effect on GH suppression, but provided a further decrease in IGF-I levels. Forty milligrams of the drug had no additional effect on GH or IGF-I compared to 30 mg. Acromegalic signs and symptoms improved during treatment. Although the fluctuations of daily mean octreotide levels were high, dosage increments caused an increase in the average serum concentration in the individual patient. Pituitary tumor size reduction was seen in all previously untreated patients (n = 4). We found only minor changes in glucose metabolism (oral glucose tolerance test and hemoglobin A1C) during treatment, but no biologically relevant changes in thyroid function (TSH, T3, and free T4). One patient developed asymptomatic gallstones, and another acquired vitamin B12 deficiency during treatment. The drug is well tolerated during long term treatment. Sandostatin LAR may well be the future medical treatment of choice for acromegalic patients.

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Sandostatin LAR in Acromegalic Patients: Long Term Treatment

A stable and sustained suppression of growth hormone (GH) secretion was noted in 101 patients treated long term with individual doses (20 and 30 mg in 89 patients, 40 mg in 12 patients) of Sandostatin® LAR® (Sandoz Pharma Ltd, Basel, Switzerland). Doses of 20 mg and 30 mg at 4-week intervals delivered average octreotide concentrations of 1,348 ± 483 ng/L and 2,631 ± 1,026 ng/L, respectively, in steady-state conditions and provided adequate control of patients who had been well controlled during treatment with 0.1 mg and 0.2 mg thrice-daily subcutaneous (SC) Sandostatin®. Suppression of GH serum concentrations to less than 5 μg, 2 μg, and even 1 μg/L was recorded in more patients and more consistently during long-term treatment with Sandostatin® LAR® than Sandostatin®. A marked decrease or even a normalization of insulin-like growth factor-1 (IGF-1) serum concentrations was observed after the first double-blind 10-, 20-, or 30-mg dose of Sandostatin® LAR®. A progressive improvement was recorded during long-term treatment, with normalization of IGF-1 serum concentrations in 65.3% of patients. A marked clinical improvement was observed in parallel, with 36 of 101 patients (35.6%) becoming asymptomatic after the nineteenth injection of Sandostatin® LAR®. A greater than 20% shrinkage of the GH-secreting adenoma was also recorded in 12 of 14 patients treated with Sandostatin® LAR® after receiving only 2 to 4 weeks of treatment with SC Sandostatin® and in 11 of 18 patients receiving Sandostatin® LAR® as adjuvant therapy after failure of surgery. The systemic tolerability of Sandostatin® LAR® was good, and most adverse events were mild and short term (1 to 2 days). No impairment of thyroid function was detected. Newly occurring gallstones were recorded in four of 101 patients and microlithiasis in four of 101 after up to 30 months of treatment with Sandostatin® LAR®. Due to its excellent efficacy, good tolerability, convenience of administration, and acceptability by patients, Sandostatin® LAR® is considered a promising therapeutic tool in the management of acromegalic patients.

Sandostatin® LAR®: A promising therapeutic tool in the management of acromegalic patients

Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo

Peter Marbach

Papers

Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux

Optical biosensor matrix

Sandostatin LAR in Acromegalic Patients: Long Term Treatment

Sandostatin® LAR®: A promising therapeutic tool in the management of acromegalic patients

Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo