Advancements in addressing drug dependence: A review of promising therapeutic strategies and interventions.

Substance dependence represents a pervasive global concern within the realm of public health. Presently, it is delineated as a persistent and recurrent neurological disorder stemming from drug-triggered neuroadaptations in the brain's reward circuitry. Despite the availability of various therapeutic modalities, there has been a steady escalation in the mortality rate attributed to drug overdoses. Substantial endeavors have been directed towards the exploration of innovative interventions aimed at mitigating cravings and drug-induced repetitive behaviors. Within this review, we encapsulate the most auspicious contemporary treatment methodologies, accentuating meta-analyses of efficacious pharmacological and non-pharmacological approaches: including gabapentin, topiramate, prazosin, physical exercise regimens, and cerebral stimulation techniques.

Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor.

States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.

Unbound (bioavailable) IGF1 enhances somatic growth.

Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

A study on strategies for improving growth and body composition after renal transplantation.

Allograft function and metabolic effects of four treatment regimens, namely, methylprednisone (MP) standard dose (MP-STD), deflazacort (DFZ), MP-late steroid withdrawal (MP-LSW), and MP-very low dose (MP-VLD), were evaluated in prepubertal patients. MP was decreased by month 4 post-transplantation to 0.2 mg/kg/day in MP-STD and DFZ patients and to <0.1 mg/kg/day in MP-LSW and MP-VLD patients. Starting in month 16 post-transplant, MP was switched to DFZ in the DFZ group and totally withdrawn in the MP-LSW group. Creatinine clearance diminished in the MP-STD and MP-LSW groups from 77 +/- 6 to 63 +/- 6 ml/min/1.73 m(2)and from 103 +/- 5 to 78 +/- 3 ml/min/1.73 m(2), respectively (p < 0.01 and p < 0.001, respectively). Height increased >0.5 SDS only in the MP-LSW and MP-VLD groups. The body mass index and fat body mass for height-age increased only in the MP-STD patients (p < 0.05 and p < 0.01, respectively). Fat body mass decreased in the DFZ group (p < 0.05), total cholesterol and LDL-cholesterol increased in the MP-STD group, while LDL-cholesterol and total cholesterol/HDL-cholesterol ratio decreased in the DFZ group (p < 0.01). Lumbar spine bone mineral density (BMD) for height-age showed an increase in the MP-LSW and MP-VLD groups (p < 0.01). Our data suggest that MP-LSW and MP-VLD strategies improve linear growth, BMD, the peripheral distribution of fat, and preservation of the bone-muscle unit and maintain the normal lipid profile. The MP-LSW patients had a concerning rate of acute rejections and graft function deterioration in prepubertal patients.