Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

BACKGROUND: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation. METHODS: We report our experience with a low-calorie diet (800 cal, sodium content 1500 mmol/day) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone). RESULTS: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean +/- SD body weight falling from 270 +/- 54 lbs (123 +/- 25 kg) to 244 +/- 61 lbs (111 +/- 28 kg) (p < 0.01). The weight loss observed was no different from that observed in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263 +/- 54 lbs (120 +/- 25 kg) to 239 +/- 52 lbs (109 +/- 24 kg); p < 0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control. CONCLUSIONS: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

Is gliclazide a sulfonylurea with difference? A review in 2016

Sulfonylureas (SUs) remain the most commonly prescribed drug after metformin in the treatment of type 2 diabetes (T2DM), despite the availability of several newer agents. The primary reason of SUs being most popular is their quick glycemic response, time-tested experience and least cost. Although SUs are one amongst the several other second line agents after metformin in all major guidelines, the new Dutch type 2 guidelines specifically advise gliclazide as the preferred second line drug instead of SUs as a class. The World Health Organization (WHO) has also included gliclazide in their Model List of Essential Medicines 2013 motivated by its safety data in elderly patients. Specifically advising gliclazide may have been based on emerging evidence suggesting cardiovascular neutrality of gliclazide over other SUs. This prompted us to do a literature review of gliclazide efficacy and safety data compared to other SUs as well as oral anti-diabetic drugs.     

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY

Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation.

Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500?mmol?day^?1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone).

Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean?±?SD body weight falling from 270?±?54?lbs (123?±?25?kg) to 244?±?61 lbs (111?±?28?kg) (p?<?0.01). The weight loss observed was no different from that observed

in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263?±?54?lbs (120?±?25?kg) to 239?±?52?lbs (109?±?24?kg); p?<?0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control.

Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

Organochlorine compounds in liver and concentrations of vitellogenin and 17β-estradiol in plasma of sea bass fed with a commercial or with a natural diet

Results from previous experiments directed to determine the effect of different nutritional factors or the effect of xenobiotics on hormonal control of reproduction, lead to the hypothesis that hormonal perturbations repeatedly observed in sea bass (Dicentrarchus labrax) broodstock feeding commercial diets could have been caused by the presence of aryl hydrocarbon receptor (AhR) ligands, such as dioxins, furans and polychlorinated biphenyls (PCBs) in the diet. To evaluate this hypothesis, dioxins and related compounds were analysed in liver of female sea bass fed with a commercial or with a natural diet consisting of trash fish (bogue, Boops boops), and concentrations of vitellogenin (VTG) and 17β-estradiol (E2) were determined in plasma obtained previously in monthly samplings of these animals. As observed in other experiments, females fed with a commercial diet exhibited lower VTG and higher E2 plasma levels than females fed with the natural diet. In liver, sea bass fed with the commercial diet exhibited a profile clearly dominated by high-chlorinated dioxins while in fish fed with the natural diet this profile was dominated by low chlorinated furans. However, typical AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin showed no differences between groups or, as is the case of planar PCBs, showed higher concentrations in the liver of fish fed with the natural diet. These results do not permit to explain the observed hormonal alterations by a possible antiestrogenic effect caused by dioxins and related compounds.     

Visceral analgesics: drugs with a great potential in functional disorders?

Irritable bowel syndrome remains an incompletely understood, common syndrome with significant unmet medical needs. In IBS patients, abdominal pain is a primary factor related to quality of life impairment, symptom severity and health care utilization, and chronic visceral hyperalgesia has been identified as an important aspect of IBS pathophysiology. However, the development of therapies aimed at reducing this hyperalgesia (visceral analgesics) has been only partially successful despite preclinical evidence supporting the potential usefulness of several preclinical compounds aimed at peripheral as well as central targets.     

Primary cutaneous nodular amyloidosis in a patient with Sjögren's syndrome

A 71-year-old woman with a history of Sj?gren's syndrome presented for evaluation of a waxy nodule present on the scalp for 6 months. Histopathologic examination revealed deposition of homogenous eosinophilic material throughout the reticular dermis consistent with amyloidosis. Primary cutaneous nodular amyloidosis is a rare phenomenon characterized by the deposition of immunoglobin light chains by a clonal plasma cell population. Patients need to be monitored for progression to systemic amyloidosis or plasma cell dyscrasias.     

Anti-inflammatory therapy with a COX-2 inhibitor in Tourette’s syndrome

An infectious/inflammatory process plays a role in at least a subgroup of patients with tics and Tourettes syndrome (TS). Successful antibiotic therapy and prophylaxis was described repeatedly. We report the case of a patient suffering from chronic TS who was treated with celecoxib additionally to the antibiotic prophylaxis. This treatment was associated with a continous improvement of tics and disturbed behaviour, such as aggression and social withdrawal. The withdrawal of celecoxib led to a marked deterioration in TS symptoms while the re-exposition had advantageous therapeutic effects. This result of the treatment with a COX-2 inhibitor supports the view that COX-2 inhibitors show therapeutic benefit in patients suffering from psychiatric disorders in which an inflammatory process is involved in the pathophysiology.     

Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate?

An increasing number of instances of lymphoma in patients with rheumatoid arthritis who are treated with methotrexate continue to appear. The majority of patients with lymphoproliferation have features of immunosuppression-associated lymphoma. Rheumatoid arthritis itself and the actions of methotrexate concur in leading to a immunosuppressed state. Possible oncogenic mechanisms and the risk factors for patients with rheumatoid arthritis to develop lymphoma while receiving methotrexate include: (i) intense immunosuppression and severe disease in combination with genetic predisposition and; (ii) an increased frequency of latent infection with prooncogenic viruses like Epstein-Barr virus. The aetiological role of methotrexate in the development of these lymphomas is supported by the spontaneous remission of these malignancies in some of patients with rheumatoid arthritis after methotrexate has been stopped. The physicians caring for patients with rheumatoid arthritis receiving methotrexate should be vigilant about signs and symptoms suggestive of lymphoma, mostly in those patients with significant comorbidity, long standing and severe disease who are more likely to be immunosuppressed. If a lymphoma appears in these patients, methotrexate should be stopped. Spontaneous remission may occur and a period of observation is advisable when clinically possible. If functional deterioration appears or there are signs of lymphoproliferative organ invasion after several months then specific antineoplastic treatment should be instituted.     

Application of a Mixture Experimental Design in the Optimization of a Self‐Emulsifying Formulation with a High Drug Load

Response surface methodology (RSM) was applied to optimize the self‐emulsifying drug delivery system (SEDDS) containing 25% (w/w) Drug A, a model drug with a high lipophilicity and low water solubility. The key objective of this study was to identify an optimal SEDDS formulation that: 1) possesses a minimum concentration of the surfactant and a maximum concentration of lipid and 2) generates a fine emulsion and eliminates large size droplets (≥ 1 µm) upon dilution with an aqueous medium. Three ingredient variables [PEG 400, Cremophor EL, and a mixture of glycerol dioleate (GDO), and glycerol monooleate (GMO)] were included in the experimental design, while keeping the other ingredients at a fixed level (25% Drug A, 6% ethanol, 3% propylene glycol, 4% water, and 2% tromethamine) in the SEDDS formulation. Dispersion performance of these formulations upon dilution with a simulated gastrointestinal fluid was measured, and the population of the large droplets was used as the primary response for statistical modeling. The results of this mixture study revealed significant interactions among the three ingredients, and their individual levels in the formulation collectively dictated the dispersion performance. The fitted response surface model predicted an optimal region of the SEDDS formulation compositions that generate fine emulsions and essentially eliminates large droplets upon dilution. The predicted optimal 25% Drug A–SEDDS formulations with the levels of Cremophor EL ranging from 40–44%, GDO/GMO ranging from 10–13%, and PEG 400 ranging from 2.7–9.0% were selected and prepared. The dispersion experiment results confirmed the prediction of this model and identified potential optimal formulations for further development. This work demonstrates that RSM is an efficient approach for optimization of the SEDDS formulation.     

Pharmacists’ experiences with a statewide naloxone standing order program in Massachusetts: a mixed methods study

ObjectivesIn a prior statewide naloxone purchase trial conducted in Massachusetts, we documented a high rate of naloxone dispensing under the state’s standing order program. The purpose of this study was to understand the factors that facilitate naloxone access under the Massachusetts naloxone standing order (NSO) program and identify any remaining barriers amenable to intervention.DesignMixed methods design involving a pharmacist survey and 3 pharmacist focus groups.Setting and participantsFocus groups were conducted at 3 separate professional conferences for pharmacists (n = 27). The survey was conducted among Massachusetts pharmacists (n = 339) working at a stratified random sample chain and independent retail pharmacies across Massachusetts. All data were collected between September 2018 and November 2019.Outcome measuresFacilitators and barriers to NSO implementation and naloxone dispensing and pharmacists’ attitudes and beliefs regarding naloxone and opioid use.ResultsMost pharmacists described NSO implementation as being straightforward, although differences were reported by pharmacy type in both the survey and focus groups. Facilitators included centralized implementation at chain pharmacies, access to Web-based resources, regularly stocking naloxone, and use of naloxone-specific intake forms. Barriers included patient confidentiality concerns and payment/cost issues. Only 31% of surveyed pharmacists reported always providing naloxone counseling; the most commonly cited barriers were perceived patient discomfort (21%) and time limitations (14%). Confidential space was also more of a concern for independent (vs. chain) pharmacists (18% vs. 6%, P = 0.008). A majority of pharmacists held supportive attitudes toward naloxone, although some reported having moral/ethical concerns about naloxone provision.ConclusionWe documented several facilitators to NSO implementation and naloxone dispensing. Areas for improvement include addressing stigma and misconceptions around opioids and naloxone use. These remain important targets for improving pharmacy-based naloxone dispensing, although our overall positive results suggest Massachusetts’ experience with NSO implementation can inform other states’ efforts to expand pharmacy-based naloxone access.     

Tumor infiltrating lymphocytes in uveal melanoma: a link with clinical behavior?

Experimental and clinical evidence indicate that immunological mechanisms might be important in the clinical course of uveal malignant melanoma (UMM). We analyzed the amount and phenotype of tumor infiltrating lymphocytes (TIL) and the expression of the apoptosis-inducing molecule Fas and its ligand, FasL, on tumor cells and TIL in a selected series of UMM with the aim to establish if a correlation between their expression and the clinical behavior of UMM exists. TIL phenotype and Fas/FasL expression were evaluated by immunohistochemistry in 61 cases of formalin-fixed, paraffin-embedded UMM. Results were compared with the follow-up data of patients. Most of the UMM showed a prevalence of CD8+ CD3+ T lymphocytes, or CD4+ and CD8+ cells in equal amounts. UMM showed a variable expression of FasL, ranging from 0 to > 40% of neoplastic cells. Fas was always expressed in TIL, although with a variable extent. A subgroup of UMM showed in TIL a strongly reduced or even absent expression of TCR zeta-chain, involved in activation of T-lymphocytes. This subgroup was characterized by a worse outcome. We hypothesized that an impaired cytotoxic immune response due to the loss of the zeta-chain expression plays a primary role in the biological course of UMM. Our results indicate that the overcoming of the impairment of TCR function may represent a prerequisite for the development of new therapeutic strategies for managing UMM, suggesting that elimination of tumor cells may be possible by activation of cytotoxic cells present within ocular melanomas.     

Structure–Pharmacokinetic Relationships in a Series of Valpromide Derivatives with Antiepileptic Activity

The following valpromide (VPD) derivatives were synthesized and their structure–pharmacokinetic relationships explored: ethylbutylacetamide (EBD), methylpentylacetamide (MPD), propylisopropylacetamide (PID), and propylallylacetamide (PAD). In addition, the anticonvulsant activity of these compounds was evaluated and compared to that of VPD, valnoctamide (VCD), and valproic acid (VPA). MPD, the least-branched compound had the largest clearance and shortest half-life of all the amides investigated and was the least active. All other amides had similar pharmacokinetic parameters. Unlike the other amides, PID and VCD did not metabolize to their respective homologous acids and were the most active compounds. Our study showed that these amides need an unsubstituted position in their aliphatic side chain in order to biotransform to their homologous acids. An amide which is not metabolized is more potent as an anticonvulsant than its biotransformed isomer. All amides were more active than their respective homologous acids. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the anticonvulsant activity was affected by the pharmacokinetics in general and by the biotransformation of the amide to its homologous acid in particular. This amide–acid biotransformation appeared to be dependent upon the chemical structure, especially upon the substitution at position of the molecule.     

Guillain-Barré syndrome in a patient with metastatic colon cancer receiving oxaliplatin-based chemotherapy

We report Guillain-Barre syndrome (GBS), developed in a patient with metastatic colon cancer, receiving oxaliplatin-based chemotherapy. The 53-year-old patient was treated with first-line chemotherapy consisting of oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day in a weekly schedule. After 13 weeks of treatment and a cumulative oxaliplatin dose of 585 mg/m2, the patient developed unsteadiness of gait, dysphagia, and weakness of both the upper and lower limbs, as well as impairment of all sensory modalities. Clinical examination, computed tomography and magnetic resonance imaging scans of the brain, blood tests, nerve conduction studies, and cerebrospinal fluid analysis confirmed the diagnosis of GBS. Intravenous immunoglobulin G was administered for 5 days and the patient recovered fully. Oxaliplatin can cause acute and delayed neurotoxicity, but this is the first report of GBS in a patient receiving oxaliplatin-based chemotherapy. Elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin, may represent the relevant causal links involved in the cascade of events which have led to the immune-mediated demyelination in the peripheral nervous system in this patient.     

Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism

Background and aims

A family history (FH) of alcoholism accounts for approximately 50 % of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB₁R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB₁R function decreases alcohol-related behaviors and enhanced CB₁R function increases them. In this first human study, we probed CB₁R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC).

Design, setting, and participants

Healthy volunteers (n?=?30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ⁹-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions.

Measurements

Primary outcome measures were subjective “high,” perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ⁹-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable.

Findings

Greater FH was correlated with greater “high” and perceptual alterations induced by Δ⁹-THC. This enhanced sensitivity with increasing FH was specific to Δ⁹-THC’s rewarding effects and persisted even when FH was calculated using an alternate method.

Conclusions

Enhanced sensitivity to the rewarding effects of Δ⁹-THC in high-FH volunteers suggests that alterations in CB₁R function might contribute to alcohol misuse vulnerability.