Analysis of physicochemical properties for drugs from nature

The chemical structure of a compound has a direct influence on its physical, chemical, and biological properties. The present study describes data pertaining to calculations and statistical analysis of the physicochemical parameters of drugs obtained directly or indirectly from nature. The study projects various physiochemical parameters required for their druggability. The study reveals that most of these drugs fall close to Lipinski’s rule of five. Among the reported physicochemical parameters, the number of aromatic rings is most interesting. Illustrations regarding the same are reported, along with their statistical trends.     

TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline) inhibits the consumption of "snacks" in mice

There is considerable evidence that alpha2-adrenergic receptor activity exerts a pivotal role in initiation of feeding behavior. The appetite suppressant and monoamine release effects of TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline), a putative selective alpha2-adrenergic compound, were compared to those of fenfluramine, a reference drug that produces an anorectic effect via presynaptic release and reuptake inhibition of serotonin. The drugs were administered to two groups of mice that had learned to consume either sweet milk or chocolate pellets (i.e. "snacks") during the low-activity/reduced-feeding "light" portion of their light/dark cycle. The selectivity of the drugs to suppress the consumption of snacks was determined by comparing doses of each drug that inhibited the animals' consumption of snacks to doses of each drug that have been shown, or were shown, to impact the motor (i.e. locomotor, rotarod, and inclined-screen side effect-like tests) or conditioned taste aversion (CTA) behavior of mice. An evaluation of TDIQ as a releaser of monoamines was determined in rodent brain synaptosomes. The administration of TDIQ or fenfluramine inhibited the consumption of the snacks, and a comparison of their ED50 doses indicated that TDIQ is about 3 times more potent than fenfluramine (1.3 mg/kg vs. 4.2 mg/kg, respectively) in the sweet milk test and almost equipotent to fenfluramine (19.4 mg/kg vs. 18.4 mg/kg, respectively) in the chocolate pellet assay. The selectivity of the appetite suppressant effect of TDIQ was differentiated from that of fenfluramine on the basis that TDIQ exhibited a wide separation between its dose-response effects that suppressed snack consumption and its minimal effects in tests that measured behavioral impairment. Moreover, TDIQ was distinguished from fenfluramine in that it displayed very low potencies as a presynaptic releaser of monoamines. Finally, TDIQ (0.3 mg/kg-30.0 mg/kg) did not induce a conditioned taste aversion. TDIQ may represent a novel chemical entity that exhibits a significantly favorable therapeutic-like (i.e. appetite suppressant) effect to side effect-like ratio.     

Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms

Intravenous immunoglobulin (IGIV) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. IGIV is beneficial in several diseases, including acute and chronic/relapsing diseases, autoimmune diseases and inflammatory disorders. Therapeutic efficacy of IGIV has also been established in a number of dermatologic diseases. Although a considerable progress has been made in understanding the mechanisms by which IGIV exerts immunomodulatory functions in autoimmune diseases, they remain not fully elucidated. The mode of action of IGIV is complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network, modulation of idiotype network, regulation of cell growth, alteration of cellular adhesion process, and effects on the activation differentiation and effector functions of T and B cells and of antigen-presenting cells. The therapeutic effects of IGIV most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. The ability of IGIV to interact through V regions with complementary V regions of antibodies and antigen receptors as well as with relevant soluble and surface molecules provides the basis for inducing the selection of immune repertoires. Since IGIV is frequently used to treat autoimmune and inflammatory diseases for which evidence of its efficacy is insufficiently documented, controlled trials, particularly of some neurologic and dermatologic diseases, are imperative.     

Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain

Summary. Radioligand binding studies were done to investigate the effect of chronic administration of fluoxetine on 5-HT₁ receptor mediated response to adenylate cyclase (AC) in rat brain. Our studies revealed a significant decrease in the densities of 5-HT₁ and 5-HT_1A receptor sites in cortex and hippocampus of rat brain after chronic administration of fluoxetine (10 mg/Kg body wt.). However there was no significant change in the affinity of [³H]5-HT and [³H]DPAT for 5-HT₁ and 5-HT_1A receptor sites, respectively. However, in striatum, along with a significant (75%) downregulation of 5-HT₁ sites, the affinity of [³H]5-HT to these sites was increased, as revealed by decrease in Kd (0.50 ± 0.08 nM). Displacement studies showed that fluoxetine has higher affinity for 5-HT_1A receptors with a Ki value of 14.0 ± 2.8 nM, than 5-HT₁ sites. No significant change was observed in basal AC activity in any region after fluoxetine exposure. However, in cortex of experimental rats the 5-HT stimulated AC activity was significantly increased (16.03 ± 0.97 pmoles/mg protein; p < 0.01), when compared to 5-HT stimulated AC activity (12.98 ± 0.78 pmoles/mg protein) in control rats. The increase in 5-HT stimulated AC activity in cortex may be due to the significant downregulation of 5-HT_1A sites in cortex after fluoxetine exposure as these sites are negatively coupled to AC. The observed significant decrease in 5-HT₁ sites with concomitant increase in 5-HT stimulated AC activity, after fluoxetine treatment, suggests that fluoxetine, which has high affinity for these sites, acts by modulating the 5-HT_1A receptor mediated response in brain. Accepted August 25, 1999     

Small cell lung cancer: from molecular biology to novel therapeutics

Small cell lung cancer (SCLC) is an aggressive tumor which metastasizes early. Patients with this disease have a poor prognosis even with immediate treatment. Because of the aggressive nature of this disease, all aspects of this tumor are studied extensively. This review will provide an update of the biology of SCLC at both the molecular and cellular levels. Cellular pathways and their relationship to cellular function will also be discussed. Treatment of both primary limited- and extensive-stage diseases as well as recurrent disease will be discussed including chemotherapy, thoracic radiotherapy, and surgery. The role of novel therapeutics being investigated will also be addressed.     

THE EFFECT OF FOOD ON THE BIOAVAILABILITY OF IBUPROFEN AND FLURBIPROFEN FROM SUSTAINED RELEASE FORMULATIONS

The effect of food on the plasma concentration–time profile of sustained release dosage forms of ibuprofen and flurbiprofen has been investigated in healthy Asian Indian volunteers, in two separate studies. In study 1, 20 volunteers were administered a single 200 mg multiple-unit sustained release capsule of flurbiprofen (Froben SR^™), after an overnight fast or a heavy vegetarian breakfast. Food produced a statistically significant increase in the mean (±SE) maximal plasma concentration (C_max ) and area under the plasma concentration–time curve (AUC_0–48 . C_max (±SE) increased from 9·88± 0·48 mg L⁻¹ (fasting) to 11·36±0·88 mg L⁻¹ (postprandial) and AUC_0–48 (±SE) increased from 120·78±9·64 mg h L⁻¹ (fasting) to 149·73±12·24 mg h L⁻¹ (postprandial). The mean (±SE) time to peak (t_max ) was also significantly delayed from 3·85±0·27 h to 8·70±0·89 h. In study 2, 18 volunteers were administered a single 800 mg erodible sustained release matrix tablet of ibuprofen (Brufen Retard^™), after an overnight fast or along with a heavy vegetarian breakfast. The formulation exhibited multiple peaks (n≥2) on the plasma concentration–time curve. Although food did not affect the bioavailability of this formulation, there was a statistically significant increase in the mean (±SE) concentration of the first peak (C_peak1 ) from 14·21±1·38 mg L⁻¹ (fasting) to 20·14±1·38 mg L⁻¹ (with food). The time at which C_peak1 was reached was not influenced by the intake of food. Results indicate that while qualitative changes in the plasma concentration versus time curves are primarily influenced by the nature of the formulation and the type of meal, bioavailability is influenced by the absorption characteristics of the drug as well. Thus, despite a significant increase in peak plasma concentrations of both drugs with a meal, the bioavailability of flurbiprofen alone was enhanced.     

Tissue Oxygenation Measurements to Aid Scalpel Debridement Removal in Patients With Diabetes

Background:Callus formation in the diabetic foot increases the risk of ulcer onset. It is standard procedure to remove these dead tissue layers to reduce rising pressures. In a surgical procedure known as scalpel debridement, or chiropody the callus tissue is removed up to the epidermal layer. Factors may influence the outcome of this surgical process such as clinician inexperience. In an effort to standardize the debridement process, tissue oxygenation (TO) measurements are obtained before and after to study the effect of debridement on callus tissue.Methods:Fifteen debridement cases were analyzed using near infrared (NIR) imaging to study changes in TO. The NIR-based device used in this study estimates effective changes in TO in terms of oxy-, deoxy-, total hemoglobin, and oxygen saturation. Weber contrasts between callus tissue and the surrounding normal tissue were compared following debridement for all TO parameters. In a secondary analysis, callus tissue was segmented into quadrants and a percent of significance (in terms of total TO change) was calculated using a t-test.Results:Results show majority of cases displayed greater than 80% as the significant change in TO following debridement, except in cases with the presence of blood clot (a common precursor for ulceration). In cases where incomplete debridement was suspected, a significant change in TO was still observed.Conclusions:With extensive systematic studies in the future, NIR imaging technique to measure changes in TO may be implemented as a low-cost hand-held imaging device useful for objectively assessing the effectiveness of the scalpel debridement process.     

Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon‐α present in serum from patients with systemic lupus erythematosus

Objective

Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon‐α (IFNα), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients.

Methods

DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs.

Results

IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%.

Conclusion

The present findings indicate that IVIG, by down‐regulating the IFNα‐mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune‐mediated inflammatory conditions.

     

Down’s Syndrome Screening in the First Trimester with Additional Serum Markers: Indian Parameters

Objective

To derive a risk calculation algorithm suitable for use in India when screening for Down’s syndrome using four first-trimester maternal serum markers either alone or with ultrasound nuchal translucency (NT).

Methods

Stored maternal serum samples (??20 °C) from 411 singleton unaffected pregnancies were retrieved and measured for pregnancy-associated plasma protein (PAPP-A), free β-human chorionic gonadotropin (hCG), placental growth factor and α-fetoprotein. Samples were taken at 10–13 weeks’ gestation. Equations were derived to express marker levels in multiples of the gestation-specific normal median, adjusted for maternal weight. Gaussian model parameters were derived and compared with six published non-Indian studies; NT parameters were derived from 27,647 women screened in India. On the basis of the maternal age distribution in 64,473 Indian women screened in 2016–2017, the model was used to predict test performance.

Results

The model predicted a detection rate for a serum-only protocol of 80% for a 5% false-positive rate. Using a 1 in 250 at term Down’s syndrome risk cut-off, the predicted detection rate was 78% and the false-positive rate was 4.1%. When NT was also included, the rates were 95% for 5% and 90% for 1.4%, respectively.

Conclusion

First-trimester screening using four serum markers only can be carried out in India. Performance is expected to be similar to the second-trimester Quad test and will also facilitate early screening for preeclampsia and open spina bifida. A protocol of NT plus the four serum markers enhances the performance compared with NT, PAPP-A and free β-hCG.