Period Of Drug Application Research Articles

A randomized controlled clinical study to evaluate the efficacy of Aragwadha Pushpa Lepa (Cassia fistula Linn.) in the management of Vyanga with special reference to Melasma

Vyanga is one of the Kshudraroga mentioned in the classics which are having Lakshana like Niruja, Tanu and Shyava Mandala. It can be correlated with Melasma in modern terms, which is also known as Chloasma. Melasma is an acquired pigmentary disorder, causing hyper-pigmented patches to appear on the facial skin. The prevalence varies between 1.5 % and 33.3 % in India. Female to male ratio in India is 4:1, indicating the high prevalence rate among females. Aragwadha Pushpa Churna along with Nimbuka Swarasa is applied over the hyper-pigmented patches in the condition of Vyanga in Cauvery river stretch of Namakkal district of Tamil Nadu as a folklore practice. A randomized clinical study was carried out to compare the efficacy with Varnya Gana Churna. The clinical study in the sample size of 30 was carried out in 2 groups with the intervention of Group A being Aragwadha Pushpa Churna Lepa and that of Group B being Varnya Gana Churna Lepa, with 30 days of drug application period and 15 days of drug-free follow up period. Differential diagnosis was ruled out with the help of Wood’s lamp. Assessment was done with the help of criterias like Amount of discolouration, Arbitrary grading and Area of the lesion. Various statistical tests like Parametric, Non-parametric, Friedman repeated measures ANOVA on ranks, etc. were carried out to analyse the results of the study. Both Aragwadha Pushpa Churna and Varnya Gana Churna have significant effect in the management of Vyanga with special reference to Melasma. When improvement in the individual criteria was compared, Aragwadha Pushpa Churna showed better results in reducing the amount of discolouration & the number of lesions. Whereas, Varnya Gana Churna showed better results in reducing area of the lesion.

Changes in the Review Period of Drug Application and a Drug Lag from the FDA and the EMA: An Industry Survey in South Korea Between 2011 and 2020

BackgroundThe Korean regulatory authority has enacted legislation to expedite the new drug approval (NDA) process. However, the effectiveness of such efforts in reducing review time and drug approval delays between Korea and the USA/EU remains to be evaluated.MethodsWe investigated NDA trends in Korea from 2011 to 2020 using approval information from pharmaceutical companies. We compared the changes in the actual review duration according to active ingredient (chemical vs. biological), orphan status, therapeutic class, and NDA review process. We estimated the submission and approval gaps of new drugs between Korea and the US and EU across the study period.ResultsFor 235 new drugs, the median NDA review time was 315 days, with a significant increase in the delay (average 15.4 days) over time. Biological drugs had a 43.2-day delay for approval than the time taken for approving chemical drugs. The median NDA review time for orphan drugs was 130.4 days faster than that for others, although the difference diminished after 2016. Good manufacturing practice reviews played a crucial role in delaying review time. The median submission and approval gaps in Korea were 493 and 551 days, respectively, compared to those of the US and EU.ConclusionsDespite recent legislative initiatives, the delay in the NDA review timeline has steadily increased over 10 years in Korea. Delays in orphan drugs reviews increased after the enactment of the ‘Rare Disease Management Act’ in 2016. Careful enforcement of relevant laws and supplementary actions is required to increase new drug accessibility.

Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats

Our lab has previously shown that when administered acutely, the methylxanthine theophylline can activate a latent respiratory motor pathway to restore function to the hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. The recovery is mediated by the antagonism of CNS adenosine A1 receptors. The objective of the present study was to assess quantitatively recovery after chronic theophylline administration, the effects of weaning from the drug, and the effects of the drug on adenosine A1 receptor mRNA expression in adult rats subjected to a C2 hemisection. Rats subjected to a left C2 hemisection received theophylline orally for 3, 7, 12, or 30 days and were classified as 3D, 7D, 12D, or 30D respectively. Separate groups of 3D animals were weaned from drug administration for 7, 12, and 30 days before assessment of respiratory recovery. Additional groups of 7D and 12D animals were also weaned from drug administration for 7 and 12 days prior to assessment. Sham-operated controls received theophylline vehicle for similar periods. Quantitative assessment of recovered respiratory activity was conducted under standardized electrophysiologic recording conditions approximately 18 h after each drug application period. Serum theophylline analysis was conducted at the end of electrophysiologic recordings. Adenosine A1 receptor mRNA expression in the phrenic nucleus was assessed with in situ hybridization and immunohistochemistry. Chronic theophylline induced a dose-dependent effect on respiratory recovery over a serum theophylline range of 1.2–1.9 μg/ml. Recovery was characterized as respiratory-related activity in the left phrenic nerve and expressed as a percentage of activity in the homolateral nerve in noninjured animals under similar recording conditions. Recovered activity was 34.13 ± 2.07, 55.89 ± 2.96, 74.78 ± 1.93, and 79.12 ± 1.75% respectively in the 3D, 7D, 12D, and 30D groups. Theophylline-induced recovered activity persisted for as long as 30 days when drug administration was stopped and serum levels of the drug were virtually undetected. Furthermore, recovered activity in 3D and 7D animals increased significantly as a function of duration of weaning. Adenosine A1 receptor mRNA expression was not significantly changed by theophylline administration. It is concluded that recovery of respiratory function in C2-hemisected rats induced by chronic theophylline is unrelated to adenosine A1 receptor mRNA expression. Recovered activity persists even when drug administration has been stopped. The significance of our results is that in the clinical application of theophylline to improve respiratory impairment, intermittent drug administration may be sufficient to engender and maintain the therapeutic benefits of the drug.

Intracellular calcium stores modulate miniature GABA-mediated synaptic currents in neonatal rat hippocampal neurons.

The whole-cell configuration of the patch clamp technique was used to record miniature gamma-aminobutyric acidA (GABAA) receptor-mediated currents (in tetrodotoxin, 1 microM and kynurenic acid 1 mM) from CA3 pyramidal cells in thin hippocampal slices obtained from postnatal (P) day (P6-9) old rats. Switching from a Ca2+-containing to a nominally Ca2+-free medium (in which Ca2+ was substituted with Mg2+, in the presence or in the absence of 100 microM EGTA) did not change significantly the frequency or amplitude of miniature events. Superfusion of thapsigargin induced a concentration-dependent increase in frequency but not in amplitude of tetrodotoxin-resistant currents that lasted for the entire period of drug application. Mean frequency ratio (thapsigargin 10 microM over control) was 1.8+/-0.5, (n = 9). In nominally Ca2+-free solutions thapsigargin was ineffective. When bath applied, caffeine (10 mM), reversibly reduced the amplitude of miniature postsynaptic currents whereas, if applied by brief pressure pulses, it produced an increase in frequency but not in amplitude of spontaneous GABAergic currents. Superfusion of caffeine (10 mM) reversibly reduced the amplitude of the current induced by GABA (100 microM) indicating a clear postsynaptic effect on GABAA receptor. Superfusion of ryanodine (30 microM), in the majority of the cells (n = 7) did not significantly modify the amplitude or frequency of miniature events. In two of nine cells it induced a transient increase in frequency of miniature postsynaptic currents. These results indicate that in neonatal hippocampal neurons, mobilization of calcium from caffeine-ryanodine-sensitive stores facilitates GABA release.

Involvement of Lipid Peroxidation in Necrosis of Skin Flaps and Its Suppression by Ellagic Acid

To evaluate the pathogenesis of lipid peroxidation in skin-flap necrosis and to select a novel herbal antioxidant to suppress lipid peroxidation and salvage the flaps, in vitro and in vivo experiments were instituted. In vitro studies revealed (1) the potentiality of the cutaneous microsomal system (vesicular fragment of endoplasmic reticulum) to generate oxyradicals by FeCl3 (oxidative agent), since NADPH-dependent lipid peroxidation was elevated time-dependently, (2) suppression of microsomal lipid peroxidation by herbal antioxidants (dose- and time-dependently), further supporting the theory of oxyradical-induced lipid peroxidation in the skin, and (3) that ellagic acid showed the strongest response, with curcumin, chlorogenic acid, and alpha-tocopherol (tocopherol) being moderate, and ferulic acid and gallic acid remaining weakest. Thus ellagic acid, curcumin, chlorogenic acid, and tocopherol at doses of 10, 60, 80 and 100 microM (twice I50, the dose which could inhibit lipid peroxidation by 50 percent) were chosen for in vivo assessments, respectively. In vivo studies were performed using rat back skin random flaps (70 x 15 mm and based anteriorly) and circular island flaps (20 mm in diameter and raised on superficial epigastric vessels). Control flaps were painted with a Tris-ethanol solution, and test flaps were painted with either ellagic acid, curcumin, chlorogenic acid, or tocopherol (above-mentioned doses per 250 microliters of Tris-ethanol per 300 mm2 of flap surface 1 hour before the operation and once a day for 3 postoperative days). Doses, frequency, and period of drug application were based on in vitro and in vivo pilot experiments. The results were as follows: (1) a direct and time-dependent relation was noticed between lipid peroxide levels and the rate of necrosis in both types of flap; (2) time-dependent elevation of lipid peroxide levels of skin, subcutaneous fat, and exudate of island flaps during ischemia and those of skin and subdermal fat after reperfusion indicated pre- and post-reflow states of lipid peroxidation rather than the original conception of merely reperfusion state; and (3) in good agreement with the results of in vitro experiments, ellagic acid exerted the strongest effect to suppress lipid peroxide levels of skin and to augment the viability of random flaps more than that of island flaps.(ABSTRACT TRUNCATED AT 400 WORDS)

An application of the [formula omitted] concept in predicting the topical efficacy of finite dose acyclovir in the treatment of cutaneous HSV-1 infections in hairless mice

This study has examined C ∗ (and its temporal pattern) as a parameter for predicting topical antiviral efficacy of acyclovir (ACV) formulations in a recently developed hairless mouse model for the treatment of HSV-1 cutaneous infections. C ∗ referred to here is the free drug concentration at the target site, which is believed to be the basal cell layer of the epidermis. Two different topical ACV formulations, one available commercially (Zovirax 5% ointment) and the other prepared in our laboratories (3% ACV suspension) were investigated in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. C ∗ was calculated from in vitro flux data and information obtained from previous baseline studies. In vitro ACV flux determinations involved an in vivo-in vitro experimental design that was believed to approximate closely the actual in vivo antiviral treatment protocol. For the in vivo antiviral efficacy studies, a 1-day delayed (after virus inoculation) 4-day treatment protocol was implemented and the animals wore a Velcro jacket to protect the formulations from being removed during the drug application period. With Zovirax 5% ointment given 3 mg every 12 h, our results showed a 0% topical efficacy which was consistent with the C ∗ predictions. In the case of the laboratory prepared 3% ACV suspension, a dose of 2 μl was given every 12 h and our results showed a modest level (33–44%) of topical effectiveness, which was somewhat higher than predicted (0–25%) from C ∗ considerations. Also, in the efficacy studies (but not in the in vitro flux studies) with the laboratory prepared formulation, there were instances (20–33%) of severe skin irritation/damage noted at the end (day 5) of the experiments. Taking this into consideration, it is suggested that these studies represent a good correlation between predictions (C ∗) based on the in vitro data and the in vivo antiviral efficacy and validate the predictive value of this approach.

A Study of the Possible Mechanisms Underlying the Convulsant Actions of a Linear Expanded Xanthine

The actions of a mixture of the 4- and 9-chloro derivatives of the linear expanded xanthine 5,7-diethyl-2-chloroimidazo[4,5-g]quinazoline-6,8 (5H,7H)-dione (chloro-DCQD) on the isolated olfactory cortex slice of the rat have been investigated. Chloro-DCQD evoked a slowly-developing depolarization which intensified over a drug application period of at least 4 min. A pharmacological investigation of the response showed that it was not mediated by blockade of potassium channels or activation of voltage-gated sodium channels, by a stimulant action at receptors to gamma-aminobutyric acid (GABA), excitatory amino acids or acetylcholine, or by antagonism of adenosine receptors. Chloro-DCQD (2.5 mM) potentiated responses evoked by N-methyl-D-aspartate (NMDA), L-aspartate and L-glutamate, probably by overcoming the magnesium ion block of the ion channel of the NMDA receptor complex. Chloro-DCQD (2.5 or 5 mM) also increased pyramidal cell excitability and abolished GABA-mediated postsynaptic inhibition but did not affect the excitability of, or neurotransmitter release from, the terminals of the lateral olfactory tract. Chloro-DCQD competitively antagonized the inhibitory actions of adenosine on the olfactory cortex. These effects are consistent with the reported convulsant actions of chloro-DCQD.

Reduction of cytotoxicity to normal tissues by new regimens of cell-cycle phase-specific drugs

A new policy for minimizing cytotoxicity to normal tissues of cell-cycle phase-specific drugs is suggested. This policy is based on short drug pulses and on an integer relation between the period of drug application and the cell-cycle length of the host susceptible tissue. The new protocol is expected to be effective even if the cell-cycle parameters of the malignant population have the same mean as those of the host cells but their variance is larger, and as long as the variance in the duration of the drug pulse is not too large. Under these conditions protocols can be determined by the host temporal parameters alone. The method has been verified in vitro, treating a leukemic cell line with cytosine arabinoside (Ara-C).

Prenatal Diazepam Exposure Affects β‐Adrenergic Receptors in Brain Regions of Adult Rat Offspring

The postnatal development of [3H]dihydroalprenolol binding to beta-adrenergic receptors has been studied in frontal cortex, cerebellum, striatum, and hypothalamus of the rat after prenatal and perinatal exposure to diazepam. Dams were injected subcutaneously with single daily doses of 1 mg of diazepam/kg from day 7 to 20 of gestation or from day 15 of gestation to day 6 after birth. Prenatal exposure had no effect on litter size or length of gestation or on the postnatal development of body and brain weights of the progeny. However, a reduced mortality of the pups was observed in relation to vehicle-treated controls until postnatal day 10. Prenatal diazepam administration decreased [3H]dihydroalprenolol binding in frontal cortex, striatum, and hypothalamus but not in cerebellum. This decrease in beta-adrenergic receptor binding was due to a decrease in receptor density rather than in receptor affinity. In contrast, perinatal diazepam exposure led to a transient decrease in [3H]dihydroalprenolol binding limited to the frontal cortex. The permanent reduction in number of beta-adrenergic receptors, which depends on the scaling and duration of the drug application period, points to the necessity of a prolonged evaluation of effects of exposure to psychotropic drugs in early stages of brain development.

Presynaptic dual inhibitory actions of guanabenz on adrenergic transmission

Actions of guanabenz, clonidine and guanethidine on adrenergic transmission were studied in rabbit atria and ilea with intact nerves. While guanabenz 3 × 10 −6 M and clonidine 3 × 10 −7 M inhibited to a similar degree atrial positive chronotropic responses to nerve stimulation at 2Hz, no inhibition was seen at 10 Hz. Phentolamine 3 × 10 −6 M completely antagonized the inhibition by clonidine, but a partial antagonism was seen against guanabenz. Cocaine 10 −5 M prevented the phentolamine-resistant inhibition by guanabenz. Guanethidine 10 −5M inhibited the responses to 2 and 10 Hz. In ilea, guanabenz 10 −5 M inhibited frequency-independent relaxation responses to 2–20 Hz. Clonidine 10 −5M inhibited preferentially the responses to lower frequencies. After the temperature of the bathing solution was kept at 4°C during the period of drug application, guanabenz no longer produced an inhibition of the transmission, whereas clonide produced the usual inhibition. Thus, guanabenz appears to have both presynaptic α-receptor stimulating and adrenergic neuron blocking actions.

The action of iontophoretically applied acetylcholine and dopamine on single claustrum neurones in the cat

The effects of iontophoretically applied acetyl-choline (ACh) and dopamine (DA) on spontaneously active claustral neurones, in chloralose-anaesthetised cats, have been investigated. Acetylcholine had both facilitatory and inhibitory effects in almost the same proportions. The action of DA was prevalently inhibitory. Two types of inhibitory response to ACh and DA are described: short-lasting inhibition and long-lasting inhibition. The excitatory response always outlasted the period of drug application.

Further evidence for the prevention by guanethidine of noradrenaline efflux from rabbit ventricular slices induced by a low external sodium concentration.

When guanethidine was applied to rabbit ventricular slices at 37 degrees C for an initial 30 min incubation period, doses of 4 X 10(-5) and 8 X 10(-5) M irreversibly inhibited increases in efflux of noradrenaline induced by the subsequent reduction of external sodium concentrations to 18 mM. This inhibition was prevented if the temperature was reduced to 0 degrees C during the drug application period. Guanethidine transported into adrenergic nerve endings appears to increase permeability to Na+, thereby leading to the reduction in efflux.