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غزل

جو دیپ پلکوں پہ دھر رہا تھا

وہ شب کا کشکول بھر رہا تھا

 

چہار سو  نور  تھا  زمیں  پر

کوئی فلک  سے اتر  رہا   تھا

 

اُدھر بھی تو ایک زندگی ہے

وہ جی رہا ہے جو مر رہا تھا

 

ہوائے شب اشتعال میں تھی

چراغ  جلنے  سے ڈر  رہا  تھا

 

ہماری آنکھوں میں تشنگی تھی

کہ  دل  کا  دریا  اتر  رہا   تھا

 

سمیٹتا کیا وہ  مجھ  کو  آ  کر

جو خود ہی ہر  پل بکھر رہا تھا

 

جو  آ  رہے  ہیں  شفیق  آصف

میں  یاد  ان  کو  ہی  کر   تھا

سماحت اور رہبانیت: شاہ ولی اللہ کا موقف

The hall mark of Shah Waliullah has been advocate moderation and the communal spirit of Isla shuns worldly attitude and abhors rejection of the wor and offers a middle path. There is no extremism in Isla and Shah Wali Ullah has preached the same. The juris the Sufis and the Muhaddisseen have taken up a differe line of thinking regarding "Tassawwuf" --- yet th essential spirit of Islam is the path of moderation. T spiritualism and physical world has to be kept in balance— with moderation and balance. It is this aspect of Sha Waliullah's writings that has been highlighted in th article.

Pharmacokinetic Interaction Study of Ranitidine With Antibiotic in Healthy Volunteers of Karachi, Pakistan

With the arrival of new drugs in the market every day, the potential of drug-drug interactions are also increasing. Multiple drug therapies have become common practice these days. There are many reasons for multiple drug therapy. The presence of more than one disease states/ comorbidities requires treatment with multiple drugs of different classes. Similarly for better coverage, more than one drug treatments are usually provided in different clinical conditions. Self medication of over the counter medicines also increases the likelihood of drug-drug interaction. A judicious selection of drugs should be done by clinicians and pharmacists in order to reduce the drug drug interaction potential. A drug interaction can occur when the pharmacokinetics and/or pharmacodynamics of one drug is altered by the other drug. Pharmacokinetic drug interactions occur when one drug affects the absorption, distribution, metabolism and excretion of other drug. Pharmacokinetic interactions are difficult but vital to predict because of toxicity and efficacy. Helicobacter pylori is the most common cause of gastrointestinal infections worldwide and its eradication significantly reduces the rates of the recurrence and complications. Amoxicillin belongs to penicillin group and is commonly used antibiotic for the treatment of gastroduodenal ulcer caused by Helicobacter pylori. Amoxicillin is usually prescribed in combination with ranitidine to treat this infection. Ranitidine is histamine H2 receptor antagonist which inhibits gastric acid production and is the most commonly used drug in the treatment of peptic ulcer and gastroesophageal reflux diseases. In present work different brands of amoxicillin 250mg capsules (AMOX 1-4) and ranitidine 300mg tablets (RAN 1-2) were selected from local market, AMOX 1 and RAN 1 were taken as reference brands, as both are the innovator products of GlaxoSmithKline Pakistan Limited. The selected brands were evaluated for pharmaceutical quality i.e. weight, thickness, hardness variation tests, disintegration test, single point dissolution test, content uniformity and assay. The mean weights of AMOX 1-4 and RAN 1-2 were found in the range of 275.725 ± 7.066mg to 305.81 ± 2.503mg and 490.201 ± 1.637mg to 501.118 ± 4.020mg whereas the mean thickness of RAN 1 and RAN 2 tablets were 4.71 ± 0.031mm and 6.46 ± 0.048mm and hardness were 16.015 ± 0.405 Kg and 12.720 ± 0.305 Kg. The disintegration time observed for RAN 1 and RAN 2 were 6.011 ± 0.170 minutes and 8.205 ± 0.125 minutes respectively. The percentage drug release of amoxicillin xxiii 250mg capsules was determined using USP apparatus I and that of ranitidine 300mg tablets using USP apparatus II and found to be in the range of 86.23 ± 2.153% to 96.88 ± 2.197% at 60 min and 100.881 ± 1.734% and 99.793±2.617% at 45 minutes respectively. For the content uniformity test and assay of amoxicillin capsules and ranitidine tablets a developed and validated HPLC method was used. The mean content uniformity test results of AMOX 1- 4 were 99.69 ± 0.076%, 99.36 ± 0.107%, 97.516 ± 0.104% and 95.626 ± 0.084%, and that of RAN 1 and RAN 2 were 98.222 ± 1.732% and 97.77 ± 1.823% respectively. The mean assay results found were 98.985 ± 0.699%, 98.299 ± 0.976%, 97.207 ± 0.376% and 95.236 ± 1.403% sequentially for AMOX 1-4 and 99.333 ± 0.519% for RAN 1 and 97.386 ± 1.170% for RAN 2. The results revealed that these brands were in acceptable pharmaceutical quality limits. For the simultaneous quantitation of these drugs in pharmaceutical formulations and plasma, an analytical HPLC method was developed and validated. The chromatographic separation of both amoxicillin and ranitidine were carried out on RP-18 column fitted with guard column and 100 µL loop at ambient temperature and detection was carried out at 230 nm. The mobile phase composition that showed the best separation was 0.02M phosphate buffer: acetonitrile (93:7) at pH 3.0 and the flow rate was kept at 1.0 mL/minute. The retention time of amoxicillin and ranitidine were around 8 and 11 minutes respectively, without any interference. According to International Conference on Harmonization guidelines, validation of the method was carried out for selectivity, accuracy, linearity, recovery, LOD, LOQ, precision and stability. The standard calibration curve was constructed for amoxicillin concentrations of 20, 10, 5, 2.5, 1.25, 0.6125, 0.3125, 0.1562, and 0.078µg/mL in mobile phase and for concentrations of 20, 10, 5, 2.5, 1.25, 0.6125, 0.3125, 0.1562, and 0.085µg/mL in plasma. The correlation coefficient was found to be 0.999. The lower limit of quantitation of 0.039 µg/mL and limit of detection of 0.078µg/mL was found in mobile phase whereas lower limit of quantitation and limit of detection were 0.085µg/mL and 0.078µg/mL in plasma. Similarly, standard calibration curve was constructed for ranitidine concentrations of 20, 10, 5, 2.5, 1.25, 0.6125, 0.3125, 0.1562, 0.078 and 0.039µg/mL in mobile phase and 20, 10, 5, 2.5, 1.25, 0.6125, 0.3125, 0.1562, 0.085 and 0.078µg/mL in plasma and the correlation coefficient of ranitidine was found to be 0.999. The limit of quantitation and limit of detection in mobile phase were found to be 0.039µg/mL and 0.0195µg/mL respectively. While in xxiv plasma, the lower limit of quantitation was 0.078µg/mL and limit of detection was 0.039µg/mL. In order to improve therapeutic outcome, in the present work pharmacokinetic interaction between amoxicillin and ranitidine was studied. The pharmacokinetic parameters of amoxicillin and ranitidine were determined and then compared to observe the potential of pharmacokinetic interaction between two drugs. In this regard both the drugs were administered to twelve local healthy male volunteers separately and then together with a gap of one week washout period in between. The study was randomized, crossover, three phasic, single dose study based on FDA guidelines. Blood samples were drawn at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours, plasma was separated and the drug concentrations were determined by the developed and validated HPLC method of analysis. The compartmental and non compartmental pharmacokinetic parameters were calculated by pharmacokinetic software, Kinetica® 4.4.1 and their comparison was made through two way analysis of variance. The current study showed that the mean peak plasma concentration (Cmax) of amoxicillin was reduced significantly from 3.127 ± 0.081 µg/mL to 2.239 ± 0.126 µg/mL when ranitidine was coadministeredand the time to achieve maximum plasma concentration slightly increasedi.e. 1.911 ± 0.019 hr to 2.220 ± 0.038 hr. The mean AUC0-t and AUC0-∞ for amoxicillin were 12.552 ± 0.297 mg/L.hr and 12.783 ± 0.301 mg/L.hr while the same parameters for amoxicillin in the presence of ranitidine were 10.445 ± 0.416 mg/L.hr and 11.128 ± 0.463 mg/L.hr consecutively. It was also observed that the absorption half life (T1/2Ka) and elimination half life (T1/2Kel) of amoxicillin slightly increased in the presence of ranitidine i.e. T1/2Ka was increased from 0.960 ± 0.045 hr to 1.069 ± 0.064 hr and T1/2Kel from 1.10 ± 0.040 hr to 1.358 ± 0.059 hr. The absorption rate constant (Ka) and elimination rate constant (Kel) of amoxicillin also reduced minutely i.e. 0.723 ± 0.037 hr-1 to 0.651 ± 0.036 hr-1 and 0.631 ± 0.023 hr-1 to 0.511 ± 0.022 hr-1 sequentially with administration of ranitidine. Whereas clearance (Cl) and the volume of distribution (Vc) of amoxicillin (alone) were found to be 19.819 ± 0.478 L/hr and 31.468 ± 1.475 L and in the presence of ranitidine, the Cl and Vc of amoxicillin were increased to 23.588 ± 0.848 L/hr and 46.221 ± 2.795 L. Non compartmental analysis was also performed, the area under first moment time curve (AUMC) and the mean residence time (MRT) were calculated and found to be 37.520 ± 0.974 mg/L.(hr)2 and 3.391 ± 0.014 hr for xxv amoxicillin (alone) and 37.131 ± 1.357 mg/L.(hr)2 and 4.284 ± 0.088 hr with ranitidine. Similarly, the pharmacokinetic parameters of ranitidine 300mg tablet were also determined. The mean Cmax value of ranitidine and with coadministered amoxicillin were found to be unchanged i.e. 0.707 ± 0.023 µg/mL and 0.702 ± 0.018 µg/mL and Tmax 3.058 ± 0.061 hr and 3.068 ± 0.049 hr successively. The mean AUC0-t and AUC0-∞ values of ranitidine were 4.082 ± 0.128 mg/L.hr and 5.081 ± 0.243 mg/L.hr respectively that remained almost same in presence of amoxicillin i.e. 4.064 ± 0.106 mg/L.hr and 5.099 ± 0.229 mg/L.hr. The mean absorption rate constant (Ka) of ranitidine alone and in the presence of amoxicillin also remained unchanged i.e. 1.120 ± 0.097 hr-1 and 1.097 ± 0.049 hr-1 and half life (T1/2 Ka) of 0.623 ± 0.058 hr and 0.633 ± 0.029 hr consecutively. Similarly, the mean elimination rate constant (Kel) of 0.216 ± 0.01 hr-1 and elimination half life (T1/2Kel) of 3.21 ± 0.15 hr were observed for ranitidine with or without amoxicillin. The clearance of ranitidine was calculated to be 61.820 ± 2.832 L/hr and in the presence of amoxicillin 62.014 ± 2.418 L/hr. The values of volume of distribution (Vc) of ranitidine with or without amoxicillin were 286.995 ± 7.238 L and 286.117 ± 8.064 L. The mean area under first moment time curve (AUMC) was 26.944 ± 2.125 mg/L.(hr)2 for ranitidine while it was 26.902 ± 1.926 mg/L.(hr)2 in the presence of amoxicillin. Similarly the mean residence time (MRT) of ranitidine found to be 6.765 ± 0.274 hours and 6.857 ± 0.294 hours that is remained almost same with or without amoxicillin. In order to observe statistical equivalence between pharmacokinetic parameters of amoxicillin and ranitidine alone and each other’s presence two way analysis of variance and two one sided t-test was applied. The analysis was carried out using Kinetica® software 4.4.1 both on log transformed and non log transformed pharmacokinetic data as per guidelines of Food and Drug Administration (FDA). Friedman test was performed using SPSS version 20 to determine differences in Tmax values of drugs. The difference between amoxicillin (AMOX) and amoxicillin with ranitidine (AMOX+RAN) were determined and at 90% confidence interval (80-125%) of the log transformed data of calculated Cmax, observed Cmax, Tmax, AUC0-∞ and AUC0-t were 68.772 - 74.369 %, 75.451 - 84.261%, 114.83-117.42%, 82.061- 86.087% and 80.832- 85.579% of amoxicillin with or without ranitidine (p = 0.0008, 0.015, 0.0001, 0.001 and 0.0033). The geometric mean ratio was 0.715, 0.797, 1.161, 0.84 and 0.831 and no significant effect of period, subject and sequence was observed. The two one sided t test also support ANOVA results. The results of non log transformed data for calculated Cmax, observed Cmax, Tmax, AUC0-∞ and AUC0-t were found similar to the results of log transformed data. Other pharmacokinetic parameters of amoxicillin which showed significant difference on log transformed and non log transformed data with or without ranitidine include Kel, MRT, λz, Vc, Vz and T1/2 λz while there was no significant effect of period, sequence or subject nested sequence observed. Similarly, comparison of pharmacokinetic parameters of ranitidine (RAN) and ranitidine with amoxicillin (RAN+AMOX)were observed on log transformed values of calculated Cmax, observed Cmax, Tmax, AUC0-∞ and AUC0-t of ranitidine with or without amoxicillin. The 90% confidence interval (80-125%) of the log transformed data was within limits i.e. 98.438-100.12% (calculated Cmax), 99.217-100.26% (observed Cmax), 99.1-101.58% (Tmax), 97.779-103.03 % (AUC0-∞) and 98.116 101.04% (AUC0-t). The effect due to period, subject and sequence was also found insignificant with p values of greater than 0.05. The two one sided t test also confirm these results. There was no significant effect of subject, period and formulation found in ANOVA on Ka of ranitidine but a significant effect of sequence observed on Ka (p = 0.012) and AUC0-t (p = 0.014) of ranitidine. Similarly there was no significant difference observed on log and non log transformed data of other pharmacokinetic parameters Kel, Vc, Cl, T1/2Kel, AUMC, MRT, λz, Vz and T1/2λz due to subject, period, sequence and formulation. On the basis of this study it can be concluded that the concomitant administration of ranitidine with amoxicillin significantly reduced the peak plasma concentration of amoxicillin and thus affected the bioavailability of amoxicillin while there was no effect of amoxicillin observed on the pharmacokinetic parameters of ranitidine. This study mainly focused on conducting pharmacokinetic interaction studies of amoxicillin and ranitidine in local population. Pharmacokinetic interaction studies must be conducted in order to identify any potential interaction between drugs given concurrently to provide safe and effective treatment to the patients." xml:lang="en_US
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