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1.  Conceptual and applied study of Snigdha and Ruksa Guna with special reference to Rasa-raktagata Sneha (hyperlipidemia) 
Ayu  2011;32(2):200-206.
Ayurveda as well as Philosophy accepted the Guna as the basic entity of the Sristi. The Maha Gunas, i.e., Sattva, Raja, and Tama are the prime energy, from where the universe evolves, along with human beings. Dravya and Guna both have a Samavayi relationship in which Gunas reside in Dravya and have a secondary place to it. Guna has multifold meanings according to its use, in social, cultural, philosophical, and literary fields. The concepts of Ayurveda are expressed with Gunas. Samanya and Visesa are usually expressed in terms of Gunas; the classification, description, and function of Dravyas depends upon Guna; Karmas are manifested forms of Guna and Samavaya is the eternal, intimate relation of Dravya and Guna. The principles like Triskandha (Hetu, linga, ousadhi) of Ayurveda also narrated by Gunas, Hetus are narrated in the terms of Guna; the Laksanas are the reflections in the status of Gunas of bodily elements, and Cikitsa is in the form of administration of Viparita Gunas. The increased elements are treated by opposite Guna. So if Ruksa Guna is increased then it is to be managed by Snigdha Guna and vice-versa. So diseases can be treated by applying the Gunas, and drugs for the required patient can be selected by applying these Gunas. In support of the above concept, a study on the persons of Rasa-raktagata Sneha (hyperlipidemia) has been carried out assuming that the condition is an increased state of Snigdha Guna and treatment is done using Ruksa property drugs. Patients were divided into two groups, i.e., treatment group (Ruksa Guna drugs) and control group (placebo). The results were assessed after 45 days with the help of a specially prepared pro forma. All the important hematological, biochemical, and urine investigations were done. According to subjective and objective criteria, significant results were found for Group A as compared to Group B.
PMCID: PMC3296341  PMID: 22408303
Ayurveda; Guna; hyperlipidemia; Rasa-raktagata Sneha; Ruksa Guna
2.  PA01.34. Catagorical interpretation in Microsoft excel of jangam dravya database from Bruhat-Trayi & Laghu-Trayi 
Ancient Science of Life  2012;32(Suppl 1):S84.
Not a single drug in Ayurveda has been termed as non-medicinal. This means every Dravya has medicinal value in this world. Jangam dravya is an animal sourced medicine. In samhita Jangam Dravya are described first. So as per Krama Varnan Vichar, Jangam Dravyas are significant in this type. In Ayurvedic literature there is more literature on Audbhid & Parthiva Dravyas. I Total available nighantu: more than 25. Total available Rasa Grantha: about 145. There is no one Grantha on Jangam Dravya which describes their whole information. Jangam Dravyas are described in Ayurvedic literature in different views and in different branches. Gross description is available in Samhitas. But they aren’t in format. They are not compiled according to their Guna Karma, Upayogitwa, Vyadhiharatwa, and Kalpa etc. Their use in Chikitsa is minimal as their ready references are not available, though very much effective. So due to sheer need of compilation of these references this topic was selected for study. The basic need for study of Jangam Dravya is to prepare its whole DATABASE. So through this study Database of Jangam Dravya can be available like Jangam Dravya.
Selection of topic this is a fundamental & literary study, Selection of material, Selection of Database software & font, Collection of data & preparation of Master Chart, Preparation of Database, Interpretation & summarization of data.
So in this paper, we are going to focus on literature availability of jangam dravya with the help of modern technique like Microsoft Excel. And also how we can prepare and use the categorical interpretation of jangam dravya with help of database
Jangam Dravyas are described in Ayurvedic literature in different views and in different branches. Importances of these dravyas are the main key point of this study.
PMCID: PMC3800966
3.  PA02.11. An insight on ayurvedic drug discovery 
Ancient Science of Life  2013;32(Suppl 2):S56.
Every dravya have its own medicinal importance in the universe. Hence, we have to study each and every drug which is available around us. The locally available drugs are considered as best. Only few drugs are mentioned in ayurvedic textbooks but many have to be explained for their quality & applications. The research on new drugs is the need of hour in Ayurveda and we have to assess all dravyas viz. herbs, metals, minerals & animal products which are available in universe.
Drug research methodology is well explained in Ayurveda along with ethno & medico botanical survey. There are certain steps of research viz. the nature of dravyas, morphological characters of dravyas, place & time of collection, preservation etc and doctrine of signature or elaborate in new drug discovery. Further taste and taste threshold examination, exothermic and endothermic reactions, experimental model for assessment of vipaka and other methods of research on new drug will be discussed. This paper will discuss in detail about the ancient research method for new drugs.
Methodical research for new drug gives not only importance of pharmecological and clinical study but also importance to seasonal derivation, collection time and different application methods. Ancient ayurvedic drug research methodology includes from survey, pharmacognostic to clinical research.
The oldest drug research methodology suits now also for all new drug research.
PMCID: PMC4147528
4.  OA02.17. Medicinal plant tissue culture and its ayurvedic perspective. 
Ancient Science of Life  2013;32(Suppl 2):S23.
Introduction of Plant tissue culture (PTC) concept to the Ayurveda realm.
1. Analysis of principles the plant tissue culture based on the literature review and real wet lab images of tissue culture 2. Analysis of ayurvedic principles which are relevant in the context 3. Logical concept development.
Plant tissue culture is based on the natural ability of plant cells to grow in to fullfledged organism, called as totipotency. Plant cell can exhibit totipotency only when it is placed in a suitable micro condition where it is supplied with all essential nutrients such as minerals, water, light source, carbon source and air. Two branches of tissue culture a. micropropagation b. in vitro adventitious root development (Sivakumar 2006), are relevant for ayurvedic industry in purview of increasing demand for good quality raw materials and decreasing wild sources of medicinal plants. Ayurvedic concept of Anukta dravya grahana (Reddy 2008; Kusuma and Joshi 2010) describes the need for understanding the properties of an undocumented drug or medicinal plant experimentally before considering it as an ayurvedic drug. Ayurvedic system dravya guna vijnana is for understanding and classification of medicinal plants based on their seven fold properties (Valiathan 2003). The concept of ‘Abhava prathinidhi dravya’ (Padma et al. 2010) explains the situations where original drugs are substituted with substances of similar qualities, which were prescribed in case of several unavailable or rare drugs. The efficacy of medicinal plants or plant part produced through tissue culture has to be determined even though those are botanically and genetically the same. Rasanirdharana method (Dhyani 2008) can be combined efficiently with phytochemical screening for this purpose.
Plant materials produced through PTC can be ideologically acceptable for ayurvedic industry when principles of plant tissue culture is analysed in detail in the light of certain ayurvedic principles.
PMCID: PMC4147492
5.  Clinical evaluation of Apamarga-Ksharataila Uttarabasti in the management of urethral stricture 
Ayu  2013;34(2):180-183.
Stricture urethra, though a rare condition, still is a rational and troublesome problem in the international society. Major complications caused by this disease are obstructed urine flow, urine stasis leading to urinary tract infection, calculi formation, etc. This condition can be correlated with Mutramarga Sankocha in Ayurveda. Modern medical science suggests urethral dilatation, which may cause bleeding, false passage and fistula formation in few cases. Surgical procedures have their own complications and limitations. Uttarabasti, a para-surgical procedure is the most effective available treatment in Ayurveda for the diseases of Mutravaha Strotas. In the present study, total 60 patients of urethral stricture were divided into two groups and treated with Uttarabasti (Group A) and urethral dilatation (Group B). The symptoms like obstructed urine flow, straining, dribbling and prolongation of micturation were assessed before and after treatment. The results of the study were significant on all the parameters.
PMCID: PMC3821247  PMID: 24250127
Mutramarga Sankocha; stricture urethra; urethral dilatation; Uttarabasti
6.  Study of the response of the penile corporal tissue and cavernosus muscles to micturition 
BMC Urology  2008;8:4.
The reaction of the corpora cavernosa (CC), the corpus spongiosum (CS), the bulbocavernosus (BCM) and ischiocavernosus (ICM) muscles to passage of urine through the urethra during micturition is not known. We investigated the hypothesis that the passage of urine through the urethra stimulates the corporal tissue and cavernosus muscles.
In 30 healthy men (mean age 42.8 ± 11.7 years), the electromyographic activity (EMG) of the CC, CS, BCM, and ICM were recorded before and during micturition, and on interruption of and straining during micturition. These tests were repeated after individual anesthetization of urethra, corporal tissue, and cavernosus muscles.
During micturition, the slow wave variables (frequency, amplitude, conduction velocity) of the CC and CS decreased while the motor unit action potentials of the BCM and ICM increased; these EMG changes were mild and returned to the basal values on interruption or termination of micturition. Micturition after individual anesthetization of urethra, corporal tissue and cavernosal muscles did not effect significant EMG changes in these structures, while saline administration produced changes similar to those occurring before saline administration.
The decrease of sinusoidal and increase of cavernosus muscles' EMG activity during micturition apparently denotes sinusoidal relaxation and cavernosus muscles contraction. Sinusoidal muscle relaxation and cavernosus muscles contraction upon micturition are suggested to be mediated through a 'urethro-corporocavernosal reflex'. These sinusoidal and cavernosus muscle changes appear to produce a mild degree of penile tumescence and stretch which might assist in urinary flow during micturition.
PMCID: PMC2270861  PMID: 18312692
7.  PA01.17. A clinical study to evaluate the effect of extract based herbal formulation on hypertension- a single blinded standard controlled randomized study 
Ancient Science of Life  2012;32(Suppl 1):S66-S67.
In Ayurveda although there is no such terminology like hypertension but still this work is an approach to establish relationship between Hypertension & vitiated functioning of three governing forces of our body i.e. Tridosha and to treat Hypertension on Ayurvedic principles. The logic behind such correlation is based on the fact that, like other physiological processes, B.P. too is normal phenomenon of our body which is governed by Tridosha. After going through modern pathogenesis of primary hypertension and its symptomology, in present study it has been correlated with Vata Kaphaja Vikara with Rasavaha, Raktavaha and Manovahi Srotas as the seat of disease. Looking at its pathogenesis, the term Uccha Vyan Bala (exaggerated physiological functioning of Vyan Vayu leading to increase contractility of heart & blood vessels) can be coined for hypertension.
Subjective criteria Headache, Palpitation, Vertigo, Dyspnoea on walks and Fatigue. Objective criteria BP value recorded by sphygmomanometer in supine position. Final assessment of results; Subjective assessment 75 to 100% disappearance of symptoms effectively cured. 50 to 74% disappearance of symptoms well cured. 25 to 49% disappearance of symptoms fairly cured. 0 to 24% disappearance of symptoms poorly cured. Objective assessment Patient showing reduction in BP by 10mmHg Poorly cured; Patient showing reduction in BP between 11 to 20mmHg Fairly cured; Patient showing reduction in BP between 21 to 30 mmHg Well cured; Patient showing reduction in BP by more than 30 mmHg Effectively cured. Research methodology Type of study-Single blinded comparative study. Study site IPD and OPD department of Shubhdeep ayurved medical college, Indore (MP). Sample size 50 patients divided randomly into two equal groups. Group A given trial drug whereas Group B given control drug. Drug dosage and vehicle 1 capsule twice daily with lukewarm water after meals. Duration of treatment one month (examined at weekly intervals.) Dietary advice to strictly restrict the daily intake of Amla, Lavana, Guru & Vidahi diet.
70% Patients found to be hypertensive were above 40 years of age. 60% Patients were fond of salty & spicy diet. Out of 50 patients 30 patients (60%) belongs to service class. Out of 50 patients 35 patients (70%) were male. Regarding prevalence of symptoms, Dyspnoea on routine work was found in 82%, Headache & palpitation in 80%, Vertigo in 78% & Fatigue in 66% patients.
As per classical texts, Vata predominant diseases are caused due to vitiation of Vata due to emaciation (Dhatu Kshaya) & obstruction (Marg avarodha). Hypertension seems to be Vata predominant disease due to obstruction. Reason being that, Lavana is Vata Shamak, & should therefore decrease Blood pressure but on contrary it increases B.P. Similarly increase in weight leads to greater chances of High Blood pressure. Above discussion favours that Hypertension can be considered Vata predominant disease due to Marg avarodha by Kapha Dosha and Pitta Dosha in Anubandh. Finally it can be concluded that the drug under study has shown enthusiastic results in reducing the overall value of blood pressure. 64% patients got effectively cured, 24% got well cured and 12% got fairly cured. Regarding symptomatic relief, out of 25 patients 8 showed more than 75% relief, 9 showed more than 50% relief, 7 showed more than 25% relief and only 1 patient showed less than 25% relief in overall symptoms. No significant side effects have been reported in any subject.
PMCID: PMC3800947
8.  PA02.07. Rational scientific analysis of modern lifestyle as a nidana w.s.r to viruddha ahara 
Ancient Science of Life  2013;32(Suppl 2):S52.
To understand the concept of viruddha ahara as a nidana in causation of diseases and to know its relavance in the present era. In the classics hitabhuk, mitabhuk, kshutabhuk, rhutubhuk are mentioned for maintaing the health of a person. Ahara that which vitiates dosha and which is antagonist to the dhatu in the body is known as viruddha ahara.
Classical literatures like bruhat trayi, laghu trayi, other texts and contemporary books are reviewed. The datas collected are analyzed scientifically with the help of contemporary science.
The eighteen types of viruddha ahara mentioned in the classics like desha, kala, agni, matra, etc. are understood with the help of examples like Agni viruddha In mandagni condition consuming guru snigdha ahara. In condition like dyspepsia where impairement in gastric, bile, pancreatic secretions are present, due to increased intake of mamsala ahara which are rich in amino acids and lipids impaires metabolism. Satmya viruddha Person satmya with katu ushna dravya sevana consuming increased swadu sheeta dravya. Persons habituated with rich spicy diet like pepper which causes irritation of gastric mucosa leading to increased gastric juice secretion, if increased intake of chilled soft drinks in such persons causes constriction of gastric mucosa leading to less gastric juice secretion. Avastha viruddha after nidra consuming kaphavardhka ahara like curd. After sleep basal metabolic rate of the body is reduced, curd which is rich in fats and carbohydrates requires more time for digestion. The rest types of viruddha ahara are analyzed and understood scientifically in the same manner as explained above.
Ayurveda emphazises on nidana parivarjanameva chikitsa, understanding the nidana is prime important. Viruddha ahara affects the body metabolism and hence the concept of viruddha ahara is relevant to present era.
PMCID: PMC4147524
9.  Studies on the Mechanism of Sodium Excretion during Drug-induced Vasodilatation in the Dog 
Journal of Clinical Investigation  1982;69(3):604-610.
The administration of vasodilating agents such as bradykinin and acetylcholine cause an increase in urinary sodium excretion. Yet the mechanisms involved in this natriuretic effect are not clear. Recent studies with another renal vasodilator, secretin have shown this drug also causes a profound increase in renal blood flow but without major changes in sodium excretion. To attempt to delineate the basis of this difference in sodium excretion with these drugs, the renal functional effects of secretin and bradykinin were compared at an equivalent vasodilating dose. Bradykinin increased renal blood flow from 222 to 342 ml/min, urine volume from 0.2 to 1.2 ml/min, and urine sodium excretion from 28 to 115 μeq/min. Urine osmolality fell from 1,230 to 401 mosmol/kg. Secretin caused a comparable increase in renal blood flow (216 to 325 ml/min) while changes in urine flow, sodium excretion, and urine osmolality were significantly less.
In further studies papillary plasma flow was estimated using the albumin accumulation technique. Control papillary plasma flow was 29 ml/min per 100 g. Bradykinin increased urinary sodium excretion 108 μeq/min and decreased urinary osmolality from 1,254 to 516 mosmol/kg in association with a rise in papillary plasma flow to 62 ml/min per 100 g. Urine sodium excretion, urinary osmolality, and urine flow rate, as well as papillary plasma flow rate (32 ml/min per 100 g) were unchanged from control when secretin was administered. Studies with acetylcholine were qualitatively similar to those of bradykinin. Renal blood flow increased from 150 to 248 ml/min, urinary sodium excretion increased from 20 to 243 μeq/min, urinary osmolality decreased from 1,237 to 411 mosmol/kg and papillary plasma flow increased from 39 to 52 ml/min per 100 g. It is suggested that the natriuretic effect of some vasodilators is due, at least in part, to alterations in medullary hemodynamics, as evidenced by the increase in papillary plasma flow seen with bradykinin and acetylcholine, but not secretin.
PMCID: PMC371017  PMID: 7061705
10.  Optimum Methadone Compliance Testing 
Executive Summary
The objective of this analysis was to determine the diagnostic utility of oral fluid testing collected with the Intercept oral fluid collection device.
Clinical Need: Target Population and Condition
Opioids (opiates or narcotics) are a class of drugs derived from the opium poppy plant that typically relieve pain and produce a euphoric feeling. Methadone is a long-acting synthetic opioid used to treat opioid dependence and chronic pain. It prevents symptoms of opioid withdrawal, reduces opioid cravings and blocks the euphoric effects of short-acting opioids such as heroin and morphine. Opioid dependence is associated with harms including an increased risk of exposure to Human Immunodeficiency Virus and Hepatitis C as well as other health, social and psychological crises. The goal of methadone treatment is harm reduction. Treatment with methadone for opioid dependence is often a long-term therapy. The Ontario College of Physicians and Surgeons estimates that there are currently 250 physicians qualified to prescribe methadone, and 15,500 people in methadone maintenance programs across Ontario.
Drug testing is a clinical tool whose purpose is to provide objective meaningful information, which will reinforce positive behavioral changes in patients and guide further treatment needs. Such information includes knowledge of whether the patient is taking their methadone as prescribed and reducing or abstaining from using opioid and other drugs of abuse use. The results of drug testing can be used with behavior modification techniques (contingency management techniques) where positive reinforcements such as increased methadone take-home privileges, sustained employment or parole are granted for drug screens negative for opioid use, and negative reinforcement including loss of these privileges for drug screens positive for opioid used.
Body fluids including blood, oral fluid, often referred to as saliva, and urine may contain metabolites and the parent drug of both methadone and drugs of abuse and provide a means for drug testing. Compared with blood which has a widow of detection of several hours, urine has a wider window of detection, approximately 1 to 3 days, and is therefore considered more useful than blood for drug testing. Because of this, and the fact that obtaining a urine specimen is relatively easy, urine drug screening is considered the criterion measure (gold standard) for methadone maintenance monitoring. However, 2 main concerns exist with urine specimens: the possibility of sample tampering by the patient and the necessity for observed urine collection. Urine specimens may be tampered with in 3 ways: dilution, adulteration (contamination) with chemicals, and substitution (patient submits another persons urine specimen). To circumvent sample tampering the supervised collection of urine specimens is a common and recommended practice. However, it has been suggested that this practice may have negative effects including humiliation experienced by patient and staff, and may discourage patients from staying in treatment. Supervised urine specimen collection may also present an operational problem as staff must be available to provide same-sex supervision. Oral fluid testing has been proposed as a replacement for urine because it can be collected easily under direct supervision without infringement of privacy and reduces the likelihood of sample tampering. Generally, the results of oral fluid drug testing are similar to urine drug testing but there are some differences, such as lower concentrations of substances in oral fluid than urine, and some drugs remain detectable for longer periods of time in urine than oral fluid.
The Technology Being Reviewed
The Intercept Oral Specimen Collection Device (Ora-Sure Technologies, Bethlehem, PA) consists of an absorbent pad mounted on a plastic stick. The pad is coated with common salts. The absorbent pad is inserted into the mouth and placed between the cheek and gums for 3 minutes on average. The pad absorbs the oral fluid. After 3 minutes (range 2min-5 min) the collection device is removed from the mouth and the absorbent pad is placed in a small vial which contains 0.8mL of pH-balanced preservative, for transportation to a laboratory for analysis. It is recommended that the person undergoing oral fluid drug testing have nothing to eat or drink for a 10- minute period before the oral fluid specimen is collected. This will remove opportunity for adulteration. Likewise, it is recommended that the person be observed for the duration of the collection period to prevent adulteration of the specimen. An average of 0.4 mL of saliva can be collected. The specimen may be stored at 4C to 37C and tested within 21 days of collection (or within 6 weeks if frozen).
The oral fluid specimen must be analyzed in a laboratory setting. There is no point-of-care (POC) oral fluid test kit for drugs of abuse (other than for alcohol). In the laboratory the oral fluid is extracted from the vial after centrifugation and a screening test is completed to eliminate negative specimens. Similar to urinalysis, oral fluid specimens are analyzed first by enzyme immunoassay with positive specimens sent for confirmatory testing. Comparable cut-off values to urinalysis by enzyme immunoassay have been developed for oral fluids
Review Strategy
Research Question
What is the diagnostic utility of the Intercept oral specimen device?
Inclusion criteria:
Studies evaluating paired urine and oral fluid specimens from the same individual with the Intercept oral fluid collection device.
The population studied includes drug users.
Exclusion criteria:
Studies testing for marijuana (THC) only.
Sensitivity and Specificity of oral fluid testing compared to urinalysis for methadone (methadone metabolite), opiates, cocaine, benzodiazepines, and alcohol.
Quality of the Body of Evidence
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A description of the GRADE system is reported in Appendix 1.
Summary of Findings
A total of 854 potential citations were retrieved. After reviewing titles and abstracts, 2 met the inclusion and exclusion criteria. Two other relevant studies were found after corresponding with the author of the 2 studies retrieved from the literature search. Therefore a total of 4 published studies are included in this analysis. All 4 studies carried out by the same investigator meet the definition of Medical Advisory Secretariat level III (not a-randomized controlled trial with contemporaneous controls) study design. In each of the studies, paired urine and oral fluid specimens where obtained from drug users. Urine collection was not observed in the studies however, laboratory tests for pH and creatinine were used to determine the reliability of the specimen. Urine specimens thought to be diluted and unreliable were removed from the evaluation. Urinalysis was used as the criterion measurement for which to determine the sensitivity and specificity of oral fluid testing by the Intercept oral fluid device for opiates, benzodiazepines, cocaine and marijuana. Alcohol was not tested in any of the 4 studies. From these 4 studies, the following conclusions were drawn:
The evidence indicates that oral fluid testing with the Intercept oral fluid device has better specificity than sensitivity for opiates, benzodiazepines, cocaine and marijuana.
The sensitivity of oral fluids testing with the Intercept oral fluid device seems to be from best to worst: cocaine > benzodiazepines >opiates> marijuana.
The sensitivity and specificity for opiates of the Intercept oral fluid device ranges from 75 to 90% and 97- 100% respectively.
The consequences of opiate false-negatives by oral fluid testing with the Intercept oral fluid device need to be weighed against the disadvantages of urine testing, including invasion of privacy issues and adulteration and substitution of the urine specimen.
The window of detection is narrower for oral fluid drug testing than urinalysis and because of this oral fluid testing may best be applied in situations where there is suspected frequent drug use. When drug use is thought to be less frequent or remote, urinalysis may offer a wider (24-48 hours more than oral fluids) window of detection.
The narrow window of detection for oral fluid testing may mean more frequent testing is needed compared to urinalysis. This may increase the expense for drug testing in general.
POC oral fluid testing is not yet available and may limit the practical utility of this drug testing methodology. POC urinalysis by immunoassay is available.
The possible applications of oral fluid testing may include:
Because of its narrow window of detection compared to urinalysis oral fluid testing may best be used during periods of suspected frequent or recent drug use (within 24 hours of drug testing). This is not to say that oral fluid testing is superior to urinalysis during these time periods.
In situations where an observed urine specimen is difficult to obtain. This may include persons with “shy bladder syndrome” or with other urinary conditions limiting their ability to provide an observed urine specimen.
When the health of the patient would make urine testing unreliable (e,g., renal disease)
As an alternative drug testing method when urine specimen tampering practices are suspected to be affecting the reliability of the urinalysis test.
Possible limiting Factors to Diffusion of Oral Fluid Technology
No oral fluid POC test equivalent to onsite urine dips or POC analyzer reducing immediacy of results for patient care.
Currently, physicians get reimbursed directly for POC urinalysis. Oral fluid must be analyzed in a lab setting removing physician reimbursement, which is a source of program funding for many methadone clinics.
Small amount of oral fluid specimen obtained; repeat testing on same sample will be difficult.
Reliability of positive oral fluid methadone (parent drug) results may decrease because of possible contamination of oral cavity after ingestion of dose. Therefore high methadone levels may not be indicative of compliance with treatment. Oral fluid does not as yet test for methadone metabolite.
There currently is no licensed provincial laboratory that analyses oral fluid specimens.
2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine
enzyme immunoassay
Enzyme Linked Immunosorbent Assay (ELISA),
Enzyme Multiplied Immunoassay Test (EMIT)
Gas chromatography
gas chromatography/mass spectrometry
High-performance liquid chromatography
Limit of Detection
Mass spectrometry
Methadone Maintenance Treatment
Oral fluid testing
Point of Care Testing
11-nor-delta-9-tetrhydrocannabinol-9-carboxylic acid
urine drug testing
PMCID: PMC3379523  PMID: 23074492
11.  Do Rotational Shifts Affect Micturition Patterns in Real Practice? A Pilot Study in Healthy, Young Female Nurses 
Healthy, young individuals are known to exhibit circadian variation in urinary functions. However, the effects of chronic circadian disturbance on voiding functions are largely unknown. The present work compared the effects of rotational shifts on the micturition patterns of female nurses to that in female nurses with routine daytime shifts.
A total of 19 nurses without lower urinary tract symptoms who worked rotational shifts for an average duration of 2 years were recruited. A voiding diary was kept for 9 consecutive days, and the overactive bladder symptom score (OABSS) questionnaire was completed three times, starting 3 days before their night duties until 3 days after completion of their night duties. For comparison, seven nurses with regular shifts completed a 3-day voiding diary and the OABSS questionnaire.
Female nurses working rotational shifts had lower overall urine production and had decreased urination frequency and nocturia than female nurses working regular shifts, even when the nurses who worked rotational shifts had a regular night's sleep for at least 7 days. Upon reinitiation of night duty, overall urine production increased significantly, with no significant changes in urgency and frequency. When these nurses returned to daytime duty, the volume of urine decreased but nocturnal urine production remained high, and the incidence of nocturia also increased significantly. However, the effects on OABSS score were not significant under the study design used.
Long-term rotational shifts resulted in adaptive changes such as decreased urine production and frequency in healthy, young female nurses. In addition, their micturition patterns were significantly affected by abrupt changes in their work schedules. Although working in shifts did not increase urgency or frequency of urination in healthy, young female nurses working rotational shifts for an average 2 years, large-scale studies are needed to systematically analyze the influence of shift work timings on micturition in humans.
PMCID: PMC4280440  PMID: 25558418
Circadian Rhythm; Work; Rotation; Urination
12.  Prevalence of post-micturition symptoms in association with lower urinary tract symptoms and health-related quality of life in men and women 
BJU international  2011;108(9):1452-1458.
To estimate the prevalence of post-micturition symptoms (a feeling of incomplete emptying following urination and post-micturition dribble) in a population-based sample of men and women, and to examine overlap with storage and voiding LUTS and associations with health-related quality of life (HRQL).
Patients and methods
Data were obtained by in-person interview in the Boston Area Community Health survey, a population-based random sample of 2301 men and 3202 women aged 30–79 years in the USA.
Lower urinary tract symptoms (LUTS) were defined using the International Prostate Symptom Score and standardized terminology.
Multivariate linear regression was used to evaluate associations between urological symptoms and validated HRQL measures (SF-12 and activities interference) cross-sectionally.
The overall prevalence of post-micturition symptoms was 11.8% in men and 8.5% in women.
The prevalence increased with age in men but not women.
In men, post-void dribbling contributed to much of the post-micturition symptoms, whereas, in women, incomplete emptying was more common.
For both genders, over 50% with voiding symptoms also had post-micturition symptoms, compared to less than 50% of respondents who reported storage symptoms.
The presence of post-micturition symptoms, particularly incomplete emptying, was indicative of mildly impaired physical HRQL and activities interference in men and women, and mental HRQL in men (P < 0.01).
Post-micturition symptoms were more prevalent than any individual voiding symptom and commonly overlapped with other LUTS.
Over half of men and women with a voiding symptom also had a post-micturition symptom.
The presence of post-micturition symptoms was indicative of impaired HRQL.
PMCID: PMC3135743  PMID: 21223471
urological diseases; urination disorders; urinary incontinence; urinary retention; prevalence; post-micturition symptoms; health-related quality of life
13.  Neurotrophins in the Lower Urinary Tract: Becoming of Age 
Current Neuropharmacology  2011;9(4):553-558.
The lower urinary tract (LUT) comprises a storage unit, the urinary bladder, and an outlet, the urethra. The coordination between the two structures is tightly controlled by the nervous system and, therefore, LUT function is highly susceptible to injuries to the neuronal pathways involved in micturition control. These injuries may include lesions to the spinal cord or to nerve fibres and result in micturition dysfunction. A common trait of micturition pathologies, irrespective of its origin, is an upregulation in synthesis and secretion of neurotrophins, most notably Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF). These neurotrophins are produced by neuronal and non-neuronal cells and exert their effects upon binding to their high-affinity receptors abundantly expressed in the neuronal circuits regulating LUT function. In addition, NGF and BDNF are present in detectable amounts in the urine of patients suffering from various LUT pathologies, suggesting that analysis of urinary NGF and BDNF may serve as likely biomarkers to be studied in tandem with other factors when diagnosing patients. Studies with experimental models of bladder dysfunction using antagonists of NGF and BDNF receptors as well as scavenging agents suggest that those NTs may be key elements in the pathophysiology of bladder dysfunctions. In addition, available data indicates that NGF and BDNF might constitute future targets for designing new drugs for better treatment of bladder dysfunction.
PMCID: PMC3263451  PMID: 22654715
NGF; BDNF; Trk receptors; bladder; LUT.
14.  Critical appraisal of Doshavaha Srotas 
Ayu  2012;33(3):337-342.
Tridoshas viz Vata, Pitta, and Kapha are responsible for health and disease depending on their normalcy and disequilibrium state. Improper usage of foods and drinks along with abnormal activities manifests diseases of respective Doshik predominance. Sira (vein) is the synonym of Srotas, keeping this in mind, Vatavaha Sira is correlated with Vatavaha Srotas, Pittavaha Sira with Pittavaha Srotas, Kaphavaha Sira with Kaphavaha Srotas, and Sarvavaha Sira with Sarvavaha Srotas. The purpose of detail understanding of Doshavaha Srotas is essential to understand the role of Doshas in the manifestation of diseases. One can easily predict by observing the color changes in particular area to be able to predict the predominance of Doshas in that area. Manifestation of a disease occurs in the body as a result of the defective Srotas favoring the Dosha–Dushya conglomeration. Hence, any defect in the Srotas must be corrected quickly for the restoration of normal health. Present article emphasis on the proper understanding of Doshavaha Srotas in a systematic manner to understand its root, causative factors, signs and symptoms, and diseases produced due to their vitiation.
PMCID: PMC3665105  PMID: 23723638
Kapha; nanatmaja vikara; pitta; Sarvavaha Srotas; sira; vata
15.  Acute Dose-Related Differential Effects of Methylphenidate on Murine Cystometric Parameters 
Methylphenidate is the most widely used central nervous system stimulant in patients with attention deficit hyperactivity disorder. However, few studies have assessed its effects on voiding. Various doses of methylphenidate were investigated for their effects on cystometric parameters in conscious mice.
Ten male C57BL/6 mice, weighing between 20 and 23 g, were used in this study. To compare the acute drug responses before and after the oral medication was administered in the awake condition, we injected the solution through a catheter inserted into the stomach. Methylphenidate (1.25, 2.5, and 5 mg/kg) in an injection volume of 0.05 mL was administered.
Four mice that received high doses of methylphenidate (2.5 and 5 mg/kg) showed no voiding contraction, with urine leakage. Six mice that received a low dose of methylphenidate (1.25 mg/kg) showed typical micturition cycles before and after administration. The micturition pressure decreased and bladder capacity increased without an increased residual volume after administration.
Methylphenidate has differential, dose-dependent effects on the function of the lower urinary tract, due to the dependent relationship between the brain and lower urinary tract. Especially at higher doses, this drug may interfere with normal micturition. Therefore, more detailed clinical or experimental studies are warranted in the future.
PMCID: PMC3895507  PMID: 24466462
Methylphenidate; Attention deficit disorder with hyperactivity; Urodynamics; Mice; Neurogenic urinary bladder
16.  Micturitional disturbance in herpetic brainstem encephalitis; contribution of the pontine micturition centre 
Micturitional disturbance is rarely mentioned in human herpetic brainstem encephalitis although the pontine tegmentum, called the pontine micturition centre, seems to regulate the lower urinary tract in experimental animals. The case of a 45 year old man, who developed subacute coma and hiccup-like dysrhythmic breathing, and needed assisted ventilation is reported. Examination of CSF showed mononuclear pleocytosis and antibody against herpes simplex virus type 1, but the opening pressure was 90 cm H2O. Brain CT showed brain swelling, predominantly in the posterior fossa, and bilateral subdural effusion. Herpetic brainstem encephalitis was diagnosed, and he received 900 mg/day vidarabine. On regaining consciousness, he had left trochlear nerve palsy, left corectopia, ageusia, and urinary retention. Brain MRI showed right side dominant, bilateral pontine segmental lesions extending slightly to the midbrain and medulla. After two weeks he was able to urinate but showed nocturnal urinary frequency, urinary incontinence, and voiding difficulty. Urodynamic studies showed a residual urine volume of 350 ml and detrusor hyporeflexia on voiding. Micturitional disturbance gradually disappeared together with the neurological signs. The bilateral pontine tegmental lesions in this patient are similar to those in previous findings on brainstem strokes, evidence of the presence of a pontine micturition centre in humans.

PMCID: PMC2169952  PMID: 9489547
17.  Rasa Nirdhāraṇa (assessment of taste) of Leonotis nepetifolia (L.) R. Br.: A preliminary study in healthy volunteers 
Ancient Science of Life  2014;33(3):186-191.
Rasa (a concept corresponding to taste) is the only perceivable parameter for drug identification in Ayurveda. The Ayurvedic pharmacological principles such as guṇa (quality), vīrya (potency) and vipāka (effect of biotransformation) are inferred based on the identified Rasa of a drug. All these principles together predict the probable spectrum of drug action in Ayurveda. It is mandatory to screen a drug in the Ayurvedic pharmacological perspective to incorporate it into Ayurvedic materia medica.
To assess the rasa of a non classical herb, Leonotis nepetifolia (L.).R.Br. based on the lakṣaṇas (characteristics) described in Ayurvedic texts for the identification of individual rasa.
Settings and Design:
The study was conducted at the Department of Dravyaguna, Institute for Post Graduate Teaching and Reaseach in Ayurveda, Gujarat Ayurved University, Jamnagar.
Materials and Methods:
The whole plant powder (3g) of Leonotisnepetifolia was administered to 50 participants (trained Ayurvedic physicians) and their responses after intake of the drug were elicited using a structured questionnaire.
Results and Conclusion:
On analyzing the data it was found that Leonotis nepetifolia possess predominantly tikta rasa (bitter taste) followed by Kaṣāya rasa (astringent taste). Recent researches and ethnomedicinal claims on Leonotis nepetifolia stand comparable with the pharmacological activities attributed to tikta and Kaṣāya rasa in Ayurvedic classics. Rasa nirdhāraṇa can be one of the preliminary steps to initiate the process of screening of an unknown drug along the lines of Ayurvedic pharmacology specially because rasa is the only perceivable parameter. According to Ayurveda, rasa of a dravya has a bearing on its karma (pharmacological action) and the identification of rasa could be one of the subjective means for inferring pāñcabhautika constitution of a substance which in turn could help in tentatively inferring guṇa, vīrya and vipāka of the dravya. This paper demonstrates how a simple method can be used without any instruments to do a preliminary assessment of the rasa or taste of a plant.
PMCID: PMC4264309  PMID: 25538356
Ayurveda; Assessment of Taste; ethnomedicinal; Leonotisnepetifolia (L.) R.Br; Rasa nirdharana; structured questionnaire; Tikta rasa
18.  Coronary artery bypass graft surgery in a patient with ureterosigmoidostomy 
A 75-year-old male patient had stable angina pectoris. After coronary angiography we decided to perform a coronary artery bypass graft surgery. Twenty years ago the patient underwent radical cystectomy and bilateral ureterosigmoidostomy because of bladder cancer. After that, his micturition was via the rectum. We did not experience that before. As is known, monitoring of urine output is very important after cardiac surgery. The patient was consulted with an urologist for how to monitor urine output in him. Transrectal catheterization was recommended for our follow-up, but before the catheterization bowel cleansing is necessary. Four-vessel on-pump coronary artery bypass graft surgery was performed without any problem. Peroperative urine volume and arterial blood gas results were normal. Urine output is a sensitive variable reflecting the patient’s effective blood volume and tissue perfusion. Urinary catheterization is a standard for all cardiac surgeries, and it allows the patients’ urine to drain freely from the bladder for collection. Monitoring of urine output in patients with ureterosigmoidostomy is impossible by standard urinary catheterization method. In this case we performed transrectal catheterization for Urine flow follow-up. Urine flow follow-up is essential after the open-heart surgery and it can be measured in different ways, as in our case.
PMCID: PMC4163771  PMID: 25232552
Open heart surgery; Urine output follow-up; Catheterization; Ureterosigmoidostomy; Coronary artery bypass graft
19.  Bladder Dysfunction in Mice with Experimental Autoimmune Encephalomyelitis 
Journal of neuroimmunology  2008;203(1):58-63.
The vast majority of patients with multiple sclerosis (MS) develop bladder control problems including urgency to urinate, urinary incontinence, frequency of urination, and retention of urine. Over 60% of MS patients show detrusor-sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. In the current study we examined bladder function in female SWXJ mice with different defined levels of neurological impairment following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of central nervous system inflammation widely used in MS research. We found that EAE mice develop profound bladder dysfunction characterized by significantly increased micturition frequencies and significantly decreased urine output per micturition. Moreover, we found that the severity of bladder abnormalities in EAE mice was directly related to the severity of clinical EAE and neurologic disability. Our study is the first to show and characterize micturition abnormalities in EAE mice thereby providing a most useful model system for understanding and treating neurogenic bladder.
PMCID: PMC2760767  PMID: 18703233
EAE/MS; autoimmune; micturition; neurogenic bladder
20.  Diurnal Variation in Urodynamics of Rat 
PLoS ONE  2010;5(8):e12298.
In humans, the storage and voiding functions of the urinary bladder have a characteristic diurnal variation, with increased voiding during the day and urine storage during the night. However, in animal models, the daily functional differences in urodynamics have not been well-studied. The goal of this study was to identify key urodynamic parameters that vary between day and night. Rats were chronically instrumented with an intravesical catheter, and bladder pressure, voided volumes, and micturition frequency were measured by continuous filling cystometry during the light (inactive) or dark (active) phases of the circadian cycle. Cage activity was recorded by video during the experiment. We hypothesized that nocturnal rats entrained to a standard 12:12 light:dark cycle would show greater ambulatory activity and more frequent, smaller volume micturitions in the dark compared to the light. Rats studied during the light phase had a bladder capacity of 1.44±0.21 mL and voided every 8.2±1.2 min. Ambulatory activity was lower in the light phase, and rats slept during the recording period, awakening only to urinate. In contrast, rats studied during the dark were more active, had a lower bladder capacities (0.65±0.18 mL), and urinated more often (every 3.7±0.9 min). Average bladder pressures were not significantly different between the light and dark (13.40±2.49 and 12.19±2.85 mmHg, respectively). These results identify a day-night difference in bladder capacity and micturition frequency in chronically-instrumented nocturnal rodents that is phase-locked to the normal circadian locomotor activity rhythm of the animal. Furthermore, since it has generally been assumed that the daily hormonal regulation of renal function is a major driver of the circadian rhythm in urination, and few studies have addressed the involvement of the lower urinary tract, these results establish the bladder itself as a target for circadian regulation.
PMCID: PMC2924395  PMID: 20808873
21.  New insights into molecular targets for urinary incontinence 
Indian Journal of Pharmacology  2010;42(5):261-266.
Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI.
PMCID: PMC2959205  PMID: 21206614
Detrusor muscle; incontinence; molecular targets; overactive bladder
22.  Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection 
PLoS Medicine  2007;4(12):e329.
Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI.
Methods and Findings
We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria.
The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.
Analyzing urine specimens from women with bladder infections, Scott Hultgren and colleagues find evidence for intracellular bacterial communities, which have been associated with recurrent urinary tract infections in mice.
Editors' Summary
Every year, nearly 10 million people in the United States—mainly women—consult their doctors because of a urinary tract infection (UTI). UTIs occur when bacteria living in the gut—usually Escherichia coli—get transferred to the opening of the urethra (the tube through which urine leaves the body), as may occur during sexual intercourse. From here, the bacteria can move into the bladder (the muscular sac that stores urine until it is excreted) where they can multiply and cause cystitis (inflammation of the bladder). If cystitis is untreated, the bacteria can move further up the urinary tract and infect the kidneys (which make urine). Symptoms of UTIs include pain when urinating, frequent and intense urges to urinate, and cloudy urine. UTIs are diagnosed by looking for bacteria and white blood cells (that fight infection) in the urine; the usual treatment is a short course of antibiotics.
Why Was This Study Done?
Half the women who get a UTI will have another attack within a year, often caused by the same bacterial strain. It is generally thought that these strains persist in the gut and reinfect the urinary tract, but recent animal studies suggest an additional explanation. In mice, E. coli strains that cause UTIs can invade the cells lining the bladder. Here, they replicate and form so-called intracellular bacterial communities (IBCs). Many of the infected cells fall off the bladder's surface into the urine, but IBCs also release bacteria, many of which have a long, slender filamentous appearance (E. coli usually have a simple rod-like shape). Immune system cells normally kill bacteria in the urine but cannot deal with filamentous bacteria. In mice, these bacteria can then reinfect the lining of the bladder and establish long-lasting intracellular reservoirs of bacteria that are protected from antibiotics and probably from the host immune system. If this IBC cycle occurs in people, it might explain why some UTIs recur and might suggest ways to manage these recurrences. In this study, therefore, the researchers have investigated whether there is an IBC cycle in women.
What Did the Researchers Do and Find?
The researchers collected urine from 80 young women with cystitis and from 20 women with no symptoms who had had cystitis previously. They identified the type of bacteria in each sample and looked for IBCs and filamentous bacteria using light microscopy, electron microscopy, and a technique called immunofluorescence. None of the women without cystitis had IBCs or filamentous bacteria in their urine, but IBCs were found in nearly 1 in 5, and filamentous bacteria were in nearly half, of urine samples from the women with cystitis. All the urine samples that contained IBCs also contained filamentous bacteria. All of the women with IBCs and most of them with filamentous bacteria had E coli infections. Finally, the women with IBCs and filamentous bacteria in their urine had higher bacterial counts in their urine and had symptoms of cystitis for slightly longer than those without.
What Do These Findings Mean?
These findings suggest that the IBC cycle identified in mice occurs in at least some women with UTIs and may be associated with infections caused by E. coli. Because only one urine sample was collected from each woman, the cycle may be more common than these findings suggest. That is, in some cases the sample may have been taken at a time when there were no IBCs or filamentous bacteria in the urine. Also, because samples were taken at only one point in time, this study does not show whether intracellular bacteria persist and contribute to recurrent UTIs in women, as they appear to do in mice. To provide more information about the IBC cycle in people and its clinical relevance, additional studies are needed to examine whether there are any associations between the presence of IBCs and filamentous bacteria and treatment responses and recurrence, and to examine what is actually happening in the bladder during UTI. Until such studies are done, the clinical implications of the current findings remain uncertain. However, one possibility is that the presence of IBCs and filamentous bacteria in urine might identify people who would benefit from longer treatment with antibiotics or treatment with antibiotics that kill bacteria inside human cells.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia contains pages on urinary tract infection, on cystitis, and on recurrent cystitis (in English and Spanish)
Information is available from the UK National Health Service Direct health encyclopedia on urinary tract infections and on cystitis
The US National Kidney and Urologic Diseases Information Clearinghouse provides information on urinary tract infections (in English and Spanish)
Information is available from the American Urological Association on urinary tract infections in adults
PMCID: PMC2140087  PMID: 18092884
The results of thirteen control experiments, designed to show the number of glomeruli in the rabbit's kidney open to the circulation under the chosen experimental conditions without intentional interference, indicate the "normal" range to be from 42 to 100 per cent. Since ten of the thirteen results fall within the figures 56 and 89 per cent, we may take these figures as the chief basis for our discussion. Three experiments only were made in which renal vasodilatation was produced by caffeine and salt. The percentage of open glomeruli found was in every case higher than any control except one. The results show without ambiguity that in rabbits, as in frogs, renal vasodilatation by caffeine is accompanied by increase in number of patent glomeruli. Our prime interest lay in the general question rather than in the action of individual substances in the group of vasodilators; hence this series was not extended further. Among the experiments designed to test the effects of renal vasoconstriction are to be found nine in which adrenalin was injected, two in which CO2 was inhaled, two in which the splanchnic nerve was stimulated, and four in which hemorrhage was induced. Not all are of equal value for our present purpose, inasmuch as the degree of certainty with which we can assume that renal vasoconstriction was actually produced is not the same in all. Enough experience with the action of adrenalin on the kidney of the anesthetized rabbit is available to permit the assertion that the dosages used in the nine adrenalin experiments were sufficient to insure constriction of renal vessels. Similar certainty exists in the experiment in which high concentration of CO2 was used; less in the case of 10 per cent CO2. Stimulation of the splanchnic nerve in rabbits so frequently fails to produce results typical of direct constriction of renal vessels that we may regard the production of this effect in the two experiments in which this was done as doubtful. In the perfusion experiments by Richards and Plant (7) the reactions of the renal vessels to stimulation of the splanchnic nerve resembled those to intravenously injected adrenalin rather than to the direct excitation of constrictor fibers. In six rabbits in which Livingston subjected the nerve to varying degrees of electrical stimulation, in one only was distinct constriction of the renal vessels produced, and in this a latent period of 45 seconds occurred between the beginning of stimulation and the production of effect. In one of our experiments a rabbit was used in which the superior cervical sympathetic ganglion on the left side had been extirpated months before. During the stimulation of the splanchnic nerve the left pupil was observed to dilate, showing increased adrenalin secretion. Hence, we are inclined to regard the two attempts to produce vasoconstriction by this means as having been largely unsuccessful. In one experiment only of the four in which hemorrhage was induced was there unmistakable evidence of compensatory vasoconstriction which may have involved the renal vessels. The blood pressure curve of this animal showed rhythmically occurring waves of the Traube-Hering type and dyspnea was noted. In this the estimate of open glomeruli was 28 per cent. In the other three experiments no such change occurred and no dyspnea was seen. In pithed frogs, hemorrhage alone of moderate extent is less apt to lessen the number of patent glomeruli than are any of the other constrictor agencies tried by Richards and Schmidt. In this discussion, therefore, we lay little weight on the results obtained in the two experiments in which the splanchnic nerve was stimulated and on those of the first three hemorrhage experiments. The chief conclusion to be drawn from these experiments is that which was anticipated from the observations of Richards and Schmidt on frogs, and of Khanolkar on rabbits; viz., that in the rabbit, renal vasodilatation and renal vasoconstriction are usually associated with increase and decrease respectively in number of glomeruli through which blood flows (see Text-fig. 1). Analogous changes apparently occur in the capillary pathway in individual glomeruli. Hence renal function in mammals may be altered by changes in the extent of glomerular filtration surface to which the blood has access. Other conditions remaining the same, it is obvious that changes in extent of filtration surface must result in proportionate changes in urinary output. The figures for rate of urine elimination at the time of injection of the dye in these experiments are in substantial agreement with these statements (see Text-fig. 2). Exceptions to our chief conclusion as stated have been encountered. In Experiment 57,86 per cent of the glomeruli were open in a constricted kidney which was excreting no urine: in Experiment 30, 16 per cent were open in the kidney which was eliminating seven drops per minute: the outputs of the kidneys in the caffeine experiments were far higher than those of control kidneys in which comparable numbers of glomeruli were open. In considering these exceptions, account must be taken of the fact that other conditions do not commonly remain constant. When a renal vasodilator is introduced we conceive not only of possible increase in extent of accessible glomerular surface, but also of increase in glomerular pressure and increased rate of renewal of fluid in contact with glomerular membranes. Hence the response is greater than can be accounted for by any one factor alone. A basis of experiment exists in support of the belief that usually sufficient differences in physiological state exist among the small arteries and arterioles of the kidney so that a constrictor influence, exerted equally upon all, elicits various degrees of response (1). Closure of some, continuing patency of others, results. Blood flow and blood pressure in the glomeruli which are supplied by the vessels which remain open may be decreased, increased, or unchanged according See PDF for Structure. to the relation between the degree of reaction in those vessels and the height of arterial blood pressure. It is not to be expected that urinary outputs will uniformly vary with the number of glomeruli remaining open. Rapid blood flow and high glomerular pressure in relatively few glomeruli may result in more urine than slow flow and low pressure in many. This argument is implicit in Hermann's original statement and is completely in harmony with the result of direct observation in the frog. It is supported by the data of Experiment 30. In Experiment 57, however, urine was suppressed by adrenalin when 86 per cent of the glomeruli remained open. The kidney in this experiment was highly diuretic before the adrenalin injection. We may, therefore, assume that all or nearly all of the glomeruli were open and that intermittent contractions of the arterioles were minimal; hence, that the physiological state of the vessels concerned was more nearly uniform than is conceived to be the case when only a fraction of the glomeruli are open and in which intermittent contractions and relaxations must be pronounced. Thus a relatively uniform constriction was produced in all of such degree as to lessen materially glomerular pressure and blood flow, but insufficient to actually close more than a few afferent arterioles. In Experiment 33, the dosage of adrenalin was such as to permit the possibility that constrictor action may have been largely confined to efferent vessels (8). While the exceptional results have been discussed at greater length than has been devoted to the majority of experiments, we believe that they do not constitute adequate ground for criticism of the chief conclusion as stated.
PMCID: PMC2131062  PMID: 19869079
24.  Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Rising Doses of Empagliflozin in Patients with Type 2 Diabetes Mellitus 
Diabetes Therapy  2013;4(2):331-345.
This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of empagliflozin, a potent and highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).
A total of 48 patients with T2DM were randomized to receive one of four doses of empagliflozin (2.5, 10, 25, or 100 mg qd) or placebo over 8 days. In every dose group, nine patients received active drug and three received placebo. The primary endpoint was safety and tolerability. Pharmacokinetic and pharmacodynamic parameters were measured as secondary endpoints.
Empagliflozin was rapidly absorbed, reaching peak levels 1.5–3.0 h after dosing and showed a biphasic decline. The mean terminal elimination half-life ranged from 10 to 19 h. Increases in exposure (area under the plasma concentration–time curve [AUC] and maximum concentration of analyte in plasma [Cmax]) were approximately proportional with dose. Empagliflozin increased the rate and total amount of glucose excreted in urine compared to placebo. After administration of a single dose of empagliflozin, cumulative amounts of glucose excreted in urine over 24 h ranged from 46.3 to 89.8 g, compared with 5.84 g with placebo. Similar results were seen after multiple doses. Fasting plasma glucose levels decreased by 17.2–25.8% with empagliflozin and by 12.7% with placebo. The frequency of adverse events was 33.3–66.7% with empagliflozin and 41.7% with placebo. There were no changes in urine volume or micturition frequency under the controlled study conditions.
Overall, pharmacokinetic assessments demonstrated a dose-proportional increase in drug exposure and support once-daily dosing. Elevated urinary glucose excretion was observed with all doses. Multiple once-daily oral doses of empagliflozin (2.5–100 mg) reduced plasma glucose and were well tolerated in patients with T2DM. EudraCT (2007-000654-32).
PMCID: PMC3889329  PMID: 23838841
BI 10773; Diabetes; Empagliflozin; Pharmacodynamics; Pharmacokinetics; Safety; Tolerability
25.  Role of fesoterodine in the treatment of overactive bladder 
Muscarinic receptors have long been the target receptors for treatment of patients with overactive bladder (OAB). These patients experience symptoms of urgency, urinary frequency and nocturia, with or without urge incontinence (the involuntary leakage of urine associated with urge). Fesoterodine, a pro-drug, structurally and functionally related to tolterodine, is the newest agent developed for the treatment of OAB. Fesoterodine is broken down to the active metabolite, 5-hydroxy-methyl-tolterodine (5-HMT) by non-specific esterases. This metabolism results in the complete breakdown of the parent compound and is responsible for dose related improvements in clinical efficacy and health related quality of life. Like other antimuscarinic agents including tolterodine, fesoterodine is associated with improvements in clinical variables related both to bladder filling (decreasing micturition frequency and increasing mean voided volume) and urgency (urgency and urge incontinence episodes). Improvements in health related quality of life following treatment with fesoterodine is indicated by improvements in 7 of the 9 variables measured by the King’s Health Questionnaire. Also like other antimuscarinic agents, fesoterodine use is associated with adverse events including dry mouth. However the incidence of dry mouth is reduced with fesoterodine, compared to oxybutynin, due to the improved bladder selectivity of 5-HMT.
PMCID: PMC3818872  PMID: 24198608
fesoterodine; 5-hydroxymethy1-tolterodine; muscarinic; overactive bladder; urgency; incontinence

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