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At least 289 records · Page 16Linked to original sources
PubMed1999

Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal.

Drug resistance is a well recognized problem in cancer therapy. Despite the current dogma that drug resistance is always an obstacle for treatment, here I show that it provides opportunities for selective protection of non-resistant cells with killing of drug-resistant cancer cells. According to the proposed 'two-drug' strategy, the first drug should be ineffective against a target drug-resistant cell (ie the drug is a substrate of MRP or Pgp pumps). In addition, it must be cytostatic but not cytotoxic. The second drug, which is applied in sequence, must be a cycle-dependent apoptotic drug to which the target cell is not cross-resistant. Thus, low doses of adriamycin, etoposide and actinomycin D, used as the first drugs, were cytostatic to parental HL60 cells. Therefore, these drugs precluded Bcl-2/Raf-1 phosphorylation, PARP cleavage and cell death which are otherwise induced by paclitaxel, a mitosis-selective apoptotic drug for HL60 cells. In contrast, HL60/ADR cells which express MRP, a transporter which pumps out the first drugs from a cell, were insensitive to the first drugs and therefore readily underwent apoptosis following the second drug. This strategy also allowed a selective killing of HL60/TX cells which express MDR-1, with the only difference being that the second drug, paclitaxel, was substituted for epothilones, non-Pgp substrates. Lack of protection by the first drug, a Pgp substrate, resulted in HL60/TX killing by the second drug, whereas parental HL-60 cells were fully protected. Therefore, drug resistant cells can be selectively killed by a combination of drugs not killing sensitive cells. Lack of toxicity against normal cells will be clinically translated in reduction of adverse side-effects of chemotherapy against drug-resistant malignancies.

Apoptosis↗
PubMed1993

[Drug resistance of M. tuberculosis and comparison of drug sensitivity test in Nepal].

In Nepal, drug sensitivity test for M. tuberculosis has been carrying out at the clinic of German-Nepal Tuberculosis Project (GENETUP) since 1986 and at National Tuberculosis Centre (NTC) since 1991. The studies of primary drug resistance and acquired drug resistance were performed at NTC. On the other hand, results of drug sensitivity test at GENETUP and NTC were compared and analyzed. In total, 160 M. tuberculosis strains which were isolated from new smear positive patients were studied for the primary drug resistance. One of 160 strains, 21 (13.1%) strains were resistant to one or more drugs. Resistance rate to one drug, two drugs and three drugs were 9.4%, 3.1% and 0.6% respectively. Resistance to four drugs and five drugs were not found. Prevalence of resistance of each drug were INH 8.1%, SM 5.0%, RFP 2.5%, EB 0.6% and Tb1 1.3% respectively. In total, 125 strains which were isolated from previously treated patients were studied for the acquired drug resistance. Out of 125 strains, 103 (82.4%) strains had resistance to one or more drugs. Resistance rate to one drug, two drugs, three drugs, four drugs and five drugs were 13.6%, 28.0%, 31.2%, 4.0% and 5.6% respectively. Resistance rate of each drug were INH 56.8%, SM 38.4%, RFP 71.2%, EB 16.8% and Tb1 24.0% respectively. Since media, criteria of resistance and definition of resistance for drug sensitivity test are different between GENETUP and NTC, it is difficult to compare the results. However, it is necessary to understand the differences well and get good agreement with both sides.

Antitubercular Agents↗
PubMed2004

Drug driving among injecting drug users in Sydney, Australia: prevalence, risk factors and risk perceptions.

AIMS: To examine the prevalence of drug driving, the prevalence of drug-related motor vehicle accidents, risk perceptions of drug driving and factors associated with drug driving among injecting drug users (IDU). DESIGN: Cross-sectional survey. SETTING: Sydney, Australia. PARTICIPANTS: Three hundred current IDU. FINDINGS: Ninety-five per cent had driven a vehicle, 74% in the previous 12 months ('current drivers'). Eighty-seven per cent of life-time drivers reported having drug driven, and 88% of current drivers had drug driven in the previous 12 months. There were no significant sex differences in life-time or recent drug driving. The most common drugs used before driving in the preceding year were: cannabis, heroin, amphetamines and cocaine. A third of life-time drivers reported having had a drug driving accident, with males more likely to have done so, and 9% of current drivers reported a drug driving accident in the previous year. The most common drugs that had been used before the most recent drug driving accident were heroin, cannabis and alcohol. Alcohol was perceived to be the most dangerous substance for driving performance and cannabis the least dangerous. Recent drug drivers perceived drug driving to be less dangerous than non-drug drivers. Recent drug drivers had driven more frequently over the preceding 12 months, had significantly higher levels of dependence, higher frequency of drug use, more extensive polydrug use and were more likely to have used and/or injected a drug in a car in the previous 12 months. CONCLUSIONS: Drug driving and drug-related accidents are large-scale public health problems among IDU. These behaviours pose serious risks to IDU themselves and to the broader community.

Accidents, Traffic↗
PubMed2003

Determination of drug synergism between the tyrosine kinase inhibitors NSC 680410 (adaphostin) and/or STI571 (imatinib mesylate, Gleevec) with cytotoxic drugs against human leukemia cell lines.

The primary growth factor receptors involved in angiogenesis and lymphomagenesis can be grouped into the vascular endothelial growth factor (VEGF) receptors and related families. Inhibition of VEGF and other growth factors, including c-Abl, c-Kit, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factor (IGF), or their receptors containing tyrosine kinase domains by antiangiogenesis drugs disrupts cell survival signal transduction pathways and may contribute to the proapoptotic pathways in malignant cells. However, clinical trials suggest that signal transduction inhibitors have considerable antitumor activity when used as single agents only for a short time, most likely due to the development of drug resistance by the host or by the tumor cells. In order to prevent this problem and to augment their antitumor efficacy, these agents could be administered in combination with cytotoxic antineoplastic drugs. We hypothesized that the combination of the antiangiogenesis tyrosine kinase inhibitors with cytotoxic drugs would produce synergistic drug regimens. Two human T-lymphoblastic leukemia cell lines that express VEGF-R1, CEM/0 (wild-type, WT) and the drug-resistant clone CEM/ara-C/I/ASNase-0.5-2, were utilized in the drug combination studies. NSC 680410, a tyrosine kinase inhibitor given at 0.1 to 1 microM for 72 h, inhibited VEGF secretion and leukemic cell growth at 90% of vehicle-treated control cultures with an IC50 value of less than 1 microM. The cytotoxic drugs idarubicin (IDA), fludarabine (Fludara), and cytosine arabinoside (ara-C) were used for the various drug combinations. One-, two-, three-, and four-drug treatments were tested. Cell viability was documented by the MTT assay and photomicrographic estimation of apoptotic cells. Both the combination index (CI) and isobologram evaluations demonstrated strong synergism between these drugs and the tyrosine kinase inhibitor. NSC 680410 was highly synergistic with IDA, IDA + ara-C, and IDA + Fludara + ara-C, over the respective cytotoxic drug regimens at concentrations easily achieved in patient plasma. NSC 680410 potentiated the activity of IDA in both leukemia cell lines by 17.8- and 221.4-fold in the WT and drug-resistant line, respectively. The activity of NSC 680410 + IDA + ara-C was also potentiated by 58.8-fold in the WT line, and the activity of NSC 680410 + IDA + Fludara + ara-C by 2.4- and 6.47x10(6)-fold in the WT and drug-resistant lines, respectively. The results suggest that IDA was not needed for optimal synergistic activity in the CEM/0 cells, but IDA was a necessary component to obtain drug synergism in the drug-resistant clone. Similarly, STI571 (imatinib mesylate, Gleevec), the p210(bcr/abl) tyrosine kinase inhibitor, demonstrated synergism with Fludara + ara-C or IDA + ara-C. Most importantly STI571 showed synergism with NSC 680410, suggesting that these drugs inhibit different tyrosine kinase domains in human leukemia cells. Lastly, pretreatment of leukemic cells with NSC 680410 showed additivity with gamma radiation in comparison to either treatment modality alone. The data, taken together, suggest that by inhibiting the pro-survival signal transduction pathway (VEGF-R1) and DNA replication by cytotoxic drugs, leukemic cells undergo apoptosis in a synergistic manner. In conclusion, the combinations of antiangiogenesis and DNA-damaging cytotoxic drugs are highly synergistic regimens in both WT and drug-resistant leukemic cell lines and they should be examined further.

Adamantane↗
PubMed2002

Employer drug benefit plans and spending on prescription drugs.

CONTEXT: With drug spending rising rapidly for working-aged adults, many employers and health insurance providers have changed benefits packages to encourage use of fewer or less expensive drugs. It is unknown how these initiatives affect drug costs. OBJECTIVE: To examine how innovations in benefits packages, such as those that include multitier formularies and mandatory generic substitution, affect total cost to insurance providers for generic and brand drugs and out-of-pocket payments to beneficiaries. DESIGN AND PARTICIPANTS: Retrospective study from 1997 to 1999 linking claims data of 420,786 primary beneficiaries aged 18 through 64 years who worked at large firms (n = 25) with health insurance benefits that included outpatient drugs. MAIN OUTCOME MEASURES: Overall drug costs; generic, single-source brand, and multisource brand costs; and drug expenditures by health insurance providers and out-of-pocket costs for beneficiaries. RESULTS: For a 1-tier plan with a 5 US dollars co-payment for all drugs, the average annual spending was 725 US dollars per member. Doubling co-payments to 10 US dollars for all drugs reduced the annual average drug cost from 725 US dollars to 563 US dollars per member (22.3%, P<.001). Doubling co-payments in a 2-tier plan from 5 US dollars for generics and $10 for brand drugs to 10 US dollars for generics and 20 US dollars for brand drugs reduced costs from 678 US dollars to 455 US dollars (32.9%, P<.001). Adding an additional co-payment of 30 US dollars for nonpreferred brand drugs to a 2-tier plan (10 US dollars generics; 20 US dollars brand) lowered overall drug spending by 4% (P<.001). Requiring mandatory generic substitution in a 2-tier plan reduced drug spending by 8% (P<.001). Doubling co-payments in a 2-tier plan increased the fraction beneficiaries' paid out-of-pocket from 17.6% to 25.6%. CONCLUSIONS: Adding an additional level of co-payment, increasing existing co-payments or coinsurance rates, and requiring mandatory generic substitution all reduced plan payments and overall drug spending among working-age enrollees with employer-provided drug coverage. The reduction in drug spending largely benefited health insurance plans because the percentage of drug expenses beneficiaries paid out-of-pocket rose significantly.

Adult↗
PubMed2004

The impact of new drug introduction on drug expenditure in primary health care in Catalunya, Spain.

BACKGROUND: Introduction of new drugs is a dynamic process with a high impact on consumption and expenditure. OBJECTIVE: To analyze the prescription of new drugs and the associated costs in public health care in Catalunya, Spain, in 2002. The analysis also attempts a perspective of consumption in relation to the grade of therapeutic innovation of the new drugs. METHODS: Prescription data on all 86 new drugs licensed for use during 1998-2002 were analyzed, using the prescription item as unit and the cost. RESULTS: Prescription for new drugs in 2002 represented 4% of overall items prescribed and 13% of the cost. The mean new drug item cost was 39, while that of overall drugs was 13. New drug item increase over the previous year was 18.6% compared with 5.2% of the overall drugs, and the proportional cost increased by 25.7% and 9.9%, respectively. Ten new drugs represented 55.1% of the expenditure of this group. Antiasthmatic drugs represented 20.7% of the expenditure on new drugs, angiotensin-receptor blockers represented 18.6%, antiaggregants 9.7%, and nonsteroidal antiinflammatory drugs 6.9%. New drugs providing significant or modest therapeutic improvement represented 25.6% of overall new drug items and 32.3% of their cost. CONCLUSIONS: New drugs have a mean cost growth rate greater than that of existing drugs, with only a quarter of them offering advantages over existing drugs. More detailed evaluations of new medications are warranted before they can be recommended for general use so that a better distribution of the limited resources available may be made when prescribing drugs that are newly available through prescription.

Drug Approval↗
PubMed2000

Rheumatoid arthritis in Sweden. Drug prescriptions, costs, and adverse drug reactions.

OBJECTIVE: Many patients with rheumatoid arthritis (RA) need continuous medication, bringing considerable costs for drugs and a need for monitoring adverse drug reactions. We studied drug exposure, drug costs, and adverse drug reactions in patients with RA in Sweden from 1987 to 1997. METHODS: Prescription patterns, drug costs, and adverse drug reactions, and their distributions and trends were analyzed by cross sectional annual data. Drug exposures and costs were assessed from the National Diagnosis and Therapy Survey. All costs were recalculated to the 1997 level using the drug price index. Information on adverse drug reactions was obtained from the national pharmacovigilance system. RESULTS: The drug prescription level was, on average, 2 defined daily doses (DDD) throughout the study period. Nonsteroidal antiinflammatory drugs (NSAID) accounted for > 40% of the drugs prescribed, methotrexate (MTX) 10%, corticosteroids 10%, and sulfasalazine 5%. Analgesics and opioids made up 14% of prescriptions - a low estimate considering the availability of over-the-counter preparations. Disease modifying antirheumatic drugs (DMARD) increased their proportion from 28.5 to 39.3%. Total costs were stable at $16 million US annually. NSAID costs decreased, while those of sulfasalazine, MTX, and cyclosporine increased. On average, 91 adverse drug reactions were reported annually. Hematological reactions (agranulocytosis, thrombocytopenia, leukopenia, pancytopenia) predominated, constituting 21% of reported reactions. Skin and gastrointestinal reactions, mainly mild, accounted for 15 and 14%, respectively. Deaths from adverse drug reactions were uncommon, about 3 per year, and were mainly attributed to hematological reactions. CONCLUSION: The total volume as well as the total cost of drug consumption for RA in Sweden was relatively constant during our 11 year observation period, despite a notable increase in the use of DMARD. This was mainly due to a decrease in costs per DDD of NSAID, and an increased use of cyclosporine. Drug related adverse reactions were dominated by hematological reactions, and fatal events were few. This emphasizes the need for an extended evaluation of which safety procedures are most cost effective for monitoring the drugs used for RA.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Illicit drugs and driving: prevalence, beliefs and accident involvement among a cohort of current out-of-treatment drug users.

Drug-driving behaviour among out-of-treatment dependent drug users has not been investigated while a theoretical perspective on the propensity of certain drug users to drive while impaired has not been suggested. This paper examines illicit drugs and driving behaviour and accident involvement among out-of-treatment current drug users. Psychological evidence of belief-based mechanisms to account for the decision to drive while impaired by drugs are provided. A total of 210 out-of-treatment current drug users were interviewed in a non-clinical setting by privileged access interviewers. Questionnaire measures were: current illicit drug use, severity of dependence, illicit drugs and driving behaviour, impaired and unimpaired accident involvement and beliefs and perceptions about the impairing effects of a number of illicit drugs. Analyses are restricted to participants who reported driving during the previous 12 months (n = 71). Fifty-eight participants (81.7%) reported driving immediately after consuming illicit drugs, primarily heroin and cannabis. Of these 41.4% (n = 24) had at least one road accident as a driver, 15 of whom (62.4%) reported accident involvement following recent drug consumption. Belief-based results showed that participants who reported never driving after using illicit drugs perceived heroin, methadone and alcohol to be greater significance for accident risk and driving skills impairment than other drugs. Those drivers who reported drugs and driving behaviour believed only alcohol to be significantly more impairing than other drugs. Findings indicated that illicit drugs and driving behaviour is common among out-of-treatment drug users. Accident involvement among this cohort is characterised by the previous consumption of illicit substances. Differential beliefs about the effects of drugs on driving performance and accident risk were shown to be dependent upon frequency of drugs and driving behaviour. Results are discussed in terms of experiential factors and consistency theories of attitude formation and change.

Accidents, Traffic↗
PubMed2000

Frequency of daily over-the-counter drug use and potential clinically significant over-the-counter-prescription drug interactions in the Finnish adult population.

OBJECTIVE: To explore the frequency of continuous use of over-the-counter (OTC) drugs among the Finnish adult population and the potential for harmful interactions between OTC drugs and prescribed (Rx) drugs. METHODS: Data were extracted from a 1995-1996 population-based interview survey on health care (n = 10,477, response rate 86%). The drug interaction classification system from the Swedish Drug Compendium FASS 1997 was used to identify OTC drugs likely to have clinically significant interactions with prescription drugs. Logistic regression was used to study factors related to continuous use and risks for interactions. RESULTS: Seventeen percent of the population had used OTC drugs and 15% had used OTC vitamins during the 2 days prior to the interview. Daily use of OTC drugs and of vitamins was reported by 7% and 9%, respectively. Continuous use of OTC drugs was related to older age, female gender, higher education, poor health status, long-term morbidity, psychosomatic symptoms (fatigue) and use of prescription drugs, but not to poor lifestyle. Four percent of the OTC drug users had taken drug combinations with potential for clinically significant interactions. Interactions were most common for ketoprofen (15% of ketoprofen users), ibuprofen (10%), and acetylsalicylic acid (ASA) (6%). The number of prescription drugs, long-term illness and lower education best explained the risk for interactions. CONCLUSION: Continuous use and potentially harmful Rx/ OTC drug interactions occur among OTC drug users. Further studies should be done to investigate whether potential combinations will actually lead to clinical problems. The possible interactions of non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with prescription drugs should especially be taken into account in drug information.

Adolescent↗
PubMedDate not supplied

[Drug costs in reformed primary care: effect of training activities on drug savings].

OBJECTIVE: To determine the influence on drug expenditures by reformed primary care services of factors relative to the personal characteristics of prescribers, their training and training activities, their professional practice, organizational factors, and characteristics of the patient population attended. MATERIAL AND METHODS: This cross-sectional, observational study was carried out in the Sabadell Primary Care Directorate, Vallés Occidental region (Barcelona, Spain). This primary care directorate is responsible for the health-care needs of 9 municipalities (with a total population of 254,971 inhabitants). It has 12 Basic Health Areas, 8 of which have Primary Care Teams. The area of study included these 8 primary care teams and the unit of analysis contained 68 of 80 staff physicians. The quantitative prescription indicators (dependent variables) were: total annual drug expenditure, drug expenditure per user and year (users being understood as patients with an open medical record), drug expenditure per visit and year, mean cost per prescription, prescription/user ratio, and prescription/visit ratio. Descriptive, bivariate, and multiple linear regression analyses were made. RESULTS: The variables predictive of greater drug expenditures were: patient age, visits, frequentation, referrals to primary-care specialists, urban municipality, physicians with primary care and hospital practice, time on staff, and physician age. Participation in training activities was predictive of drug savings, with each primary-care training session attended producing a mean annual savings in drug expenditures of 50 ptas and 15 ptas per user and visit, respectively. Every hour dedicated to training in the community produced a savings of almost 60,000 ptas in annual drug expenditures. For each rational-drug-use session, the mean price of prescriptions decreased by 52 ptas. In the multiple linear regression models obtained, the variables that most frequently helped to explain variations between prescribers in relation to drug expenditures were: patient age, urban municipality, and primary-care-team training activities (as factors in drug savings). CONCLUSIONS: This study confirmed that patient age, frequentation, and type of municipality increased drug expenditures. Urban municipalities, as opposed to rural or semirural municipalities, were associated with a significantly greater expense, in contrast with prevailing opinion. Our results suggested that drug expenditures increase with referrals to specialists. An interesting new finding is that physicians with simultaneous primary care and hospital practice generated more drug expenditures. Finally, we emphasize the importance of training the primary-care team in promoting drug savings (four models: drug expenditures by users, drug expenditures per visit, prescriptions per user, and prescriptions per visit), rational-drug-use activities, which tended to reduce the mean cost of prescriptions, and community training activities, which clearly reduced annual total drug expenditures.

Aged↗
PubMedDate not supplied

Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds.

Prediction of the degree of drug-like character in small molecules is of great industrial interest. The major barrier, however, is the lack of a definition for drug-like character. We used the concept of the multilevel chemical compatibility (MLCC) between a compound and a drug library as a measure of the drug-like character of a compound. The rationale is that the local chemical environment of each atom or group of atoms in a compound largely contributes to the stability, toxicity, and metabolism in vivo. A systematic comparison of the local environments within a compound and those within the existing drugs provides a basis for determining whether and how much a compound is drug-like. We applied the MLCC calculations to four test sets: top selling drugs, compounds under biological testing prior to the preclinical test, anticancer drugs, and compounds known to have poor drug-like character. The following conclusions were obtained: (1) A convergent number of unique local structure types were found in the analysis of the library of the existing drugs. It suggests that the current drug library contains about 80% of all the viable types; therefore, discovery of a drug with new local structures is only an event of relatively small probability. (2) The method is highly selective in discerning drug-like compounds: most of the top drugs are predicted to be drug-like, about one-quarter of the biological testing compounds are drug-like, and about one-fifth of the anticancer drugs are drug-like. (3) The method also correctly predicted that none of the known problematic compounds are drug-like. (4) The method is fast enough for computational screening of virtual combinatorial chemistry libraries and databases of available compounds.

Combinatorial Chemistry Techniques↗
PubMed2005

Are incorrectly used drugs more frequently involved in adverse drug reactions? A prospective study.

OBJECTIVES: The aims of this study were to identify and evaluate the frequency of drugs involved in adverse drug reactions (ADRs) for which recommendations of the Summary of Product Characteristics (SPC) had not been respected and to compare the percentages of drugs suspected of being the cause of ADRs when correctly and incorrectly used. METHODS: All ADRs reported to the Regional Pharmacovigilance Centre of Tours (RPC) over a period of 5 months were analysed to identify drugs used "incorrectly" defined by drug use beyond the recommendations of the SPC, i.e. drugs used when contra-indicated and/or drugs used for an off-label indication, and/or drugs used at an inappropriate dose, and/or inappropriate duration of treatment, and/or drugs used in the presence of a potentially or definitely interacting drug. RESULTS: Included in the study were 182 ADRs involving 182 patients. Of 642 drugs, 169 (26%) were incorrectly used and for 81 patients (44.5%) ADRs involved at least one "incorrectly" used drug. These included 10% (64 of 642) drug interactions, 7.3% (47 of 642) off-licence indications, 5% (32 of 642) inadequate dosage, 3% (20 of 642) incorrect duration of treatment and 1% (6 of 642) contraindications. "Correctly" used drugs appeared to be less often the cause of the ADRs than "incorrectly" used drugs (59.4% versus 75%, P=0.0001). CONCLUSION: "Incorrectly" used drugs were more often causally linked to ADR than correctly used drugs. A meaningful number of ADRs could probably be avoided if SPC guidelines for a safe and effective drug use are carefully adhered to.

Adverse Drug Reaction Reporting Systems↗
PubMed1995

From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat.

The development of drug taking from controlled intake to drug addiction was studied by means of an animal model. Outbred rats had continuous free access to water and drinking fluids containing different concentrations of a drug for 7-9 months. After an abstinence period of 4-9 months, the drug was offered again (retest). Previous ethological classification of each rat and changes of housing conditions were used to study the modifiability of drug taking. With ethanol and the mu-agonistic opiate etonitazene, two stages followed each other. Controlled drug intake was adjusted to situational and individual variables. Social isolation of the rats raised the intake of ethanol and opiate. Dominant rats took less drugs than subordinate ones, but, in contrast to the latter, increased drug consumption after social disturbances. The adjustment of drug taking to social variables, was accompanied by changes in the dopaminergic and GABAA-ergic neurotransmission and by altered responses to acute drug administrations. Further, place preference, associated with reinforcing stimuli was modulated by subchronic sensitization/desensitization of dopaminergic transmission. Controlled drug intake lasted for 6-8 months, after which a spontaneous increase of drug consumption was found which latently continued during abstinence periods of 1 month. In the retest after abstinence, drug intake of these rats was strongly increased compared with both their previous consumption and that of drug-naive controls. Since drug taking could no longer be modulated by gustatory, environmental or individual factors (loss of control), it was considered as addictive. Addiction appeared to be specific to the kind of the drug. It persisted for the rest of the rat's life. After long periods of abstinence, ethanol-addicted rats revealed a completely altered pattern of response to self-administered alcohol compared with controlled drinkers. Their dopaminergic D1-transmission was irreversibly altered. Drug addiction only developed when the rat had free choice between water and drug-containing solutions. Long-term forced administration of ethanol or opiate, only led to physical dependence bot not to addiction. Some applications of the animal model are discussed, concerning the assessment of risk factors, the intake of drug combinations, residual neurochemical changes and concepts of treatment.

Animals↗